Your co-operation partner for research. EUROPEAN UNION European Regional Development Fund

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1 Med Austron Research Your co-operation partner for research EUROPEAN UNION European Regional Development Fund

2 MedAustron MedAustron offers protons and carbon ions for therapy and research. With MedAustron, one of the most up-to-date therapy and research centres of this country will be built in Wiener Neustadt. It will concentrate on cancer treatment with the application of ion irradiation. Start: 2014 Capacity: 1200 patients per year Through the highly accurate regulation down to the millimeter range of the beam and through direct energy deposition within the tumour, ion therapy shows in comparison to photons a higher potential for local tumour control as well as for considerably fewer side effects in the surrounding healthy tissue. Ion therapy is therefore the optimal treatment of certain types of cancer, such as eye cancer, brain and base of skull tumours or tumours near the spinal cord. Especially children with cancer can benefit from the treatment with ions, as their tissue is still growing and therefore particularly sensitive to side effects of radiation. Proton therapy is already an established irradiation treatment; therapy with carbon ions however is still in development. Proton therapy: Carbon ion therapy: > treated patients worldwide, in 27 centres > treated patients worldwide, in 3 centres

3 MedAustron-Research MedAustron-Research s vision is to become a national and international centre for research with ion beams. It provides state-of-the-art infrastructure and equipment. National and international researchers from universities, institutes and the industry The centre will enable research in the fields of: Medical Radiation Physics Radiation Biology Experimental Physics Proton, carbon ions, optional further particles Room for at least 24 researchers In co-operation with universities MedAustron-Research will also play a key role as a training centre.

4 Accelerator B1 B2 B3 B4 The accelerator facility consists of three main systems: the injector, the synchrotron and the high-energy-beam-delivery (HEBT). In the injector area, four ion sources deliver the desired particle (protons, carbon ions and optionally other particles), which will be preaccelerated by the linear accelerator (Linac) and channeled into the synchrotron. The particles will then be brought up to the requested energy level and consequently guided through the high-energy-beamdelivery to the irradiation rooms (B1-B4). Protons Beam energy (min. max.) MeV Beam intensity per Spill Extraction duration (min. max.) 0,1 10 s Repetition rate (max.) 1 Hz Carbon ions Beam energy (min. max.) MeV/u Beam intensity per Spill Extraction duration (min. max.) 0,1 10 s Repetition time (max.) 1 Hz Beam parameters

5 Irradiation Rooms MedAustron provides four irradiation rooms. Three are primarily intended for patient treatment (B2, B3, B4). Beam-Scanning max. target dimension 20 x 20 cm Proton gantry PSI Irradiation room B1 will be used for nonclinical research only. This room is designed for a maximum beam energy of 800 MeV. It has a size of 8 x 12 metres and two isocentres. Beam delivery The medical irradiation rooms are accessible for nonclinical research outside of the clinical operation times. B1 and B2: horizontal beam line B3: horizontal and vertical beam line B4: proton gantry Radiobiological experimental area GSI

6 White Books International experts discuss in two white books the potential of MedAustron-Research and give insight into the various opportunities for research in this new accelerator facility. Research Opportunities for Medical Radiation Physics and Radiation Biology Physics Opportunities at MedAustron These books are intended for potential users and new co-operation partners of MedAustron. To order the books, please contact:

7 Three Research Fields Medical Radiation Physics Radiation Biology Experimental Physics The nonclinical research supports medical goals through a wide range of research programs in the areas of radiation biology and medical radiation physics. Core topics are research areas aiming at a better understanding of biological and physical mechanisms of ions. Furthermore, the improvement and development of novel therapy concepts as well as of diagnostic, planning, positioning and therapy equipment is of great interest. Translational research from-bench-to-bedside under one roof For the field of experimental physics, the accelerator system will provide an impulse for the development of accelerator physics in Austria. Interested researches and participating institutions will, for the first time, be able to work on such research programs and young academics will be able to benefit from education and training with state-of-the-art technology. Co-operations can be initiated and exchange with the international scientific community can be enhanced. Development of accelerator physics in Austria Even the industry can access the state-of-the-art equipment for their research and development work.

8 Medical Radiation Physics Treatment planning The focus of the research areas in medical radiation physics lays on the development and improvement of ion beam therapy in order to push cancer treatment with ion beams to the next level and make optimal use of MedAustron s resources; the aim is to establish strategies for a highly effective, individualized treatment of malignancies with maximal reduction of side effects. Infrastructure in MedAustron- Research: Dosimetry laboratory Software development room Mechanical workshop Large storage room Four irradiation rooms available for use Water phantom European and national radiation protection legislation requires employing accredited Medical Physics Experts (MPE) when performing radiation therapy. MedAustron could therefore serve as a European centre for professional training of MPEs in ion beam therapy. Medipix Detector CERN

9 Medical Radiation Physics Dosimetry Typical dosimetry applications in radiation oncology are beam calibration accelerators, patient-specific pretreatment quality assurance or the experimental benchmarking of novel dose calculation algorithms. Dosimetry in clinically used ion beams has to catch up with photon and electron beams for which a much longer tradition of dosimetry exists. This holds true for dosimetric uncertainties including those of fundamental quantities (stopping powers, energy required to produce ion pairs in air, etc.) as well as protocols for absorbed dose determination and consistent beam calibration. Furthermore, purpose-built multi-dimensional detectors for scanned ion beam delivery and active energy variations need to be developed and their dosimetric properties investigated. Dose calculation and optimization Current (semi-)analytical models for dose calculation in human tissues are based on assumptions and approximations. Tissue heterogeneities such as air cavities, lung, bone and metallic prostheses are well known to cause uncertainties in dose calculation. This problem is extremely important for light ion beams where tissue heterogeneities have direct impact on the range of ions. Monte Carlo transport simulations are the most powerful method for reducing uncertainties due to heterogeneities and developing faster and more accurate dose calculation algorithms. The investigation into ion species that are not currently applied in clinics but have great potential for radiation oncology e.g. helium ions and lithium is necessary. Due to the higher biological efficiency of ions compared to photon and electron beams, it is necessary for ion beam therapy treatment planning to convert physical doses into biological ones. This conversion is still one of the main sources of uncertainty. Computerised treatment plan optimization ( inverse planning ) has become a key issue in radiation oncology to determine treatment-related machine parameters taking into account physical and patient-specific radiobiological treatment objectives. Treatment planning Treatment planning comparisons have been the method of choice for comparing treatment techniques against one another. As the indications for ion beam therapy are not yet settled, there are numerous options

10 Medical Radiation Physics to assess the possible therapeutic gains of ions for various tumour sites. One of the currently less-explored options is the combination of treatment techniques involving conventional beam qualities (photons/electrons) and ion beams with high- and low-let. Biological imaging methods need to be developed and explored in order to define biological targets, such as hypoxic areas in the tumour. For combined modality treatments, such as photon irradiation followed by a proton boost, or proton irradiation followed by a carbon ion boost, the assessment of the composite treatment plan remains a challenge. The main difficulty is the changing patient anatomy or topography of the patient (due to weight loss or tumour response during treatment). In order to account for variations in anatomy, non-rigid image registration tools are necessary and methods need to be developed for voxel tracing that include dosimetric information from the different treatment sessions. Image-guided radiotherapy and adaptive ion therapy The actual delivered dose to the patient might differ from the planned dose because of anatomical changes during beam delivery in a treatment fraction (intra-fraction variations) or in between fractions (interfraction variations), as compared to the time of treatment planning. Recently, on-line imaging tools for image-guided radiotherapy have been developed for conventional radiotherapy in order to allow assessment and calculation of these effects. It is important to realise that organ movements and anatomical changes during the course of radiotherapy lead to larger errors in ion beam therapy than in photon therapy. Firstly, different organ fillings or respiratory motion can cause severe density variations, which consequently influence particle range and thus tumour control and normal tissue complication probabilities. Secondly, dose is usually much better conformed to the target with particle therapy than in the case of conventional radiation and small set-up uncertainties might lead to geographic misses of the tumour. Thirdly, for beam delivery with time variable fluence patterns, there might be interplay effects with intra-fraction organ motion. Research in the field of image-guided particle therapy is thus crucial for optimal use of the higher concentration of the dose and, in the case of carbon ions, of its larger biological effectiveness at the end of the range in the patient body.

11 Medical Radiation Physics In-situ monitoring of ion therapy Methods for the assessment of patient positioning used in conventional X-ray based radiation therapy rely on the transmission of the megavoltage treatment beam through the patient, or on kilovoltage in-room imaging devices. Some of these techniques are not applicable in ion therapy and some of them are not ideal because they do not involve the treatment beam. The only real-time diagnostic tool currently available is in-vivo imaging of the positron-emitting nuclides produced by hadrons during therapeutic exposures. Given the limited number of research centres for ion beam therapy with access to PET devices and the limited clinical experience, in-situ monitoring of ion therapy is in general a broad research topic itself. In recent years another technique has been proposed for ion beam therapy besides PET-monitoring, namely in-beam dose monitoring with prompt single particles, in particular photons and protons. This is a new field and the exploration of its potential value for ion beam therapy has just begun. Quality assurance and radiation protection In contrast to radiotherapy with high-energy photon and electron beams, there are no guidelines for quality assurance and radiation protection at the patient level in ion beams. The international experience is very limited and there are no international recommendations or guidelines either. The development and testing of purpose-built phantoms for ion beam studies and inter-comparisons incorporating physical and biological dose endpoints is of utmost importance. Results of such studies are needed to determine variations in the overall reliability and accuracy of dose delivery in a facility, covering imaging, physical and biological modelling in the treatment planning system, beam delivery and automated corrections for image-guided radiotherapy. Furthermore, radiation protection aspects such as neutron contamination during ion beam delivery are much less explored than in radiation oncology using conventional beam qualities. Improving existing technologies There is a vast number of issues in ion beam therapy demanding improvement in order to bring them up to the standards of conventional and advanced X-ray therapy.

12 Radiation Biology Cell culture Head phantom GSI Radiation biology investigates the effects of ionising rays on biological objects. It is therefore an indispensable companion in the manipulation and use of new forms of radiation. In the case of individual standardised treatments, and especially in the case of non-standardised treatments such as in the context of clinical studies, radiation biology offers valuable assistance, e.g. in the estimation of equivalence doses, interpretation of side-effects, and the development of biomarkers for radiation therapy. Furthermore, new and previously unexplored treatment combinations should not only be investigated with classical combination partners of radiotherapy, such as chemotherapy, but also in combination with modern immunotherapies and/or modulating molecules ( targeted therapies ). Infrastructure in MedAustron- Research: Irradiation room Main lab Chemical laboratory Cell culture Storage room for biological samples Mechanical workshop It is therefore of importance to better understand the mechanisms and consequences of new forms of therapy with protons and carbon ions in the human body from the molecular to the organ level. Apoptosis

13 Radiation Biology Comparison of the biological effects of ions with photons Aside from some similarities, there are also fundamental differences between conventional (photon) therapy and new ion radiation therapy (including both proton and carbon ion therapy). For this reason, comparative studies must undertaken investigating the impact on the molecular, cellular and systematic level (toxicity, cell and organ damage), the mechanisms of radiation-induced cell death, DNA repair mechanisms, biological microdosimetry as well as other fundamental mechanisms of implemented ion rays (which have been for photon therapy already partially established). A central aspect of the fundamental research will be the generation of RBE (RBE = relative biological effectiveness) data, most importantly for carbon ions, which will have to be collected from eligible biological models. These data represent the central connection between medical radiation physics and radiation biology, since they contribute to the verification and improvement of biological dose calculation for therapy. Algorithms that calculate the dose must also take into account physical as well as biological (clinical) effects. In order to achieve homogenous dose division, a RBW model has to be included in the radiation planning system. This model must furthermore take the relatively complex dependence of various factors into account (linear energy transfer, dose per fraction, projectile fragmentation, and cell or tissue type). Modulation of molecular targets (molecular targeting) Molecular targeting refers to the targeted modulation by pharmacological means of the activity of cellular target structures such proteins, genes and other molecules, which are of clinical relevance. This may achieved through the application of cytokines, antibodies or small molecules. This field of research is closely connected to biomarker research. The ultimate goal is to increase tumour radiation sensitivity or decrease of normal tissue sensitivity. Target structures include, among others, genes and proteins that regulate DNS repair, cell cycle, cell death, oxidation status, inflammatory processes, fibrosis and angiogenesis, as well as physiological processes of the micromilieu surrounding the tumour. Through the recent implementation of new technologies, knowledge regarding potential intracellular target structures and their biological functions has been rapidly increasing, giving a rational avenue for the testing of corresponding therapy-modulating strategies within the framework of MedAustron.

14 Radiation Biology Research on biomarkers The prediction of individual radiation sensitivity and tumour response is the paramount goal of radiation biology research. Therefore, it is necessary to develop predictive indicators for the risk of normal tissue reactions and the response to therapy. With help of functional global gene expression studies or through global protein expression analyses (based on DNA-chip/protein-chip-technology) in cell lines, animal models and most importantly through clinical studies, specific markers can be sought that allow determination of individual patient side-effect risks and prediction of the tumour response on the molecular level even before starting radiation therapy. These data have been collected as yet predominantly in the context of photon irradiation. An integral research focus at MedAustron will therefore be the investigation of new biomarkers for proton and carbon ion therapy. Novel treatment combinations In the last two decades, advancements in cancer therapy have been primarily achieved through the combination of surgery, chemotherapy and immunotherapy (radio-chemotherapy, radio-immunotherapy). These combination therapies lead to, in the case of certain tumours, a distinct improvement in tumour control and survival. In this connection, proliferation and cell cycle regulation, DNA damage repair, growth factors (cytokines) and their surface receptors and protein kinase all play a decisive role. Knowledge of the molecular mechanisms of pharmacotherapeutics and their interaction with radiation is a fundamental prerequisite for any effective further development of combined treatment modality. Space research Interesting research aspects for MedAustron are opening themselves in the realm of space exploration. Protons and carbon ions available at MedAustron also present meaningful ion components of the solar and cosmic spectrum and allow for the study of the effects of the radiation to which astronauts are exposed. Correspondingly proposed questions revolve around, among others, genetic changes, reactions of tissue to radiation, late effects (e.g. carcinogenesis) and the implementation of radiation sensitivity modulators.

15 Experimental Physics Infrastructure in MedAustron- Research: Irradiation room with two isocentres Preparation room Decay room Two large storage rooms Mechanical workshop RF-Laboratory Electronic Laboratory Clean workshop The MedAustron Accelerator complex will mainly be designed for the purpose of supplying protons and carbon ions for the treatment of tumours (protons MeV, carbon ions MeV/u). The increase of proton energy to 800 MeV represents a compromise that, however, allows also for valuable research opportunities for experimental physicists (detector development, dosimetry research, material research) - topics for which it is often difficult to schedule beam time in the big nuclear and particle research centres. Detector module CERN Target Chamber PSI MedAustron will be an ideal facility for training in various physical areas of expertise using state-of-the-art technology, e.g. areas of experimental particle physics, detector physics and accelerator physics. Radiation sample Co-operation TU Bratislava, GSI

16 Experimental Physics Detector development and test Scientific progress in nuclear and particle physics strongly depends on the development and continuous improvement of detector technology. The MedAustron facility can contribute to these advancements as a test beam facility. For optimum detector signal response, described by the Bethe-Bloch theory, there is a clear preference for the highest achievable proton beam energy. 800 MeV has been found to be an appropriate upper limit. Semiconductor, gaseous and scintillating type tracking detectors can be tested at the MedAustron facility, with the spatial resolution being limited only by the maximum beam energy. The energy range available at MedAustron is of interest for testing calorimeters used in nuclear physics. Irradiation studies at the MedAustron facility will be possible for an integrated flux of up to particles per square centimetre within a run period of about one day. Rate and saturation tests of detectors and related electronics are possible with event rates comparable to expected rates for innermost detectors of high luminosity machines. Proton scattering experiments With a proton beam energy of up to 800 MeV, MedAustron offers interesting conditions for a proton scattering facility (PSF). Such a facility would allow for a wide range of studies, covering from nuclear structure to high-energy nuclear physics. Although low beam intensities do not allow for competition with state-of-the-art nuclear physics research centres, a PSF at MedAustron could provide valuable beam time for experiments with either limited or no access to such dedicated facilities. One promising application for the PSF is the improvement of not yet fully established measurements of nuclear radii with advanced methods, e. g. using Fraunhofer diffraction. The feature of variable proton beam energies from 60 MeV to 800 MeV is of particular interest for applications using proton-proton scattering physics.

17 Experimental Physics Material research Higher proton beam energies improve the resolution quality of proton-computed tomography due to the reduced multiple Coulomb scattering. Such high energy proton-computed tomography could be developed and implemented at MedAustron. The carbon ion beam could be used to realise a single-hit micro-probe to prepare solid-state material for physical modification on areas with lateral dimensions in the nanometer scale over ion track lengths. The specific equipment for providing beams" with single ions is also of greatest interest to commercial applications, e.g. nanochannels in ion-track etched polymembranes offer a wide spectrum of possibilities in the field of Biotechnology. They are also suited for the detection of biomolecules and present a highly selection molecular filter. For space research, the investigation of radiation hardness of electronic devices and the shielding effects of spacecraft materials are of great interest. Materials with a high hydrogen content and little atomic mass shield from space-related radiation more effectively than aluminum. Light target cores assist in the fragmentation of more heavily loaded particles and minimise the development of secondary neutron radiation. Radiation protection and dosimetry The beam quality available at MedAustron allows for dosimetry studies in various areas. The most attractive items identified are solid-state nanodosimetry based on thermoluminescence and simulations of cosmic ray components such as solar proton events in the several hundred mega-electron Volt range.

18 Ground Floor ENTRANCE research research light shaft therapy light shaft light shaft light shaft light shaft ENTRANCE therapy delivery radiationbiology light shaft light shaft light shaft medical radiation physics experimental physics research radiation room B1 + control room medical radiation rooms B2- B4 offices, meeting rooms, etc accelerator B1 B2 B3 B4

19 Basement utility area offices, facilities light shaft light shaft experimental physics 2 storage rooms mechanical workshop, rf-lab, clean workshop electronic lab, synergetically used

20 Scien fic Advisors Medical Radia on Physics Ao. Univ.-Prof. DI Dr. Dietmar Georg Department of Radiotherapy Division Medical Radia on Physics Medical University of Vienna Radia on Biology Ao. Univ.-Prof. Dr. Edgar Selzer Department of Radiotherapy Division Radia on Biology Medical University of Vienna Experimental Physics Univ. Prof. DI Dr. Gerald Badurek Dean of the Faculty of Physics Technical University of Vienna Dkfm. Theodor Krendelsberger CEO T +43 (0) F +43 (0) Dr. Ingeborg Zeh Scien fic Coordinator E office@medaustron-research.at I Responsible for the content: PEG MedAustron GmbH Viktor Kaplan-Straße 2 A-2700 Wiener Neustadt