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This work presents the study of the optical density as function of absorbed dose for radiochromic films (model EBT3 Gafchromic) irradiated with protons of energies below 5 MeV. Once the calibration curves are obtained, the study of the optical density as function of the linear energy transfer (LET) is presented. Such studies are useful in proton dosimetry applied to pre-clinical and in vitro radiobiological research. Measurements were performed at the National Centre of Accelerators (CNA) in Seville with a proton beam produced by a 3 MV Tandem accelerator. The incident energy onto the films was measured with an ion implanted silicon detector, and the particle fluence was monitored using a parallel plate ionization chamber. With this proton beam it is possible to investigate the interaction of high LET protons with EBT3 films with narrow energy spreads, as compared with therapeutic proton beams in the Bragg peak region. The data of the beam energy at the position of the film were used to simulate the energy deposition in the active layer of the film, by means of Monte Carlo codes. The measurements were performed for dose values up to 30 Gy and for five values of incident energy, obtained with a passive degradation of the beam by interposing mylar foils of different thickness upstream the EBT3 film. For each energy and corresponding value of proton LET, curves of the optical density as function of the dose are provided for the three color channels red, green and blue (RGB). The dose has been calculated considering two scenarios: dose to water (considering the film composition made by water) and dose to lucite (assuming the real composition of the film). The first corresponds to the case of clinical interest and the second to the real situation of the measurements. The comparison shows a non-negligible shift of the calculated doses even if density corrections are included. In the plateau region of the Bragg curve the film response can be well described by a simple polynomial function (at low doses up to about 4 MeV the response is almost linear). In regions covering the Bragg maximum the film response suffers a quenching and the optical density values were found to be 20–30 % lower than expected., This work is supported by the following research projects: Spanish Ministerio de Ciencia y Competitividad No. FPA2016-77689-C2-1-R and No. FPA2015-67694-P; by the Andalusian Research Projects No. P12-FQM-1605 and No. FQM-0387; and by the European Regional Fund (ERDF).

Trabajo presentado en 2nd OMA Topical Workshop on Diagnostics for Beam and Patient Monitoring, celebrado en Ginebra (Suiza), del 4 al 5 de junio de 2018

Trabajo presentado en Rábida 2018: International Scientific Meeting on Nuclear Physics, celebrado en La Rábida (Sevilla, España), del 18 al 22 de junio de 2018, In the last decades, particle radiation therapy, mainly performed with protons and carbon ions, has gained great interest in the medical community thanks to its excellent clinical results. The bases of this success are: (1) the physical advantages of protons and heavier ions with respect to conventional radiation therapy with photons, due to their more selective energy deposition in depth; and (2) their increased radiobiological effectiveness, since protons and heavier ions offer a higher cell-killing effectiveness if compared to photons for a same level of absorbed dose, property usually referred to as Relative Biological Effectiveness or RBE. The RBE depends on different factors, both physical and biological, such as radiation quality, track structure, linear energy transfer (LET), tissue type, biological endpoint, etc. However, in the case of protons, there is still place for improvements in what concerns the understanding of the behaviour of the RBE on both cancer and healthy cells, and its role in treatment planning and delivery. Even if it is agreed that proton RBE varies towards the distal Bragg peak region, increasing with LET, nowadays in clinical proton therapy treatments, a uniform RBE value of 1.1 is generally used, leading possibly to suboptimal proton treatment plans, as stated in Wedenberg et al. Therefore, studies of RBE at low proton energies are necessary in order to optimize proton therapy treatment plans and reach a consensus on the RBE variations near the Bragg peak. However, not many proton facilities can provide a monochromatic beam for radiobiological measurements at low energies (roughly below 20 MeV). With this purpose, we are preparing an experimental setup at the external beam line of the 18MeV proton cyclotron facility installed at the CNA (Seville, Spain) to cover this gap. [Methods and Results] In this work, we present our first feasibility studies. At present, the experimental beam line installed at the cyclotron facility counts on two Faraday cups for beam diagnostics, and on two collimators of 1.5 cm diameter placed at 1 m distance one from the other, the second of them mounted together with a 100 µm Aluminium exit window, for beam delivery and shaping. Two are the main constraints when dealing with cell irradiations: low beam intensity, of the order of some pA, to control properly the fluence during irradiation time, and broad irradiation field, of the order of 3cm side, uniform in both energy and space. In order to improve the homogeneity and decrease the beam intensity, we have decided to use a completely defocused beam and to scatter the beam downstream the exit window, both placing tungsten foils of different thicknesses and changing the amount of air between the window and the samples position. So far, we have measured the properties of wide beams produced with tungsten scattering foils of various thicknesses. With a 150 m thick tungsten foil, we could produce a 10 MeV proton beam with almost homogeneous intensity, having deviations of the order of ~10% in the central 35 mm and at ~50 cm distance from the exit window. Furthermore, we have performed preliminary dosimetric studies, using EBT3 radiochromic films and a transmission ionization chamber for dose and proton fluence evaluation. Studies of this nature are of great interest, since radiochromic films would be a handy and easy to use dosimeter solution for proton RBE studies. Finally, we are developing with the Geant4 toolkit a Monte Carlo tool, which reproduces accurately the cyclotron beam properties with the aim of simulating future improvements proposed on the final optimization of the setup for the irradiation of biological samples., This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 675265, OMA Optimization of Medical Accelerators, and from the Spanish Ministry of Economy and Competitiveness under grand No FPA2016-77689-C2-1-R. The Monte Carlo simulations were carried out at the FIS-ATOM cluster hosted at CICA (Seville, Spain).

Trabajo presentado en el 3rd OMA Topical Workshop on Accelerator Design and Diagnostics, celebrado en Darmstadt (Alemania), del 11 al 18 de diciembre de 2018

Trabajo presentado en las II Jornadas RSEF / IFIMED de Física Médica, celebradas en Madrid (España), del 14 al 15 de junio de 2018, In the last decades, proton therapy has gained great interest in the medical community thanks to its excellent clinical results. The bases of this success are: (1) the physical advantages of protons with respect to conventional radiation therapy with photons, due to their more selective energy deposition in depth; and (2) their increased radiobiological effectiveness as compared with photon radiotherapy for a same level of absorbed dose, property usually referred to as Relative Biological Effectiveness or RBE. Even if it is agreed that proton RBE varies towards the distal Bragg peak region, increasing with LET, nowadays in clinical proton therapy treatments, a uniform RBE value of 1.1 is generally used. Therefore, studies of RBE at low proton energies are necessary in order to reach a consensus on the RBE variations near the Bragg peak, which could be significant in the optimization of proton therapy treatment plans. With the purpose of providing a monochromatic beam for RBE measurements at low energies (below 18 MeV in our case), we are preparing an experimental setup at the external beam line of the 18MeV proton cyclotron facility installed at the CNA (Seville, Spain). In this work, we present our first feasibility studies. Two are the main constraints when dealing with the irradiation of biological samples in our setup: low beam intensity, of the order of some pA, to control properly the fluence during irradiation time, and broad irradiation field, of the order of 3cm side, uniform in both energy and space. To improve the homogeneity and decrease the beam intensity, we have decided to use a completely defocused beam and to scatter the beam downstream the exit window, both placing tungsten foils of different thicknesses and changing the amount of air between the window and the position of the samples. So far, we have measured the properties of wide beams produced with tungsten scattering foils of various thicknesses. With a 150 m thick tungsten foil, we could produce a 10 MeV proton beam with almost homogeneous intensity, having deviations of the order of ~10% in the central 35 mm and at ~50 cm distance from the exit window. Furthermore, we have performed preliminary dosimetric studies, using EBT3 radiochromic films and a transmission ionization chamber for dose and proton fluence evaluation. Studies of this nature are of great interest, since radiochromic films would be a handy and easy to use dosimeter solution for proton RBE studies. Finally, we are developing with the Geant4 toolkit a Monte Carlo tool, which reproduces accurately the cyclotron beam properties with the aim of simulating future improvements proposed on the final optimization of the setup for the irradiation of biological samples., This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 675265, OMA - Optimization of Medical Accelerators, and from the Spanish Ministry of Economy and Competitiveness under grant No FPA2016-77689-C2-1-R. The Monte Carlo simulations were carried out at the FIS-ATOM cluster hosted at CICA (Seville, Spain).

Tesis llevada a cabo para conseguir el grado de Doctor por la Universidad de Sevilla--2017-09-15, This thesis work is based on the knowledge about the interaction of radiation with matter to develop new methods with the aim of applying them to the radiation therapy and radiobiology, specifically to dose measurements in radiation therapy, dose measurements with low energy proton beams and DNA damages caused by these protons on cancer cells. Thus, it presents two main parts: one regarding the presentation of a novel prototype based on silicon detector technology for treatment verification in radiotherapy, and the other, the instrumentation and the methodology for low energy proton beam characterization, dosimetry, with a special focus on the response of radiochromic films to protons, and finally the application on biological samples to study the DNA damage produced by protons. The first part of this work presents a novel system with improved performances with respect to a previous system which was filed for a patent in September 13th 2011 at the OEMP - “Oficina Espa˜nola de Patentes y Marcas”- Ministry of Industry, Tourism and Commerce, under reference number P201101009. This work was also published in specialized reviews and thesis works. The characterization of the response in terms of absorbed dose of this novel detector was presented Here, this study was repeated because of some modifications introduced in the electronics and in one of the detector’s cables, which was modified due to a breakdown. The application of this system for complex treatment verification providing a 2D dose map reconstruction in the axial plane is presented for the first time in this thesis work. The second part of the work presents the installation of instrumentation for dosimetry and radiobiology studies using proton beams produced by the 3 MV Tandem accelerator at Centro Nacional de Acceleradores, Sevilla. The original work within this part can be divided into three main points: i) the elaboration of a protocol which allows to obtain a beam profile with low current and an homogeneous profile over the whole sample surface; ii) dosimetry with low energy protons using ionization chambers and radiochromic films; iii) study of the dosimetry at the Bragg peak. Last, the application of these studies to the irradiation of cell cultures is presented and preliminary results of the DNA damage produced by protons are shown.

Traditionally, the verification of complex photonradiotherapy treatments, like Intensity Modulated Radiation Therapy (IMRT), has been carried out by means of radiographic films, which are inserted in a water-equivalent phantom and irradiated by an accelerator. The radiographic films have to be developed and read with a scanner. The dose map is then obtained as a function of the optic density. The use of these films has some disadvantages such as the manipulation sensitivity and the time-consuming film development process. In addition, the increased use of digital radiometers is leading to the disappearance of films and development devices. Despite these inconveniences, films have some advantages which until today could not have been achieved by any other method: first they provide excellent spatial resolution (<, This work is supported by Spanish Research Project Nos. FPA2013-47327-C2-1-R and FPA2014-53290-C2-2-P; by Andalusian Research Project No. P12-FQM-1605; by Radia 2 Contract No. 68/83-Ref. 0214/0129; and by Consolider-Ingenio 2010 Project No. CSD2007-004.

A feasibility study of an experimental setup for the irradiation of biological samples at the cyclotron facility installed at the National Centre of Accelerators (Seville, Spain) is presented. This cyclotron, which counts on an external beam line for interdisciplinary research purposes, produces an 18 MeV proton beam, which is suitable for the irradiation of mono-layer cultures for the measurement of proton cell damages and Relative Biological Effectiveness (RBE) at energies below the beam nominal value. Measurements of this kind are of interest for proton therapy, since the variation of proton RBE at the distal edge of the Bragg curve may have implications in clinical proton therapy treatments. In the following, the characteristics of the beam line and the solutions implemented for the irradiation of biological samples are described. When dealing with the irradiation of cell cultures, low beam intensities and broad homogeneous irradiation fields are required, in order to assure that all the cells receive the same dose with a suitable dose rate. At the cyclotron, these constraints have been achieved by completely defocusing the beam, intercepting the beam path with tungsten scattering foils and varying the exit-window-to-sample distance. The properties of the proton beam thus obtained have been analysed and compared with Monte Carlo simulations. The results of this comparison, as well as the experimental measurement of the lateral dose profiles expected at the position of samples are presented. Meaningful dose rates of about 2–3 Gy/min have been obtained. Homogeneous lateral dose profiles, with maximum deviations of 5%, have been measured at a distance of approximately 50 cm in air from the exit window, placing a tungsten scattering foil of 200 µm in the beam path., This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant No. 675265, OMA—Optimization of Medical Accelerators, from the Spanish Ministry of Economy and Competitiveness under Grant No. FPA2016-77689-C2-1-R, and from the Council for Innovation, Science and Commerce of the Andalusian Government under Grant No. P12-FQM-1605.