215 NON-INVASIVE TREATMENT OF ATRIAL FIBRILLATION WITH A SCANNED CARBON ION BEAM

S107 Material and Methods: Human CRL5876 NSCLC of female smoker origin, were exposed to single and combined treatments with erlotinib and protons. Irradiations were performed in the middle of the 62 MeV proton therapeutic spread out Bragg peak (SOBP) with single doses of 2, 4, 8, 12 and 16 Gy. Cells were irradiated 72 h after seeding. Efficiency of erlotinib was evaluated by colorimetric sulforhodamine assay. Exponentially growing CRL5876 cells were treated with 5, 10, 25, 50 and 100 μm erlotinib and incubated for 24, 48 and 72 h. For the analysis of the effects of combined treatments, erlotinib was applied immediately after irradiation. Cell survival was assessed using colony forming assay 7 days after exposure to protons and/or erlotinib. Cell proliferation was evaluated using bromodeoxiuridine assay 48 h and 7 days after treatment, as well as flow cytometric analysis of the cell cycle phase distribution. Flow cytometric analysis of apoptosis was performed after 48 h. Results: Concentration of 10 μm erlotinib was found to be the half maximal inhibitory concentration (IC50) for the CRL5876 cells and was used in combined treatments with protons. Radiobiological characterisation of these cells indicated high level of cellular radio-resistance with respect to g-rays and protons. Although these cells are rather resistant, trend of increased inactivation with the rise of dose was observed. This was especially seen after combined treatments. Proliferative capacity of the CRL5876 cells decreased after all analyzed treatments. Combined treatments revealed stronger antiproliferative activity than corresponding single treatments, particularly after 7 days. The CRL5876 cells showed low apoptotic cell death after all analyzed treatments (2.5 – 9 %). The analysis of cell cycle distribution of the CRL5876 cells pointed out that single treatments with erlotinib or protons induced G2 phase arrest after 48 h and 7 days. More prominent induction of G2 arrest was observed after 48 h. When the CRL5876 cells were exposed to higher doses of protons after incubation for 7 days, accumulation in S phase was noticed as well. Combined treatments induced G2 arrest at both analyzed time points. This arrest was followed by the increase of cells in S phase. Conclusions: Obtained results showed high radioresistance of the human CRL5876 lung adenocarcinoma cells and indicated that combined treatments with proton radiation and erlotinib induced higher level of inhibition of cell proliferation than single treatments. Antitumour effect of protons and/or erlotinib was achieved through the induction of G2 arrest. 214 DEVELOPMENT OF AN EXPERIMENTAL BEAMLINE FOR RADIOBIOLOGICAL STUDIES RELEVANT TO PARTICLE RADIOTHERAPY AND THE IMPORTANCE OF RADIATION TRACK STRUCTURE A. Nagano1, M. Hill2, F. Fiorini3, E. Zare4, S. Green5, D. Parker3, B. Jones2, G. McKenna6 1 PTCRI, University of Oxford 2 Gray Institute, University of Oxford 3 University of Birmingham 4 University of London) ; 5 University Hospital Birmingham NHS Trust 6 Department of Oncology, University of Oxford

ICTR-PHE 2012 Charged particle therapy is becoming increasing used around the world for radiotherapy and offers advantages over conventional radiotherapy using xrays. As charged particles slow down the amount of energy transferred to a material per unit track length (LET - linear energy transfer) increases up to the Bragg peak, this not only leads to an increase in dose, but also an increase in biological effectiveness with depth. Additionally, increasing LET results in a decrease in OER (Oxygen Enhancement Ratio) and decrease in the variation of response observed between cells with different repair capacities. Increased understanding of the mechanisms underpinning the radiation action on biological systems is important in understanding, not only the risks associated with exposure, but also in optimising radiotherapy treatment of cancer. Differences in the biophysical features of the radiation track structure and resulting DNA damage, associated with different qualities of ionising radiation, is important in determining the subsequent biological response in DNA, cells and ultimately the efficacy of treatment. This becomes increasingly important for heavier ions. Despite the world-wide implementation of charged particle therapy, there remain important issues which can be addressed experimentally using non-clinical research beam-lines with associated cell and tissue handling facilities. These include issues of basic radiobiology in understanding the mechanisms of radiation damage, cell response to this damage and the ultimate consequence of cell irradiation with different light ions as a function of energy and microenvironment. Also of interest are studies looking at the interaction of these beams with candidate dose enhancing and/or repair inhibition agents. Although this looks promising for conventional x-rays, it is unclear what the effect of these agents will be in charged particle therapy. Such an experimental beamline has been designed at the University of Birmingham to enable irradiation with protons, 3He, 4He and N ions. This can produce uniform and well calibrated ion beams over a diameter of 4 cm with dose rates up to a few hundred Gy/s. Depth-dose measurements were performed using an NPL calibrated Markus chamber in PMMA for proton energies of 29 and 36 MeV, and in Mylar with an 4He ion energy of 38 MeV (peak-toplateau ratios of 5.5, 5.9 and 4.3 respectively) and compared with FLUKA simulations. The design and performance of the Birmingham beamline and the initial proton radiobiological clonogenic survival data obtained will be presented and compared with 4He ion (α-particle) and gamma-ray data. The importance of spatial distribution of energy deposition on the scale of DNA (in determining the frequency and complexity in clustered DNA damage), cells (in determining the complexity of chromosomal aberrations) and tissue (dose and LET distribution), for both sparsely ionizing radiation (such as x-rays and gamma-rays) and densely ionizing radiations (such as â-particle and other charged particles) will be discussed in association with experimental data. 215 NON-INVASIVE TREATMENT OF ATRIAL FIBRILLATION WITH A SCANNED CARBON ION BEAM A. Constantinescu1, O. Blanck2, M. Durante1, C. Bert1

S108 1 GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Darmstadt, Germany; Technische Universitaet Darmstadt, Germany) 2 Universitätsklinikum Schleswig-Holstein, Lübeck, Germany; Cyberknife

Arrhythmias describe a wide range of cardiac conditions associated with abnormal heart beats. One of the most common arrhythmias is atrial fibrillation, describing an irregular and often rapid heart rhythm caused by misled electrical impulses in the upper chambers of the heart. Although not considered life threatening, it causes a range of complications and significantly increases the risk of suffering a stroke. The treatment possibilities for atrial fibrillation are manifold and based on pharmaceuticals, external defibrillation like cardioversion or invasive methods (e.g. implantation of cardioverter defibrillator). Furthermore, patients with chronic atrial fibrillation can also be treated with ablation, either surgically or via a catheter. For these approaches, the source of the misled electrical signal is destroyed and a small scar is created, leading to an inactivation of the triggering. Both procedures lasts several hours and require hospitalization of the patient, increasing the risk of sequelae. Recent studies reported by Sharma et al. successfully showed that non-invasive ablation seems feasible [1]. Only a single irradiation fraction with a focused photon beam achieved to have an impact on the electrical triggering in animal hearts without damaging the nearby tissue. While this new modality reduced the treatment time to only one to two hours, the precision is limited to 5-20 mm depending on the system used for irradiation. More complex systems, such as the CyberKnife used in the Sharma et al. studies, enable a higher precision but with the cost of invasive marker implantation in the heart. All systems available for stereotactic radiosurgery use focused photon beams. Based on the experiences gained in cancer treatment, even more promising results are expected for the creation of cardiac lesions with ion beams. Especially carbon ions have certain advantages compared to photons when irradiating a deep seated target. Among them are an inverse depth-dose profile, leading to an increased dose deposition at the end of the particle track and hence enabling an irradiation of the target region while sparing healthy tissue, as well as a reduced lateral scattering and an increased relative biological effectiveness. The deflection of ions is furthermore facilitated due to their electrical charge. Consequently, an improved precision in creating cardiac ablation with ions as well as a drastically reduced treatment time of a few minutes are expected. The basic feasibility of treating cardiac arrhythmias with a scanned carbon ion beam was assessed in treatment planning studies using TRiP4D [2]. As an interference between the heart’s trajectory (due to heart beat and respiration of the patient) and the movement of the carbon ion beam can lead to dose inhomogeneities, the motion influences needed to be carefully examined. Therefore we studied on one hand four dimensional computed tomography data (4DCTs) , originally used for lung tumor treatment. Here we redefined the target volume to include volumes of interest for the treatment of arrhythmias (e.g. atrioventricular node, pulmonary veins). On the other hand cardiac CTs of animal hearts were used. This

ICTR-PHE 2012 enabled to study the different motion influences and the subsequently resulting need of motion compensation. Different irradiation techniques, known from the treatment of moving tumors (rescanning, gating, beam tracking), as well as their combinations, have been tested. The dose deposition to the target area itself as well as to the nearby tissue and especially to the organs at risk (e.g. esophagus, heart) have been carefully examined. [1] Sharma et al., Noninvasive stereotactic radiosurgery (CyberHeart) for creation of ablation lesions in the atrium, Heart Rhythm 7(6), 802-10, 2010 [2] Richter et al., 4D Treatment Planning Implementations for TRiP98, GSI Sci. Rep. 42, 500, 2009 216 RADIO-RESISTANT HUMAN MALIGNANT CELLS AFTER IRRADIATIONS WITH 1H AND 12C IONS OF DIFFERENT LET I. Petrović1, A. Ristić-Fira1, D. Todorović2, L. Korićanac1, J. Žakula1, G.A.P. Cirrone3, F. Romano3, G. Cuttone3 1 Vinča Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia; 2 Medical faculty, University of Kragujevac, Kragujevac, Serbia; 3 Laboratori Nazionali del Sud, Istituto Nazionale di Fisica Nucleare, Catania, Italy Purpose/Objective: Efficiency of high ionizing radiation has been widely analyzed in the past on the variety of radio-sensitive cell lines. Therefore, the aim of this study was to investigate the behavior of radioresistant human malignant cells, thus enabling better understanding of radiobiological effects of ions. Various radiobiological parameters and events characterising behaviour of these cells after irradiations with protons and carbon ions of different linear energy transfer (LET) were evaluated. The obtained results would contribute to the data base that is needed for the improvement of numerical algorithms for the simulations of the treatment planning procedures. Material and Methods: The in vitro experiments were performed using the human HTB140 melanoma cells and the non-small lung cancer cell line CRL5876. Exponentially growing cells were irradiated with the 62 MeV/u protons and carbon ions at the dose levels of 2, 4, 8, 12 and 16 Gy. The irradiations with protons were carried out at positions along the therapeutic spreadout Bragg peak (SOBP), while those with 12C ions on the proximal part of the Bragg peak. In this way a variety of LET values was provided. For the precise positioning of the cell samples along the Bragg curves a specially designed device was used. Additional dosimetry control was done by GafChromic HS films. Cell survival was evaluated by the clonogenic assay and proliferation capacity was estimated by the colorimetric assays. Fluorescence activated cell sorting analysis were used to investigate cell cycle redistribution and the induction of apoptosis. All assays were performed 7 days after irradiation. Results: The best fit survival curves were obtained by fitting the dose dependent experimental survival data to the linear–quadratic equation. For the HTB140 cells surviving fraction for γ-rays at 2 Gy (SF2) was 0.93. Along the proton SOBP SF2 ranged from 0.88 at the entrance, through 0.86 and 0.81 in the middle and at the end of SOBP, reaching 0.59 at the distal declining end