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Measurements aimed at investigating the quenching of sensitivity of Gafchromic EBT3 films irradiated with charged particles at radiotherapy energy levels have been carried out. Films have been irradiated with beams of protons and carbon ions of interest for Hadron Therapy. The broadening of pencil beams in water phantom as a function of initial energy has been studied and the quenching of EBT3 film sensitivity has been quantified. A procedure for correcting the dose images obtained by means of EBT3 films has been improved and its application to an irradiation test has show the validity of the proposed methodology.

International audience; The IRIS group at IFIC-Valencia has developed a second version of a Compton camera prototype for hadron therapy treatment monitoring, with the aim of improving the performance with respect to its predecessor. The system is composed of three Lanthanum (III) bromide (LaBr 3) crystals coupled to silicon photomultipliers (SiPMs). The detector energy resolution has been improved to 5.6 % FWHM at 511 keV and an angular resolution of 8.0 • has been obtained. Images of a 22 Na point-like source have been reconstructed selecting two and three interaction events. Moreover, the experimental data have been reproduced with Monte Carlo simulations using a Compton camera module (CCMod) in GATE v8.2 obtaining a good correlation.

In recent years the use of hadrons for cancer radiation treatment has grown in importance, and many facilities are currently operational or under construction worldwide. To fully exploit the therapeutic advantages offered by hadron therapy, precise body imaging for accurate beam delivery is decisive. While traditional X-ray Computed Tomography (xCT) fails in providing 3D images with the precision required for hadrons treatment guidance, Proton Computer Tomography (pCT) scanners, currently in their R&D phase, can. A pCT scanner consists of a tracker system, to track protons, and of a calorimeter, to measure their residual energy. In this paper we will present the iMPACT project, which foresees a novel proton tracking detector with higher scanning speed, better spatial resolution and lower material budget with respect to present state-of-the-art detectors, leading to enhanced performances. The tracker will be matched to a fast, highly segmented proton range calorimeter.

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.

Hadron therapy was first proposed in 1946 and is by now widespread throughout the world, as witnessed with the design and construction of the CNAO, HIT, PROSCAN and MedAustron treatment centres, among others. The clinical interest in hadron therapy lies in the fact that it delivers precision treatment of tumours, exploiting the characteristic shape (the Bragg peak) of the energy deposition in the tissues for charged hadrons. In particular, carbon ion therapy is found to be biologically more effective, with respect to protons, on certain types of tumours. Following an approach tested at NIRS in Japan [1], carbon ion therapy treatments based on C-12 could be combined or fully replaced with C-11 PET radioactive ions post-accelerated to the same energy. This approach allows providing a beam for treatment and, at the same time, to collect information on the 3D distributions of the implanted ions by PET imaging. The production of C-11 ion beams can be performed using two methods. A first one is based on the production using compact PET cyclotrons with 10-20 MeV protons via N-14(p,alpha)C-11 reactions following an approach developed at the Lawrence Berkeley National Laboratory [2]. A second route exploits spallation reactions F-19(p,X)C-11 and Na-23(p,X)C-11 on a molten fluoride salt target using the ISOL (isotope separation on-line) technique [3]. This approach can be seriously envisaged at CERN-ISOLDE following recent progresses made on C-11(+) production [4] and proven post-acceleration of pure C-10(3/6+) beams in the REX-ISOLDE linac [5]. Part of the required components is operational in radioactive ion beam facilities or commercial medical PET cyclotrons. The driver could be a 70 MeV, 1.2 mA proton commercial cyclotron, which would lead to 8.1 x 10(7) C-11(6+) per spill. This intensity is appropriate using C-11 ions alone for both imaging and treatment. Here we report on the ongoing feasibility studies of such approach, using the Monte Carlo particle transport code FLUKA [6,7] to simulate pristine Bragg Peaks of C-11, in order to compare its performance with C-12, in the context of hadron therapy. (C) 2016 The Authors. Published by Elsevier B.V.

A nano-microdosimetric tissue-equivalent proportional counter (TEPC) capable of measuring microdosimetric spectra of ionizing radiation in the range 500–25 nm was designed, constructed and deeply characterized in order to fill the gap between nanodosimetry and experimental microdosimetry. This work describes the first microdosimetric characterization at nanometric level of a 195.2 MeV/u carbon ion beam available at CNAO (National Centre for Oncological Hadron Therapy). The detector was properly placed at different depths in PMMA phantom across the depth-dose profile of the primary beam for measuring microdosimetric distributions for different simulated site sizes down to 25 nm at different depths. The acquired spectra show that this TEPC is capable of reproducing the beam slowing down, showing a shift towards higher lineal energies as the primary particles slow-down. Moreover, the distributions at different simulated site sizes for the same depth are influenced by secondary electrons: smaller site size spectra exhibit a shift towards higher lineal energies as the site decreases, while this is not the case for more distal positions, where the edge of the spectra is almost independent of the simulated site size. Monte Carlo simulations performed with the FLUKA code show a good agreement with the experimental results obtained in the present paper.

Hadron therapy (including protons and ions) is still expanding worldwide, although still limited by the cost and thus the number of available facilities. If the historical indications remain eye melanomas, skull base tumours and paediatric tumours for protontherapy; and salivary glands, paranasal sinus and nasal cavity tumours, and soft tissue sarcomas for carbon ions, no conclusion can be drawn about the role of these modalities for other tumours, such as prostate, lung cancers. Since 2013, more than 100 clinical trials are on-going, including comparisons between advanced photons modalities, protontherapy and carbon ions therapy. An important technological and scientific (physics, radiobiology) effort has been made in parallel in order to reduce the cost of the facilities and to fully take advantages of the beam properties: standardization of beam scanning, image guided treatment, robust and 4D planning. Furthermore, the increasing number of facilities, the development of hypofractionation and the selection of indications will contribute to find the true place of particle therapy, despite the "screening effect" of the cost. The long term effects assessment on large patient cohorts will allow or not to correlate adverse effects and dosimetric data, always evoked.

A proton-therapy hospital installation, based on multiple beam extraction systems from a fixed-field synchrotron, is presented and commented. Potential interest as hospital operation efficiency, as well as estimates of the impact of continuous, multiple-port extraction, on the cost of a session, are discussed.

Particle therapy (including protons and carbon ions) allows a highly conformal treatment of deep-seated tumours with good accuracy and minimal dose to surrounding tissues, compared to conventional radiotherapy using X-rays. Following impressive results from early phase trials, over the last decades particle therapy in Europe has made considerable progress in terms of new institutes dedicated to charged particle therapy in several countries. Particle therapy is a multidisciplinary subject that involves physicists, biologists, radio-oncologists, engineers and computer scientists. The European Network for Light Ion Hadron Therapy (ENLIGHT) was created in response to the growing needs of the European community to coordinate such efforts. A number of treatment centres are already operational and treating patients across Europe, including two dual ion (protons and carbon ions) centres in Heidelberg (the pioneer in Europe) and Pavia. However, much more research needs to be carried out and beamtime is limited. Hence there is a strong interest from the biomedical research community to have a facility with greater access to relevant beamtime. Such a facility would facilitate research in radiobiology and the development of more accurate techniques of dosimetry and imaging. The Low Energy Ion Ring (LEIR) accelerator at CERN presents such an opportunity, and relies partly on CERN's existing infrastructure. The ENLIGHT network, European Commission projects under the ENLIGHT umbrella and the future biomedical facility are discussed.

Aim Investigation of the bystander effect in Chinese Hamster Ovary cells (CHO-K1) co-cultured with cells irradiated in the dose range of 0.1–4 Gy of high LET 12C ions and X-rays. Background The radiobiological effects of charged heavy particles on a cellular or molecular level are of fundamental importance in the field of biomedical applications, especially in hadron therapy and space radiation biology. Materials and methods A heavy ion 12C beam from the Heavy Ion Laboratory of the University of Warsaw (HIL) was used to irradiate CHO-K1 cells. Cells were seeded in Petri dishes specially designed for irradiation purposes. Immediately after irradiation, cells were transferred into transwell culture insert dishes to enable co-culture of irradiated and non-irradiated cells. Cells from the membrane and well shared the medium but could not touch each other. To study bystander effects, a clonogenic survival assay was performed. Results The survival fraction of cells co-cultured with cells irradiated with 12C ions and X-rays was not reduced. Conclusions The bystander effect was not observed in these studies.

The energy delivered by a swift proton beam in materials of interest to hadron therapy (liquid water, polymethylmethacrylate or polystyrene) is investigated. An explicit condensed-state description of the target excitation spectrum based on the dielectric formalism is used to calculate the energy-loss rate of the beam in the irradiated materials. This magnitude is the main input in the simulation code SEICS (Simulation of Energetic Ions and Clusters through Solids) used to evaluate the dose as a function of the penetration depth and radial distance from the beam axis. This work has been financially supported by the Spanish Ministerio de Economía y Competitividad and the European Regional Development Fund (Project FIS2010-17225). PdV thanks the Conselleria d’Educació, Formació i Ocupació de la Generalitat Valenciana for its support under the VALi+d program. This paper is part of the COST Action MP 1002, Nanoscale Insights in to Ion Beam Cancer Therapy.

Purpose Glioblastoma multiforme (GBM) is the most aggressive types of central nervous system tumors. The aim of the project is to validate an innovative molecule developed by Lead Discovery Siena [LDS] showing inhibitory activity against Src kinases to be associated with proton therapy treatments. Materials Human glioblastoma cells (U87) were treated at INFN-LNS in Catania with 2 and 10 Gy of proton beams at dose rate of 10 Gy/min in the middle of the extended modulated Bragg peak and in combination with different concentrations of the LDS molecule (10 and 20 μM). The fraction of surviving cells (SF) was evaluated with the clonogenicity test 15 days after irradiation. Results The data in the figure show the synergistic effect of the combined treatment with LDS. Conclusions In vitro studies confirmed the efficacy of the hadron therapy treatment in combination with the molecule. The next step is to translate these studies on the mouse model thanks to the existence of an Animal Facility created by the synergy between the following institution: the LNS-INFN, the University of Catania – Capir Center, IBFM-CNR and H. Cannizzaro, with the departments of Nuclear Medicine and Medical Physics. The facility will be able to provide unique research activities in the European panorama: hadron therapy treatments, dose distribution studies using the Monte Carlo GEANT4 method, molecular imaging using microPET/ CT tomography with different radiotracers and image processing implementation for therapy response quantification.

Radiotherapy is a key cancer treatment, which greatly modified its practice in recent years thanks to medical imaging and technical improvements. The systematic use of computed tomography (CT) for treatment planning, the imaging fusion/co-registration between CT/magnetic resonance imaging (MRI) or CT/positron emission tomography (PET) improve target identification/selection and delineation. New irradiation techniques such as image-guided radiotherapy (IGRT), stereotactic radiotherapy or hadron therapy offer a more diverse therapeutic armamentarium to patients together with lower toxicity. Radiotherapy, as well as medical oncology, tends to offer a personalized treatment to patients thanks to the IGRT, which takes into account the inter- or intra-fraction anatomic variations. IGRT leads to adaptive radiotherapy (ART) with a new planification in the treatment course in order to decrease toxicity and improve tumor control. The use of systemic therapies with radiations needs to be studied in order to improve efficiency without increasing toxicities from these multimodal approaches. Finally, radiotherapy advances were impacted by radiotherapy accidents like Epinal. They led to an increased quality control with the intensification of identity control, the emergence of in vivo dosimetry or the experience feedback committee in radiotherapy. We will illustrate through the example of lung cancer.

Proton irradiation has been developed to achieve the clinical benefit of improved 3D-dose distribution, with biological properties similar to X-rays. Neutron irradiation, though much less 3D-conformal than proton treatment, has been developed to take advantage of increased relative biologic effectiveness (RBE). Irradiation with hadrons heavier than protons (e.g. carbon and neon ions) exhibits the unique combination of improved 3D-dose distribution and increased RBE. The synchrotron technology is rapidly developing to improve the efficiency of delivering these heavier hadrons clinically, but important issues remain regarding optimization of dose and fractionation parameters in the treatment of various histopathologies located in different portions of the anatomy. Many laboratory animal and in vitro cellular studies, and some clinical studies, have been performed to enable better understanding of how to adjust dose-fractionation selection to improve the therapeutic ratio of tumor-cell kill to normal-tissue injury. This paper highlights the enhanced therapeutic potential and associated risks of treatment with these heavier hadrons.

Cancer is a major social problem, and it is the main cause of death between the ages 45–65 years. In the treatment of cancer, radio therapy (RT) plays an essential role. RT with hadrons (protons and light ions), due to their unique physical and radiobiological properties, offers several advantages over photons. In particular, they penetrate the patient with minimal diffusion, they deposit maximum energy at the end of their range, and they can be shaped as narrow focused and scanned pencil beams of variable penetration depth. Hadron beams allow highly conformal treatment (where the beam conforms to the shape of the tumour) of deep-seated tumours with great accuracy, while delivering minimal doses to surrounding tissues. Hadron therapy, thus, has great prospects for being used in early stages of tumour disease not amenable to surgery. It is likely that, besides its more impressive effect on radio-resistant tumours, post-treatment morbidity will be lower in patients treated with hadrons due to the lower dose and toxicity to normal tissues. Visionary physicist and founder of Fermilab, Robert Wilson first proposed the use of hadrons for cancer treatment in 1946. This idea was first put into practise at the Lawrence Berkeley Laboratory (LBL) where 30 patients were treated with protons between 1954 and 1957. Since then the total number of patients treated with hadrons in the world now exceeds 50,000, of which 5000 new patients were treated last year. Several dedicated hospital-based centres with significant capacity for treating patients are now taking the place of the first R&D facilities hosted by the Physics Research Laboratories (e.g. LBL, GSI). Europe is playing a key role in the advancement of light ion therapy facilities with five financed centres using actively scanned carbon ions (of which two are already under construction in Heidelberg and Pavia) and several proton therapy centres which will become operational soon. In the US, three proton therapy centres are running and four more are under construction. In Japan two carbon ion and four proton centres are running and, in the Far East, also Korea and China are investing in hospital-based hadron therapy centres. The European Network for Research in Light-ion Hadron Therapy (ENLIGHT) was established in 2002 to co-ordinate European efforts in radiation therapy using light-ion beams. ENLIGHT has been instrumental in bringing together different European centres to promote hadron therapy, in particular with carbon ions. ENLIGHT created a multidisciplinary platform, uniting traditionally separate communities so that clinicians, physicists, biologists and engineers with experience in ions work together. The success of the network has encouraged the scientific community to promote more inclusive collaboration between the researchers and regional activities and to enlarge the collaboration to include the proton community. Hence, ENLIGHT++ continues the vision started by ENLIGHT.

At Laboratori Nazionali del Sud of the Instituto Nazionale di Fisica Nucleare of Catania (Sicily, Italy), the first Italian hadron therapy facility named CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) has been realized. Inside CATANA 62 MeV proton beams, accelerated by a superconducting cyclotron, are used for the radiotherapeutic treatments of some types of ocular tumours. Therapy with hadron beams still represents a pioneer technique, and only a few centers worldwide can provide this advanced specialized cancer treatment. On the basis of the experience so far gained, and considering the future hadron-therapy facilities to be developed (Rinecker, Munich Germany, Heidelberg/GSI, Darmstadt, Germany, PSI Villigen, Switzerland, CNAO, Pavia, Italy, Centro di Adroterapia, Catania, Italy) we decided to develop a Monte Carlo application based on the GEANT4 toolkit, for the design, the realization and the optimization of a proton-therapy beam line. Another feature of our project is to provide a general tool able to study the interactions of hadrons with the human tissue and to test the analytical-based treatment planning systems actually used in the routine practice. All the typical elements of a hadron-therapy line, such as diffusers, range shifters, collimators and detectors were modelled. In particular, we simulated the Markus type ionization chamber and a Gaf Chromic film as dosimeters to reconstruct the depth (Bragg peak and Spread Out Bragg Peak) and lateral dose distributions, respectively. We validated our simulated detectors comparing the results with the experimental data available in our facility.

The MedAustron hadron therapy centre will provide proton and carbon ion beams for tumour treatment. The accelerator complex is based on a synchrotron that will employ slow resonant extraction to provide beams with the time structure required for active scanning. Four medical treatment rooms and two research rooms are foreseen for the centre. The present paper describes the optics design of the extraction lines that link the synchrotron to the different beam application rooms. A modular approach has been adopted to facilitate running-in and operation and to minimise the number of different magnets and power converters to reduce the overall cost. Specific attention was given to the rather special transverse properties of the slow-extracted beam and to the correct matching of the strongly asymmetric beam to the rotational optics of the gantries. Another important aspect for the design was the overall compactness of the centre.

Summary In 1991 the author involved the Italian institute of nuclear physics (INFN) in R&D work in the field of hadrontherapy. In 1992 the TERA Foundation was created with the purpose of forming and employing people fully devoted to the design, promotion and construction of hadrontherapy centres in Italy and in Europe. The present contribution describes the main project of TERA, the CNAO (Centro Nazionale di Adroterapia Oncologica), and the status of its construction in Pavia. The Italian Centre is based on the optimised medical synchrotron designed in the framework of the "Proton Ion Medical Machine Study" (PIMMS) carried out at CERN from 1996 to 2000 with CERN, the Med-AUSTRO project, Oncology 2000 (Prague) and TERA as partners. In the following years TERA introduced modifications and improvements in the original PIMMS design producing what is now dubbed the PIMMS/TERA design. Since 2001 the construction of CNAO has been endorsed by the Italian government to the CNAO Foundation formed by five major hospitals, seated in Milan and Pave, and by TERA. Since 2003 INFN is an Institutional Participant. The site chosen at the beginning of 2003 (37000 m 2 ) is in the close vicinities of one of the five hospitals, the San Matteo University Hospital of Pave. The construction plan foresees the treatment of the first patient at the end of 2007.

Summary Background: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy Materials and Methods: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. Results: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. Conclusion: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

Cyclotrons are versatile ion-accelerating machines which find many applications in medicine. In this short review their use in hadron therapy is briefly discussed. Proton therapy is gaining significance because of its capability to treat deep-lying tumours. A strong area of application of cyclotrons involves the production of short-lived neutron deficient radiotracers for use in emission tomography, especially positron emission tomography. This fast and quantitative in vivo diagnostic technique is being increasingly used in neurology, cardiology and oncology. Besides routine patient care, considerable interdisciplinary work on development of new positron emitters is under way. A short account of those efforts is given. The use of cyclotrons in the production of radionuclides for internal radiotherapy is also briefly described.

The vast majority of radiation treatments for cancerous tumors are given using electron linacs that provide both electrons and photons at several energies. Design and construction of these linacs are based on mature technology that is rapidly becoming more and more standardized and sophisticated. The use of hadrons such as neutrons, protons, alphas, or carbon, oxygen and neon ions is relatively new. Accelerators for hadron therapy are far from standardized, but the use of hadron therapy as an alternative to conventional radiation has led to significant improvements and refinements in conventional treatment techniques. This paper presents the rationale for radiation therapy, describes the accelerators used in conventional and hadron therapy, and outlines the issues that must still be resolved in the emerging field of hadron therapy.

We report on the test results obtained with a prototype beam profiler based on a thin slit and a CsI scintillator, read out by means of a compact photomultiplier. Such a device has proven to be suitable to perform ion beam diagnostics at low and very low intensities. In particular, our device is suitable for being used in the energy and intensity ranges expected at the EXCYT radioactive ion beam facility, that is currently under development at LNS Catania.

The treatment of cancer with accelerator beams has a long history with betatrons, linacs, cyclotrons and now synchrotrons being exploited for this purpose. Treatment techniques can be broadly divided into the use of spread-out beams and scanned `pencil’ beams. The Bragg-peak behaviour of hadrons makes them ideal candidates for the latter. The combination of precisely focused `pencil’ beams with controllable penetration (Bragg peak) and high, radio-biological efficiency (light ions) opens the way to treating the more awkward tumours that are radio-resistant, complex in shape and lodged against critical organs. To accelerate light ions (probably carbon) with pulse-to-pulse energy variation, a synchrotron is the natural choice. The beam scanning system is controlled via an on-line measurement of the particle flux entering the patient and, for this reason, the beam spill must be extended in time (seconds) by a slow-extraction scheme. The quality of the dose intensity profile ultimately depends on the uniformity of the beam spill. This is the greatest challenge for the synchrotron, since slow-extraction schemes are notoriously sensitive. This paper reviews the extraction techniques, describes methods for smoothing the beam spill and outlines the implications for the extraction line and beam delivery system

We proposed to apply the MLE method for determining the range of heavy ions and demonstrated the effectiveness of this method by experiments with 12 C beams. We performed irradiation experiments with stable 12 C ions of mono-energetic 290 MeV/u to a water, a polyethylene and a PMMA target. The theoretical ranges for 12 C ions of 290 MeV/u in these targets are 160.5, 157.9 and 139.8 mm, respectively. The annihilation events from positron emitters generated by 12 C ions were detected with a positron camera for 500 s just after the irradiation. To evaluate the range of 12 C ions, the MLE method was applied to the annihilation gamma ray distribution. The derived ranges for the three targets were 160.6, 158.9 and 140.4 mm, respectively. Therefore, we can conclude that the range of 12 C ions was determined within an accuracy of 1.0 mm for all targets.