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In this paper, we investigate the use of a positron emission tomography (PET) system to monitor the proton therapy. The monitoring procedure is based on the comparison between the ${ \beta }+$ activity generated in the irradiated volume during the treatment, with the ${ \beta }+$ activity distribution obtained with Monte Carlo (MC) simulation. The dedicated PET system is a dual head detection system; each head is composed of nine scintillating LYSO crystal matrices read out independently with a custom modularized acquisition system. Our experimental data were acquired at the Cyclotron Centre Bronowice, Institute Nuclear Physics in Krakow, Poland, and were simulated with the FLUKA MC code. Homogeneous and heterogeneous plastic phantoms were irradiated with monoenergetic 130 MeV protons. The capabilities of our PET system to distinguish different irradiated materials were investigated, and the proton pencil-beams were used as probes. Our focus was to analyze the activity width and the total activity event number in several cases. Irradiations were performed using either single pencil-beams one at a time, or two pencil-beams during the same data taking. The comparison of 1-D activity profile for experimental data and MC simulation were always in good agreement showing that, the treatment quality assessment in proton therapy can be based on ${ \beta }+$ activity measurements.

(1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams, however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom, the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.

The study that we present is part of the preparation work for the setup of the FOOT (FragmentatiOn Of Target) experiment whose main goal is the measurement of the double differential cross sections of fragments produced in nuclear interactions of particles with energies relevant for particle therapy. The present work is focused on the characterization of the gas-filled drift chamber detector composed of 36 sensitive cells, distributed over two perpendicular views. Each view consists of six consecutive and staggered layers with three cells per layer. We investigated the detector efficiency and we performed an external calibration of the space–time relations at the level of single cells. This information was then used to evaluate the drift chamber resolution. An external tracking system realized with microstrip silicon detectors was adopted to have a track measurement independent on the drift chamber. The characterization was performed with a proton beam at the energies of 228 and 80 MeV. The overall hit detection efficiency of the drift chamber has been found to be 0 . 929 ± 0 . 008 , independent on the proton beam energy. The spatial resolution in the central part of the cell is about 150 ± 10 μ m and 300 ± 10 μ m and the corresponding detector angular resolution has been measured to be 1 . 62 ± 0 . 16 mrad and 2 . 1 ± 0 . 4 mrad for the higher and lower beam energies, respectively. In addition, the best value on the intrinsic drift chamber resolution has been evaluated to be in the range 60 − 100 μ m. In the framework of the FOOT experiment, the drift chamber will be adopted in the pre-target region, and will be exploited to measure the projectile direction and position, as well as for the identification of pre-target fragmentation events.

PURPOSE In-beam Positron Emission Tomography (PET) is one of the modalities that can be used for in-vivo non-invasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy to interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify and visualize regions with possible morphological changes occurring over the course of treatment. MATERIALS AND METHODS We selected a patient treated for Squamous Cell Carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the Voxel-Based Morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify inter-fractional morphological changes and to visualize them superimposed on the Computed Tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal inter-fractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments. This article is protected by copyright. All rights reserved.

Open physics 19(1), 383 - 394 (2021). doi:10.1515/phys-2021-0032, Published by de Gruyter, Berlin

The use and interest in Monte Carlo (MC) techniques in the field of medical physics have been rapidly increasing in the past years. This is the case especially in particle therapy, where accurate simulations of different physics processes in complex patient geometries are crucial for a successful patient treatment and for many related research and development activities. Thanks to the detailed implementation of physics processes in any type of material, to the capability of tracking particles in 3D, and to the possibility of including the most important radiobiological effects, MC simulations have become an essential calculation tool not only for dose calculations but also for many other purposes, like the design and commissioning of novel clinical facilities, shielding and radiation protection, the commissioning of treatment planning systems, and prediction and interpretation of data for range monitoring strategies. MC simulations are starting to be more frequently used in clinical practice, especially in the form of specialized codes oriented to dose calculations that can be performed in short time. The use of general purpose MC codes is instead more devoted to research. Despite the increased use of MC simulations for patient treatments, the existing literature suggests that there are still a number of challenges to be faced in order to increase the accuracy of MC calculations for patient treatments. The goal of this review is to discuss some of these remaining challenges. Undoubtedly, it is a work for which a multidisciplinary approach is required. Here, we try to identify some of the aspects where the community involved in applied nuclear physics, radiation biophysics, and computing development can contribute to find solutions. We have selected four specific challenges: i) the development of models in MC to describe nuclear physics interactions, ii) modeling of radiobiological processes in MC simulations, iii) developments of MC-based treatment planning tools, and iv) developments of fast MC codes. For each of them, we describe the underlying problems, present selected examples of proposed solutions, and try to give recommendations for future research.

The standard of neutron beam quality for Boron Neutron Capture Therapy (BNCT) of deep-seated tumours is currently defined by its physical characteristics in air: the epithermal neutron flux, the ratio of thermal and epithermal neutron flux, the fast neutron and photon dose contamination, and the beam collimation. Traditionally, the beam design consists in tailoring a Beam Shaping Assembly (BSA) able to deliver a neutron beam with the recommended values of these figures of merit (FOMs). This work investigated the possibility to produce an epithermal neutron beam able to guarantee the best clinical performance for deep-seated tumours, starting from a 5 MeV, 30 mA proton beam coupled to a beryllium target. Different Beam Shaping Assemblies were designed using those physical FOMs which, however, were not enough to establish a clear ranking of the different beams, nor to describe their clinical relevance. To go beyond this traditional approach, beams were then evaluated employing new criteria based on the dose distributions obtained in-phantom and on the calculation of the Uncomplicated Tumour Control Probability (UTCP). Such radiobiological FOM allows establishing the therapeutic potential of the beams. Moreover, we included the concept of suitability as a criterion to select the safest BSA design, calculating the in-patient out-of-beam dosimetry. The clinical relevance of the selected beam was finally tested in the treatment planning of a clinical case treated at the FiR 1 beam in Finland, where several patients have safely and successfully received BNCT in the last years. Despite the selected beam does not comply with all the standard physical recommendations, it shows a therapeutic potential comparable and even better than that of FiR 1. This confirms that establishing the performance of a beam cannot rely only on its physical characteristics, but requires additional criteria able to predict the clinical outcome of a BNCT treatment.

In a carbon ion treatment the nuclear fragmentationof both target and beam projectiles impacts on the dose releasedon the tumor and on the surrounding healthy tissues. Carbon ionfragmentation occurring inside the patient body has to be stud-ied in order to take into account this contribution. These dataare also important for the development of the range monitoringtechniques with charged particles. The production of chargedfragments generated by carbon ion beams of 115-353 MeV/ukinetic energy impinging on carbon, oxygen, and hydrogen tar-gets has been measured at the CNAO particle therapy center(Pavia, Italy). The use of thin targets of graphite (C), PMMA(C2O5H8) and polyvinyl-toluene [plastic scintillator (PS), CbHa]allowed to measure fragments production cross sections, exploit-ing a time-of-flight (ToF) technique. PS detectors have been usedto perform the ToF measurements, while LYSO crystals havebeen used for the deposited energy measurement and to performparticle identification. Cross sections have been measured at 90◦and 60◦with respect to the beam direction. The measured pro-ton, deuteron, and triton differential production cross sectionson C, O, and H, obtained exploiting the target subtraction strat-egy, are presented here as a function of the fragment kineticenergy.

Simple Summary Proton therapy is now an established external radiotherapy modality for cancer treatment. Clinical routine currently neglects the radiobiological impact of nuclear target fragments even if experimental evidences show a significant enhancement in cell-killing effect due to secondary particles. This paper quantifies the contribution of proton target fragments of different charge in different irradiation scenarios and compares the computationally predicted corrections to the overall biological dose with experimental data. Abstract Clinical routine in proton therapy currently neglects the radiobiological impact of nuclear target fragments generated by proton beams. This is partially due to the difficult characterization of the irradiation field. The detection of low energetic fragments, secondary protons and fragments, is in fact challenging due to their very short range. However, considering their low residual energy and therefore high LET, the possible contribution of such heavy particles to the overall biological effect could be not negligible. In this context, we performed a systematic analysis aimed at an explicit assessment of the RBE (relative biological effectiveness, i.e., the ratio of photon to proton physical dose needed to achieve the same biological effect) contribution of target fragments in the biological dose calculations of proton fields. The TOPAS Monte Carlo code has been used to characterize the radiation field, i.e., for the scoring of primary protons and fragments in an exemplary water target. TRiP98, in combination with LEM IV RBE tables, was then employed to evaluate the RBE with a mixed field approach accounting for fragments’ contributions. The results were compared with that obtained by considering only primary protons for the pristine beam and spread out Bragg peak (SOBP) irradiations, in order to estimate the relative weight of target fragments to the overall RBE. A sensitivity analysis of the secondary particles production cross-sections to the biological dose has been also carried out in this study. Finally, our modeling approach was applied to the analysis of a selection of cell survival and RBE data extracted from published in vitro studies. Our results indicate that, for high energy proton beams, the main contribution to the biological effect due to the secondary particles can be attributed to secondary protons, while the contribution of heavier fragments is mainly due to helium. The impact of target fragments on the biological dose is maximized in the entrance channels and for small α/β values. When applied to the description of survival data, model predictions including all fragments allowed better agreement to experimental data at high energies, while a minor effect was observed in the peak region. An improved description was also obtained when including the fragments’ contribution to describe RBE data. Overall, this analysis indicates that a minor contribution can be expected to the overall RBE resulting from target fragments. However, considering the fragmentation effects can improve the agreement with experimental data for high energy proton beams.

Charged particle therapy is a technique for cancer treatment that exploits hadron beams, mostly protons and carbon ions. A critical issue is the monitoring of the beam range so to check the correct dose deposition to the tumor and surrounding tissues. The design of a new tracking device for beam range real-time monitoring in pencil beam carbon ion therapy is presented. The proposed device tracks secondary charged particles produced by beam interactions in the patient tissue and exploits the correlation of the charged particle emission profile with the spatial dose deposition and the Bragg peak position. The detector, currently under construction, uses the information provided by 12 layers of scintillating fibers followed by a plastic scintillator and a pixelated Lutetium Fine Silicate (LFS) crystal calorimeter. An algorithm to account and correct for emission profile distortion due to charged secondaries absorption inside the patient tissue is also proposed. Finally detector reconstruction efficiency for charged particle emission profile is evaluated using a Monte Carlo simulation considering a quasi-realistic case of a non-homogenous phantom.

In proton therapy, secondary fragments are created in nuclear interactions of the beam with the target nuclei. The secondary fragments have low kinetic energies and high atomic numbers as compared to primary protons. Fragments have a high LET and deposit all their energy close to the generation point. For their characteristics, secondary fragments can alter the dose distribution and lead to an increase of RBE for the same delivered physical dose. Moreover, the radiobiological impact of target fragmentation is significant mostly in the region before the Bragg peak, where generally healthy tissues are present, and immediately after Bragg peak. Considering the high biological impact of those particles, especially in the case of healthy tissues or organs at risk, the inclusion of target fragmentation processes in the dose calculation of a treatment planning system can be relevant to improve the treatment accuracy and for this reason it is one of the major tasks of the MoVe IT project. In this study, Monte Carlo simulations were employed to fully characterize the mixed radiation field generated by target fragmentation in proton therapy. The dose averaged LET has been evaluated in case of a Spread Out Bragg Peak (SOBP). Starting from LET distribution, RBE has been evaluated with two different phenomenological models. In order to characterize the mixed radiation field, the production cross section has been evaluated by means of the FLUKA code. The future development of present work is to generate a MC database of fragments fluence to be included in TPS.

Summary: Charged particle therapy exploits proton or 12C beams to treat deep-seated solid tumors. Due to the advantageous characteristics of charged particles energy deposition in matter, the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However, the beam nuclear interactions with the patient tissues induces fragmentation both of projectile and target nuclei and needs to be carefully taken into account. In proton treatments, target fragmentation produces low energy, short range fragments along all the beam range, which deposit a non negligible dose in the entry channel. In 12C treatments the main concern is represented by long range fragments due to beam fragmentation that release their dose in the healthy tissues beyond the tumor. The FOOT experiment (FragmentatiOn Of Target) of INFN is designed to study these processes, in order to improve the nuclear fragmentation description in next generation Treatment Planning Systems and the treatment plans quality. Target (16O and 12C nuclei) fragmentation induced by –proton beams at therapeutic energies will be studied via an inverse kinematic approach, where 16O and 12C therapeutic beams impinge on graphite and hydrocarbon targets to provide the nuclear fragmentation cross section on hydrogen. Projectile fragmentation of 16O and 12C beams will be explored as well. The FOOT detector includes a magnetic spectrometer for the fragments momentum measurement, a plastic scintillator for ΔE and time of flight measurements and a crystal calorimeter to measure the fragments kinetic energy. These measurements will be combined in order to make an accurate fragment charge and isotopic identification. Keywords: Hadrontherapy, Nuclear fragmentation cross sections, Tracking detectors, Scintillating detectors

Preliminary studies for the design of an accelerator-based BNCT clinical facility are presented. The Beam Shaping Assembly neutron activation was evaluated experimentally and with Monte Carlo simulations. The activations of patient, air and walls in the room, the absorbed doses by the patient and the in-air dose distributions were evaluated. Based on these calculations, different walls compositions were tested to optimize the environmental conditions. Borated concrete, advantageously reducing the thermal flux in the room, was proven the best choice.

Charged Particle Therapy (CPT) is a powerful radiotherapy technique for the treatment of deep-seated tumours characterized by a large dose released in the Bragg peak area (corresponding to the tumour region) and a small dose delivered to the surrounding healthy tissues. The precise measurement of the fragments produced in the nuclear interactions of charged particle beams with patient tissues is a crucial task to improve the clinical treatment plans. The FOOT (FragmentatiOn Of Target) experiment is an international project, funded by the Istituto Nazionale di Fisica Nucleare (INFN), aimed to study the dose released by the tissues and particle beams fragmentation. The target (16O, 12C) fragmentation induced by 150-400 MeV/n proton beams will be studied via the inverse kinematic approach, where 16O and 12C therapeutic beams collide on graphite and hydrocarbon target to provide the cross section on Hydrogen. A table-top detector is being developed and it includes a drift chamber as a beam monitor upstream of the target to measure the beam direction, a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a ΔE detector, with TOF capability, for the particle identification. A setup based on the concept of the “Emulsion Cloud Chamber”, coupled with the interaction region of the electronic FOOT setup, will complement the physics program by measuring lighter charged fragments to extend the angular acceptance up to about 70 degrees. In this work, the experimental design and the requirements of the FOOT experiment will be discussed and preliminary results on the emulsion spectrometer tests will be presented.

FOOT (FragmentatiOn On Target) is an applied nuclear physics experiment aimed at measuring the production cross sections of fragments for energies, beams and targets relevant in particle therapy and radioprotection in space. The Δ E-TOF detector will measure the energy deposited by the fragments in a wall of plastic scintillators and the time of flight with respect to a start detector. These two quantities allow to determine the charge Z of the fragment. In this work, we summarize the charge identification procedure of a detector prototype with two scintillator modules.

In hadron therapy, the accelerated ions, interacting with the body of the patient, cause the fragmentation of both projectile and target nuclei. The fragments interact with the human tissues depositing energy both in the entrance channel and in the volume surrounding the tumor. The knowledge of the fragments features is crucial to determine the energy amount deposited in the human body, and - hence - the damage to the organs and to the tissues around the tumor target. The FOOT (FragmentatiOn Of Target) experiment aims at studying the fragmentation induced by the interaction of a proton beam (150-250 MeV/n) inside the human body. The FOOT detector includes an electronic setup for the identification of Z ≥ 3 fragments integrated with an emulsion spectrometer to measure Z ≤ 3 fragments. Charge identification by nuclear emulsions is based on the development of techniques of controlled fading of the particle tracks inside the nuclear emulsion, that extend the dynamical range of the films developed for the tracking of minimum ionising particles. The controlled fading strongly depends on temperature, relative humidity and treatment duration. In this study the performances in terms of charge separation of proton, helium and carbon particles, obtained on a batch of new emulsion films produced in Japan are reported.

Nuclear physics processes are an important source of uncertainty in dose calculations in particle therapy and radioprotection in space. Accurate cross section measurements are a crucial ingredient in improving the understanding of these processes. The FOOT (FragmentatiOn Of Target) experiment aims at measuring the production cross sections of fragments for energies, beams and targets that are relevant in particle therapy and radioprotection in space. An experimental apparatus composed of several sub-detectors will provide the mass, charge, velocity and energy of fragments produced in nuclear interactions in a thin target. A crucial component of the FOOT apparatus will be the Δ E-TOF detector, designed to identify the charge of the fragments using plastic scintillators to measure the energy deposited and the time of flight with respect to a start counter. In this work, we present a charge reconstruction procedure of produced fragments at particle therapy energies. We validate it by measuring the charges of various fragments at an angle of 3.2°and 8.3°with respect the beam-axis, using a small-scale detector and clinical beams of carbon ions at the CNAO oncology center. Experimental results agree well with FLUKA Monte Carlo simulations.

This paper describes the development and characterization of a Δ E-TOF detector composed of a plastic scintillator bar coupled at both ends to silicon photomultipliers. This detector is a prototype of a larger version which will be used in the FOOT (FragmentatiOn Of Target) experiment to identify the fragments produced by ion beams accelerated onto a hydrogen-enriched target. The final Δ E-TOF detector will be composed of two layers of plastic scintillator bars with orthogonal orientation and will measure, for each crossing fragment, the energy deposited in the plastic scintillator ( Δ E), the time of flight (TOF), and the coordinates of the interaction position in the scintillator. To meet the FOOT experimental requirements, the detector should have energy resolution of a few percents and time resolution of 70 ps, and it should allow to discriminate multiple fragments belonging to the same event. To evaluate the achievable performances, the detector prototype was irradiated with protons of kinetic energy in the 70–230 MeV range and interacting at several positions along the bar. The measured energy resolution σ Δ E ∕ Δ E was 6–14%, after subtracting the fluctuations of the deposited energy. A time resolution σ between 120 and 180 ps was obtained with respect to a trigger detector. A spatial resolution σ of 1.9 cm was obtained for protons interacting at the center of the bar.

The present study aims at offering empirical evidence to improve existing knowledge and theory building on research infrastructure evaluation. Through an inductive case study research strategy, an innovative cost–benefit analysis framework has been used to assess the impact of an applied research infrastructure. The case study is the National Hadrontherapy Centre for Cancer Treatment (CNAO) located in Pavia (Italy). CNAO is an applied research facility specialised in hadrontherapy, an advanced oncological treatment showing clinical advantages as compared to traditional radiotherapy, at the same time being more expensive as it exploits non-commercial accelerators technology and sophisticated control and dose delivery systems. The analysis shows that with a fairly high probability the Centre provides a positive net contribution to society's welfare. Source of benefits are mainly health treatments to patients, for whom gains in terms of longer or better lives are guaranteed as compared to a counterfactual situation where they are treated with conventional therapies or they have no alternatives. Such benefits are the direct consequences of the application to end users of the knowledge developed in the Centre with research activities and are quantified and assessed on the basis of conventional cost–benefit analysis (CBA) approaches for health benefits. Additional benefits generated by the Centre are typical of research infrastructures in different scientific domains and refer to technological spillovers (namely creation of spin-offs, technological transfer to companies in the supply chain and to other similar facilities), knowledge creation (production of scientific outputs), human capital formation (training of doctoral students, technicians and professionals in the field of hadrontherapy) and cultural outreach (students, researchers and wider public visiting the facilities). Evidences show that the adopted CBA framework is a promising avenue as compared to existing alternative methodologies informing decision-making. Further research is however needed to fine tune the methodology, in particular for what concerns technological spillovers and knowledge creation benefits.

Protons and carbon ions have been extensively used for radiotherapy treatments, and in comparison to conventional radiotherapy, they allow a more conformal dose to the target tumor, especially in case of deep-seated tumors. However, the accuracy of hadron therapy treatments is affected by uncertainties in the particle range calculations. Several techniques are under development for in-vivo range verification, one of which consists on measuring the activity distributions of positron emitters, such as 10C, 11C and 15O, which are produced in the patient body during proton and carbon ion treatments. A comparison between measured and expected positron emitter activity distributions can provide information on the quality of the delivered treatment and accuracy of the particle range calculations. In this work the FLUKA production cross sections for 10C, 11C and 15O originated from proton and carbon ion beams in carbon and oxygen targets were compared with experimental data, at low and therapeutic energies.

The advantages of using C, He and O ions as therapeutical beam particles in Particle Therapy is related to their enhanced Relative Biological Effectiveness and Oxygen Enhancement Ratio, resulting in an improved efficacy in damaging the cancerous cells. However, an accurate on-line control of the dose release spatial distribution is required to spare the healthy tissues surrounding the tumor area, preventing undesired damages caused by, for example, morphological changes occurred in the patient during the treatment with respect to the initial CT scan. This monitor technology is currently missing in clinical practice, and several studies are being performed to develop beam range verification systems exploiting the detection of the emitted secondary radiation. Charged secondary particles, produced by the projectile fragmentation in the collisions with the patient tissues, represent an interesting chance for C, He and O treatments since they are also emitted at large angles with respect to the beam direction and can be detected with high efficiency in a nearly background free environment. The Dose Profiler detector is a scintillating fibre tracker that allows an online charged fragments reconstruction and backtracking. The construction and preliminary tests performed on the DP, carried out using the Carbon ions beam of the CNAO treatment centre using an anthropomorphic phantom as a target, will be reviewed in this contribution.

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment. The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model. The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found. In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images.

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the β+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

In vivo range monitoring techniques are necessary in order to fully take advantage of the high dose gradients deliverable in hadrontherapy treatments. Positron emission tomography (PET) scanners can be used to monitor beam-induced activation in tissues and hence measure the range. The INSIDE (Innovative Solutions for In-beam DosimEtry in Hadrontherapy) in-beam PET scanner, installed at the Italian National Center of Oncological Hadrontherapy (CNAO, Pavia, Italy) synchrotron facility, has already been successfully tested in vivo during a proton therapy treatment. We discuss here the system performance evaluation with carbon ion beams, in view of future in vivo tests. The work is focused on the analysis of activity images obtained with therapeutic treatments delivered to polymethyl methacrylate (PMMA) phantoms, as well as on the test of an innovative and robust Monte Carlo simulation technique for the production of reliable prior activity maps. Images are reconstructed using different integration intervals, so as to monitor the activity evolution during and after the treatment. Three procedures to compare activity images are presented, namely Pearson correlation coefficient, Beam's eye view and overall view. Images of repeated irradiations of the same treatments are compared to assess the integration time necessary to provide reproducible images. The range agreement between simulated and experimental images is also evaluated, so as to validate the simulation capability to provide sound prior information. The results indicate that at treatment end, or at most 20 s afterwards, the range measurement is reliable within 1-2 mm, when comparing both different experimental sessions and data with simulations. In conclusion, this work shows that the INSIDE in-beam PET scanner performance is promising towards its in vivo test with carbon ions.

The capabilities and physics models implemented inside the FLUKA code are briefly described, with emphasis on hadronic interaction. Examples of the performances of the code are presented including basic (thin target) and complex benchmarks, and radiation detector specific applications. In particular the ability of FLUKA in describing existing calorimeter performances and in predicting those of future ones, as well as the use of the code for neutron and mixed field radiation detectors will be demonstrated with several examples.

Particle therapy uses protons or $^{12}$C beams for the treatment of deep-seated solid tumors. Due to the features of the energy deposition of charged particles in matter, a limited amount of dose is released to the healthy tissue in the beam entrance region, while the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However nuclear interactions between beam and patient tissues induce fragmentation both of projectile and target. This has to be carefully taken into account since different ions have different effectiveness in producing a biological damage. par In $^{12}$C treatments the main concern are long range forward emitted secondary ions produced in projectile fragmentation that release dose in the healthy tissue after the tumor. Instead, in a proton treatment, the target fragmentation produces low energy, short range fragments along all the beam range. The FOOT experiment (FragmentatiOn Of Target) is designed to study these processes. Target nuclei ($^{16}$O, $^{12}$C) fragmentation induced by 150-250 MeV proton beam will be studied by means of the inverse kinematic approach: $^{16}$O,$^{12}$C therapeutic beams, at the quoted kinetic energy per nucleon, collide on graphite and hydrocarbons target. The cross section on Hydrogen can be then extracted by subtraction. This configuration explores also the projectile fragmentation of these O and C beams, or other ions of therapeutic interest, such as $^4$He for instance. The detector includes a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a $\Delta E$ detector, with TOF capability, to achieve the needed energy resolution and particle identification. In addition to the electronic apparatus, an alternative setup based on the concept of the "Emulsion Cloud Chamber", coupled with the interaction region of the electronic FOOT setup, will provide the measurement of lighter charged fragments: protons, deuterons, tritons and Helium nuclei. The FOOT data taking is foreseen in the available experimental rooms existing in the presently operational charged particle therapy facilities in Europe, and possibly at GSI. An initial phase with the emulsion setup will start in early 2018, while the complete electronic detector will take data starting in 2019. In this work a general description of the FOOT experiment and of its expected performances is presented.

The quality assurance of particle therapy treatment is a fundamental issue that can be addressed by developing reliable monitoring techniques and indicators of the treatment plan correctness. Among the available imaging techniques, positron emission tomography (PET) has long been investigated and then clinically applied to proton and carbon beams. In 2013, the Innovative Solutions for Dosimetry in Hadrontherapy (INSIDE) collaboration proposed an innovative bimodal imaging concept that combines an in-beam PET scanner with a tracking system for charged particle imaging. This paper presents the general architecture of the INSIDE project but focuses on the in-beam PET scanner that has been designed to reconstruct the particles range with millimetric resolution within a fraction of the dose delivered in a treatment of head and neck tumors. The in-beam PET scanner has been recently installed at the Italian National Center of Oncologic Hadrontherapy (CNAO) in Pavia, Italy, and the commissioning phase has just started. The results of the first beam test with clinical proton beams on phantoms clearly show the capability of the in-beam PET to operate during the irradiation delivery and to reconstruct on-line the beam-induced activity map. The accuracy in the activity distal fall-off determination is millimetric for therapeutic doses.

The RDH project is presently coordinating a number of activities for the development of innovative solution for charged particle therapy, on the basis of the scientific and technological know-how in nuclear and particle physics existing within the INFN institute. The status of the project is presented, summarizing the main activities with particular attention to those connected with detector development.

The purpose of this work is to investigate the capability of the FLUKA Monte Carlo (MC) code to simulate the Elekta Leksell Gamma Knife Perfexion (LGK-PFX) and reproduce the Treatment Planning System (TPS) Leksell GammaPlan version 8.2 (LGP) dose calculations for the case of a water equivalent phantom target. Thanks to the collaboration with Elekta Instruments AB, the collimation system geometry, the source positions and all the involved material have been simulated in detail. The relative linear dose distribution along the three coordinate axes, for each collimator size, and the Relative Output Factors (ROF) have been investigated. The simulation has been validated comparing simulated linear dose profiles with measurements performed with EBT radiochromic films. The acceptance criterion between experimental data and FLUKA results is based on the gamma index (GI) method. The FLUKA MC calculation for the ROF provided the values of 0.920 for the 8 mm collimators and 0.800 for the 4 mm collimators. These values are in good agreement with the Elekta reference data of 0.924 and 0.805 respectively. The percentage difference between calculated and reference values for the ROF is under 1% and within the FLUKA uncertainty. Also the simulated relative dose profiles show a good agreement with the LGP calculation expressed by means of the gamma index method. This established accuracy proves that FLUKA is a suitable and powerful tool in order to reproduce successfully the LGP calculations for the homogeneous media.

In the field of radiotherapy, Monte Carlo (MC) particle transport calculations are recognized for their superior accuracy in predicting dose and fluence distributions in patient geometries compared to analytical algorithms which are generally used for treatment planning due to their shorter execution times. In this work, a newly developed MC-based treatment planning (MCTP) tool for proton therapy is proposed to support treatment planning studies and research applications. It allows for single-field and simultaneous multiple-field optimization in realistic treatment scenarios and is based on the MC code FLUKA. Relative biological effectiveness (RBE)-weighted dose is optimized either with the common approach using a constant RBE of 1.1 or using a variable RBE according to radiobiological input tables. A validated reimplementation of the local effect model was used in this work to generate radiobiological input tables. Examples of treatment plans in water phantoms and in patient-CT geometries together with an experimental dosimetric validation of the plans are presented for clinical treatment parameters as used at the Italian National Center for Oncological Hadron Therapy. To conclude, a versatile MCTP tool for proton therapy was developed and validated for realistic patient treatment scenarios against dosimetric measurements and commercial analytical TP calculations. It is aimed to be used in future for research and to support treatment planning at state-of-the-art ion beam therapy facilities.

The calculation algorithm of a modern treatment planning system for ion-beam radiotherapy should ideally be able to deal with different ion species (e.g. protons and carbon ions), to provide relative biological effectiveness (RBE) evaluations and to describe different beam lines. In this work we propose a new approach for ion irradiation outcomes computations, the beamlet superposition (BS) model, which satisfies these requirements. This model applies and extends the concepts of previous fluence-weighted pencil-beam algorithms to quantities of radiobiological interest other than dose, i.e. RBE- and LET-related quantities. It describes an ion beam through a beam-line specific, weighted superposition of universal beamlets. The universal physical and radiobiological irradiation effect of the beamlets on a representative set of water-like tissues is evaluated once, coupling the per-track information derived from FLUKA Monte Carlo simulations with the radiobiological effectiveness provided by the microdosimetric kinetic model and the local effect model. Thanks to an extension of the superposition concept, the beamlet irradiation action superposition is applicable for the evaluation of dose, RBE and LET distributions. The weight function for the beamlets superposition is derived from the beam phase space density at the patient entrance. A general beam model commissioning procedure is proposed, which has successfully been tested on the CNAO beam line. The BS model provides the evaluation of different irradiation quantities for different ions, the adaptability permitted by weight functions and the evaluation speed of analitical approaches. Benchmarking plans in simple geometries and clinical plans are shown to demonstrate the model capabilities.

Hadrontherapy permits treating cancer with very conformable dose distributions and increased radiobiological effects. Monitoring systems to verify particle range while treating are needed to fully exploit these advantages. The INSIDE project aims at building a bimodal system to acquire photons, coming from positron annihilations, and prompt charge particles related to the beam position inside patients [1] . In January 2016, the in-beam PET detector was installed at the Italian Center of Oncological Hadrontherapy (CNAO) and characterized with phantoms [2] , [3] . In December 2016, the INSIDE in-beam PET monitored two consecutive treatment sessions with protons on its first patient. In-beam PET images must be compared with an expected prior image, therefore a FLUKA-based [4] , [5] simulation tool has been developed. The framework includes the simulations of the patient/phantom, the detector, the beam line and temporal structure. The beam delivery follows either the treatment plan or the measurements from the Dose Delivery System and the detector geometry and resolution are taken into account. During the characterization phase, a good agreement between measurements and simulations was found [2] , [3] . Preliminary results on the first patient treatments indicate that after about two minutes of a four-minutes long irradiation the PET image has significant statistics to be compared with the prior image. During the 2017, the INSIDE in-beam PET system and simulation tool will be further tested in-vivo and optimized for clinical routine.

Boron Neutron Capture Therapy (BNCT) is an experimental radiotherapy that uses the combination of neutron irradiation and 10B to treat neoplasms. By means of this technique, many clinical trials were performed worldwide with promising results [1] using research nuclear reactors as neutron sources. Anyhow, these machines have several problems that hinder the development of dedicated BNCT hospitals. This issue can now be overcome by using intense-current proton accelerators, which coupled with beryllium or lithium targets yield more than 1014 neutron per second. This can be a boost to BNCT because accelerators are more compact and can be installed within hospitals.The Italian National Institute of Nuclear Physics (INFN) designed and manufactured a Radiofrequency Quadrupole proton accelerator (RFQ) [2], which delivers 5 MeV protons with 30 mA current in a Continuous Wave (CW) mode and it is coupled to a beryllium target. This accelerator could be installed at Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia.In this work we present the MC calculations for the tailoring of a BNCT neutron beam obtained by the described RFQ. Firstly, we show that MC transport codes such as MCNP and PHITS are not able to simulate the correct neutron spectra from 5 MeV protons interacting on beryllium. Therefore, the neutron double differential source implemented in MCNP was extracted from the measurements performed by Agosteo et al. [3]. As the energy range goes up to 3.5 MeV, neutrons need to be moderated and collimated by a Beam Shaping Assembly (BSA), because BNCT requires a spectrum peaked between 1 and 10 keV. Differently from the past, where the optimal configuration was chosen according to physical characteristics of the beam, in this case the results were evaluated on the basis of the dosimetry obtained in a real clinical case by treatment planning simulation. What emerges, is that the classical figures of merit employed for the tailoring of a clinical BNCT [4] should be taken as a first guideline, while the dosimetric assessment on realistic clinical scenarios is the most appropriate criterion for beam evaluations. Fil: Postuma, I.. Unit of Pavia; Italia Fil: Bortolussi, S.. University of Pavia; Italia Fil: Protti, N.. Unit of Pavia; Italia Fil: Fatemi, S.. Unit of Pavia; Italia. University of Pavia; Italia Fil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina Fil: Battistoni, G.. Unit of Milan; Italia Fil: Altieri, S.. Unit of Pavia; Italia. University of Pavia; Italia

Purpose: The calculation of patient-specific dose distribution can be achieved by Monte Carlo simulations or by analytical methods. In this study, fluka Monte Carlo code has been considered for use in nuclear medicine dosimetry. Up to now, fluka has mainly been dedicated to other fields, namely high energy physics, radiation protection, and hadrontherapy. When first employing a Monte Carlo code for nuclear medicine dosimetry, its results concerning electron transport at energies typical of nuclear medicine applications need to be verified. This is commonly achieved by means of calculation of a representative parameter and comparison with reference data. Dose point kernel (DPK), quantifying the energy deposition all around a point isotropic source, is often the one. Methods: fluka DPKs have been calculated in both water and compact bone for monoenergetic electrons (10{sup -3} MeV) and for beta emitting isotopes commonly used for therapy ({sup 89}Sr, {sup 90}Y, {sup 131}I, {sup 153}Sm, {sup 177}Lu, {sup 186}Re, and {sup 188}Re). Point isotropic sources have been simulated at the center of a water (bone) sphere, and deposed energy has been tallied in concentric shells. fluka outcomes have been compared to penelope v.2008 results, calculated in this study as well. Moreover, in case of monoenergeticmore » electrons in water, comparison with the data from the literature (etran, geant4, mcnpx) has been done. Maximum percentage differences within 0.8{center_dot}R{sub CSDA} and 0.9{center_dot}R{sub CSDA} for monoenergetic electrons (R{sub CSDA} being the continuous slowing down approximation range) and within 0.8{center_dot}X{sub 90} and 0.9{center_dot}X{sub 90} for isotopes (X{sub 90} being the radius of the sphere in which 90% of the emitted energy is absorbed) have been computed, together with the average percentage difference within 0.9{center_dot}R{sub CSDA} and 0.9{center_dot}X{sub 90} for electrons and isotopes, respectively. Results: Concerning monoenergetic electrons, within 0.8{center_dot}R{sub CSDA} (where 90%-97% of the particle energy is deposed), fluka and penelope agree mostly within 7%, except for 10 and 20 keV electrons (12% in water, 8.3% in bone). The discrepancies between fluka and the other codes are of the same order of magnitude than those observed when comparing the other codes among them, which can be referred to the different simulation algorithms. When considering the beta spectra, discrepancies notably reduce: within 0.9{center_dot}X{sub 90}, fluka and penelope differ for less than 1% in water and less than 2% in bone with any of the isotopes here considered. Complete data of fluka DPKs are given as Supplementary Material as a tool to perform dosimetry by analytical point kernel convolution. Conclusions: fluka provides reliable results when transporting electrons in the low energy range, proving to be an adequate tool for nuclear medicine dosimetry.« less

Purpose: In Charged Particle Therapy (CPT), besides protons, there has been recently a growing interest in 4He, 12C and 16O beams. The secondary radiation produced in the interaction of those beams with a patient could be potentially used for on-line monitoring of range uncertainties in order to fully exploit the advantages of those light ions resulting from increased Radio Biological Effectiveness, reduced multiple scattering and Oxygen Enhancement Ratio. The study and precise characterization of secondary radiation (beta+, prompt gamma, charged fragments) is the cornerstone of any R&D activity aiming for online monitoring development and purpose of the analysis presented here. Methods: We present the measurements of the secondary radiation generated by He, C and O beams impinging on a beam stopping PMMA target. The data has been collected at the Heidelberg Ionbeam Therapy center (HIT), where several millions of collisions were recorded at different energies, relevant for therapeutical applications. Results: The experimental setup, as well as the analysis strategies will be reviewed. The detected particle fluxes as a function of the primary beam energy and the emission angle with respect to the beam direction will be presented and compared to the results of other available measurements. In addition, the energy spectra and emission shapes of charged secondary particles will be shown and discussed in the context of the primary beam range monitoring technique that is being developed by the ARPG collaboration, within the INSIDE project funded by the Italian research ministry. The implications for dose monitoring applications will be discussed, in the context of the current (or planned) state-of- the-art detector solutions. Conclusion: The characterization of the radiation produced by 12C, 4He and 16O beams fully supports the feasibility of on-line range monitoring in the clinical practice of CPT by means of secondary particles detection.

Monte Carlo codes are increasingly spreading in medical physics community due to their capability of performing a detailed description of radiation transport and interaction with matter. This contribution will address the recent developments of the FLUKA code and its practical application in medical physics. FLUKA is being used in radiation therapy and nuclear medicine. At present, it is of particular interest in the context of particle therapy, thanks to the development of accurate and reliable physical models capable of handling all components of the expected radiation field. At the same time, the code can be interfaced to different radiobiological models. These features become extremely important for correctly performing not only physical but also biologically based dose calculations, especially in cases where ions heavier than protons are involved. At the same time, in order to support the application of FLUKA in hospital-based environments, the FLUKA graphical interface has been enhanced with the capability of translating CT DICOM images into voxel-based computational phantoms in a fast and well-structured way. The interface is capable of importing also radiotherapy treatment data described in DICOM RT standard. Therefore, the FLUKA code not only is a reliable instrument for the simulation of therapeutic beams, but it is also used in some of the leading European hadron therapy centers as an accurate tool for Treatment Planning verification and correction. In addition, it allows an accurate prediction of emerging secondary radiation and this is of the utmost importance in innovative areas of research aiming at in vivo treatment verification. Here we shall review the features of the FLUKA code, pointing out the recent refinements of the nuclear models, relevant for the therapeutic energy interval, which lead to an improved description of the mixed radiation field. Benchmarks against experimental data with both proton and ion beams will be shown. Examples of clinical application will be presented, together with a review of some results in medical physics research.