56 RELATIVE BIOLOGICAL EFFECTIVENESS OF PROTON CLUSTERS – A THEORETICAL FRAMEWORK

S19 A preliminary retrospective study involving 209 kVCBCT guided fractions based on 14 pancreatic patients treated in our department showed that the detected patient setup shifts can be accurately modeled as a Gaussian with mean of 0.14cm, 0.02cm, 0.06cm and standard deviation of 0.28cm, 0.38cm, and 0.37cm in the lateral, anterior/posterior and superior/inferior directions respectively. Such shifts, although corrected prior to “beam on” only represent a “snap shot” of the patient geometry without regards to possible deviations during beam on. For some patients, one or more kV-CBCT images may be acquired intermittently between beams for verification purposes which although beneficial will impart additional dose to the patient. Complementing kV-CBCT with ultrasound (US) for soft tissue target radiotherapy such as pancreas is attractive for several reasons; US is inexpensive, nonionizing, has high soft tissue contrast and high temporal resolution suitable for real-time monitoring. Technical challenges in the future implementation of the proposed dual modality approach must be addressed prior to clinical application. Our intent is to plan and treat the patient with the US probe in position. Our study focuses on the requisite reproducibility of the probe induced deformations from simulation to the treatment room. Materials and Methods: Two deformable gel phantoms with slight difference in compressibility were employed to quantify the reproducibility of US probe induced deformations. Twelve PMMA bb’s with diameters of 1.2mm, 2.8mm and 3.2mm, respectively were imbedded into each gel phantom as fiducial markers. Our approach is to employ robot assisted probe placement to overcome the general concern of userdependent US imaging and the associated variable deformation. A passive prototype robotic arm was assembled to hold the US probe for the purposes of our phantom experiments. The desired orientation of the robotic arm was determined by the location of the probe that resulted in the best quality US image. The robotic arm and probe were then locked into this position. A linear actuator was then used to move the probe such that repeatable pressure could be applied against the phantom in 1D. As the presence of a clinical US probe would result in image artifacts in both CT and kV-CBCT, a model hollow probe with identical physical dimensions as the clinical US probe was constructed from water equivalent material. The model probe produced artifact-free CT images. Planning CT and treatment CBCT imaging studies were performed to determine if the deformations generated by either clinical or model probes were similar under the same applied pressure to the phantom. Thus our experimental setup was to quantify: (1) Phantom deformation using the model versus clinical probe; (2) Intra- and inter-fraction reproducibility of the phantom deformation via repeat scans; (3) Reproducibility of the deformation from CT simulation to treatment setup as verified by CBCT. Results: All twelve bb’s were identified on each CT and CBCT images with the model probe in place. Only nine bb’s were identified when the model probe was replaced by the clinical probe due to image artifacts. The deformations induced by the model and clinical probe were similar with an average difference of 0.2 ± 0.2mm quantified in 3D. Intra- and interreproducibility, quantified as the maximum deviation

ICTR-PHE 2012 in each bb position between repeat scans was observed as 0.4mm, 0.4mm and 1mm in the X (left/right), Y (anterior/posterior) and Z (superior/inferior) axes respectively for intra-reproducibility and 0.3mm, 0.7mm and 1mm for inter-reproducibility. The large maximum z deviation was due to the slice resolution of the CT scan. Finally, similar deformation of the gel phantom was observed in the planning CT and the CBCT acquired in the treatment position. The average 3D deviation was 0.35 ± 0.24mm. Conclusions: Our feasibility study demonstrates the reproducibility of intra- and inter-fraction deformations to within sub-millimeter. The comparable deformation observed between the model and the clinical US probe indicates that the model probe can be used to acquire artifact-free CT images for treatment planning and initial treatment setup, to be replaced with the clinical probe for continuous real-time IGRT. Overall, the integrated CT and robot assisted US system provides an inexpensive, non-ionizing, non-invasive approach for IGRT of soft tissue targets. Preparation of an IRB approved study is on-going to validate the efficacy of this system for target localization in pancreatic patients with implanted fiducial marker as surrogates for x-ray image based IGRT. 56 RELATIVE BIOLOGICAL EFFECTIVENESS OF PROTON CLUSTERS - A THEORETICAL FRAMEWORK, E. Fourkal, I. Veltchev Fox Chase Cancer Centre, Philadelphia, USA Purpose: To develop the theoretical framework for the increased LET of proton clusters and to explain the recently measured elevated RBE value of laseraccelerated protons. When protons are generated in a laser-plasma interaction the initial inter-particle distances are small enough in order to facilitate the observation of the effects of proton clustering. Methods: Applying the dynamic linear response theory we investigate the increased LET of a group of closely separated protons and find how the experimentally obtained RBE(LET) curves are modified as a result. Analysis of the dependence of RBE on residual range of closely separated protons offers insight into the increased RBE of the whole cluster. Results: The theoretical model suggests that the LET of a cluster of protons depends on the velocity and interparticle distance through an interference term. Closely separated fast particles exhibit larger deviation from the well known stopping power of a single proton. The residual range of particles with elevated RBE is therefore extended, offering explanation of the recent experimental observations. When the inter particle distance is 0.5 microns and the velocity of the cluster is 0.1c, the traveling range of protons with RBE=1.25 is extended such that 30% more cells are being damaged. Based on the theoretical predictions of this study we suggest modified experiment in which the RBE increase due to proton clustering will be better observed. Conclusion: In this study the experimentally observed enhanced RBE of laser accelerated protons is explained in terms of proton clustering. Closely separated projectiles (cluster of protons) experience modified LET dependence on velocity and as a result travel longer distances with an elevated RBE as compared to single

S20 protons. Proton clustering is an efficient way of increasing the RBE of protons and can be explored in the future clinical applications of laser-particle accelerators. 58 DIFFERENCES IN METABOLISM BETWEEN ADENOAND SQUAMOUS CELL NON-SMALL CELL LUNG CARCINOMAS ACCORDING TO GLUT1 AND MCT4 EXPRESSION T.W.H. Meijer1, O.C.J. Schuurbiers2, M.G. LooijenSalamon3, P.N. Span1, J. Bussink1 Departments of 1Radiation Oncology, 2Pulmonary Diseases, 3Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Purpose/Objective: Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. Material and Methods: GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. Results: Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032). Conclusions: Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation. 59 FKBPL AND PEPTIDE DERIVATIVES FOR ANGIOGENESIS INHIBITION A. Valentine1, M. O’Rourke1, A. Yakkundi1, G. Cotton2, T. Harrison2, I. James2, T. Robson1 1 School of Pharmacy, Queen’s University Belfast, BT9 7BL, UK; 2 Almac Discovery, 20 Seagoe Industrial Estate,

ICTR-PHE 2012 Craigavon, BT63 5QD, UK. Anti-angiogenic therapies can be an important adjunct to the management of many malignancies. However, responses have been modest and evasive resistance has been observed clinically with the VEGF-targeted agents. Here we present evidence that a novel, secreted anti-angiogenic protein (FKBPL), similar to FK506 binding proteins, inhibits endothelial cell migration, tubule formation and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s antiangiogenic activity was identified and a 24 amino acid peptide (AD-01) spanning this sequence was synthesised. It was potently anti-angiogenic and strongly inhibited human tumor xenograft growth when administered systemically, either on its own, or in combination with docetaxel. The anti-angiogenic activity of FKBPL and AD-01 is dependent on the cell surface receptor CD44 and signalling downstream of this receptor promoted an anti-migratory phenotype. Thus, these agents offer the potential of an attractive new approach to anti-angiogenic therapy. 60 PHYSICAL ACTIVITY AND THE RISK OF ACUTE COMPLICATION IN BREAST CANCER PATIENTS RECEIVING ADJUVANT RADIOTHERAPY FOR BREAST-CONSERVING SURGERY. A. Saito, S. Kyogoku, K. Sasai Juntendo University, Tokyo, Japan Purpose/Objectives: Exercise is known to optimize recovery in cancer survivors following completions of primary cytotoxic therapy. Moreover the hormetic effects of exercise training have previously been shown to enhance cellular protection against oxidative stress. Recently animal experiences showed that exercise training attenuate the harmful effects of radiation induced by oxidative stress. We conducted a study investigating the radio-protective effect of exercise for skin toxicity in our breast cancer patients. Material and Methods: From January 2009 to September 2011, 201 breast cancer patients who underwent adjuvant radiotherapy for breastconserving surgery at our institution were included in this study. To make the patients population as homogeneous as possible, we excluded all the patients who underwent additional regional lymph node irradiation. Patients were asked to fill out a questionnaire. The questionnaire consisted of 2 parts; questionnaire regarding exercise status during the radiotherapy period, and questionnaire for the Hospital Anxiety and Depression Scale (HAD). To prevent bias caused from the questionnaire itself, it was done on the last day of treatment. The patients were divided into 2 groups regarding their frequency and duration time of exercise. To be included in the exercise group (Ex) the duration time of each exercise had to be at least 20 minutes and the frequency had to be at least 2 times a week. We investigated if there was any correlation between exercise status and the following entry; acute skin toxicity (grade 1< or not) and HAD (anxiety and depression). Result: Out of the 256 patients who underwent adjuvant radiotherapy in our institution, 219 met the eligibility criteria. Among these 201 patients agreed to answer the questionnaire. Three patients had to be