Novel approaches in the study of bladder cancer - Radiotherapy and

S109 ESTRO 36 _______________________________________________________________________________________________ medical physicists built a document management system that follows the patient process from university clinics to the Skandion Clinic. It contains all guiding and supporting documents, procedures and instructions. An essential experience acquired was that it is very important to write the required documents on so many procedures, guidelines and instructions as much as possible before the first patient treatment. Thus it was found that once the clinic was up and running with patient treatments, it was much easier to revise an existing procedure that to get time to write entirely new ones. Acceptance and measurement, education and training. It was decided early on that the RTT/nurses would work in team with the medical physicists on measurement and acceptance of IBA's equipment so there was at least one RTT/nurse during the daytime. Then we continued during the first half of the year with a medical physicist and a RTT/nurse to work together on the morning checks. The clinical training included the IBA Web training from UPenn in Philadelphia as well as study visits for two weeks in the proton clinic in Philadelphia. To this the IBA on site clinical training at the Skandion Clinic was added. We were given training on all new systems including trolley transport, CT scanning, journal system, fire and safety, CPR, etc. Another valuable experience was gathered from end-toend testing, when a mock patient went through all phases of the process from each university clinic to the Skandion Clinic and back. An empty House to a functioning clinic. RTT/nurses had responsibility for equipping the premises with all that may be needed in order to start up a functioning clinic. This included practically everything from staff clothing to consumables and medicines, the toys for the children and even the special requirements of the anesthesia personnel. In summary, it has been hard work, frustrating at times, but extremely educational and stimulating most of the time, and above all a fun time to start up a clinic. SP-0217 Workflow in a proton therapy department – real difference from photon therapy? F. Fellin1 1 Ospedale Santa Chiara di Trento, U.O. Protonterapia, Trento, Italy In Europe, there was a significantly increase in proton therapy (PT) facilities in the last few years. In PT, Radiation Therapy Technologists (RTTs) have a key role throughout the patient’s therapeutic course, such as in photon therapy. The physical characteristics of protons are an advantage for saving the organs at risk (OARs) and/or for increasing the dose to the target, but they imply some important criticalities during the patient workflow. Pencil Beam Scanning (PBS) is the most advanced technique for PT but this is the proton technique with more criticality. RTTs, should know these critical issues and be aware of the impact that they have in the patient workflow and in their working activities. RTTs are involved in several steps of the patient workflow in PT; in general, they are the same as in photon therapy: simulation CT, diagnostic imaging, treatment planning, delivery of therapy. However, in each single step, there are important differences compared to photon therapy. Starting from the simulation, the main differences relate to the choice of the immobilization devices, both for their purchase that for each specific patient, and the definition with tatoo of the treatment isocenter that, especially with PBS, it can be defined directly during the acquisition of simulation CT. In addition, since the dose delivery is very accurate, the definition of target volumes and OARs must be very strict. For this reason, the PT facilities are usually equipped with MR and PET-CT systems; RTTs must be able to use this equipment and to acquire the necessary images. In the treatment planning step, the Medical Dosimetrists

(MDs) work with the Medical Physicists in the plans optimization; they will use all the experience to get the best plan for each patient. In addition to all the attention that MDs must have during treatment planning, which are common in photon therapy, in PT there are other situations in which they must be careful. For example, it is very important to set the correct direction of the fields based on the tissues that the beams must pass through before reaching the target and it is recommended to avoid that all fields have the distal fall-off in the same area (in particular near OARs); it is important to limit the use of the range shifter and to select the most appropriate irradiation technique based on the specific case (SFO, MFO); MDs must know and evaluate all possible uncertainties (range, RBE, …); they must adopt robust optimization techniques and field specific PTV. Even for the delivery of therapy sessions, there are some important differences between photon and proton therapy. First, the equipment is quite different: RTTs must know in detail the PT equipment operation. Proton therapy equipment is much larger and more complex compared to photon therapy system. In PT, the patient setup is checked every day; generally, RTTs use flat panels with x-ray tubes system (for 2D images) or CBCT (for 3D images). In some facilities, a CT on-rails is installed in the treatment room and RTTs use this one for monitoring the patient position before the therapy. The advantage of CT on-rails is that, in principle, you can use the daily images for checking the dose distribution every day. In PT, tattoos performed during the simulation CT are important especially in the first treatment session. They are used to align the patient and move manually the treatment couch on the isocenter, for defined the setup position. Afterwards, RTTs capture the couch coordinate for setup position and, during subsequent sessions, the table will be aligned automatically. In all sessions except the first one, tattoos are important only in treatments with immobilization devices that are not perfectly indexed on the couch, e.g. in the case of treatments in pelvic area. RTTs must be very careful during the proton dose delivery with PBS. There isn’t a proper ratio between dose and monitor units delivered; the number of monitor units depend on the field size: the greater the size of the target, the greater the number of MU and the beam-on time. Given the precision of proton dose delivery, small anatomical changes can lead to important variations of dose distribution in the patient. For this reason, RTTs must observe and communicate any anatomical variations that they see during the patient setup. In this way, it is possible to perform any dosimetrical checks in the course of therapy. In these cases, it is very useful to have a CT onrails. In PT, RTTs will have to acquire a weekly control CT for treatments of areas prone to anatomical changes. It will be used by Physicists or MDs to perform dose assessments during the treatment and, if necessary, they will organize a replanning. These are some of the most significant differences observed in proton therapy compared to photon therapy; they change the work of RTTs in patient workflow. PT is an advanced, complex and precise radiation therapy technique and it requires very high skills for RTTs. Symposium with Proffered Papers: Combining tumour and normal tissue models SP-0218 Novel approaches in the study of bladder cancer A. Kiltie1 1 Oxford, United Kingdom, Patients with muscle-invasive bladder cancer can be treated by removal of their bladder (cystectomy) or by bladder preserving strategies, which include the use of

S110 ESTRO 36 _______________________________________________________________________________________________ radiotherapy and chemotherapeutic agents which act as radiosensitisers. In assessing the efficacy of drugs as radiosensitising agents, it is important to determine their effects on normal tissues as well as tumours. We have developed a modified crypt assay to assess acute toxicity on bowel surrounding the bladder in vivo. Furthermore, as murine small intestine is exquisitely sensitive to the doses of radiation used, we have developed an irradiation method which avoids the small intestine, using a small animal radiation research platform (SARRP), to assess late bowel toxicity associated with bladder cancer radiotherapy. Our methods should help identify those agents which may be suitable to take forward to clinical trials. SP-0219 Optimising the output of preclinical lung models to optimize the chances of succes into the clinic. E. Deutsch1 1 Institut Gustave Roussy, Villejuif, France Despite the numerous promising preclinical data, increasing the therapeutic efficacy of chest radiotherapy using novel drugs-radiotherapy combinations has often failed to show promise in the frame of clinical trials.In some cases, these novel approaches failed to increase the anti-tumor efficacy of standard radiotherapy suggesting that preclinical models were not appropriate enough to recapitulate the complexity and the most recent advances in our understanding of tumor biology (i.e. the spectrum of mutational events, the tumor/immune host interactions..). In other cases, new drugs- radiotherapy combinations induced severe toxicities that justified the discontinuation of clinical development plans. This underscores the fact that in many circumstances, preclinical models have been overlooking normal tissue response to radiotherapy. As an illustration of this, major monoclonal antibodies used in the clinic such as anti EGFr or anti VEGF were developed in the clinic on the basis of preclinical rationale that were not able to detect any impact on normal tissue response. Another reason for these limited effects is the fact that many preclinical experiments fail to associate and to combine with chemoradiation and use radiation alone as a comparator. The development of orthotopic, syngenic tumor models offers the opportunity to evaluate within the same series of experiments both the normal tissue and the tumor response. The rising interest in the field of immuno oncology is also increasing our need for such models since the immune / stromal component which is not only an emerging player during tumor response to radiotherapy. As an illustration of this, we will present data from our group underscoring the fact that modulating the immune stroma affects normal response of the normal lung to radiotherapy. We make the make the assumption that such models could be a mean to minimize the early discontinuation of new drugs radiotherapy clinical trials and eventually to increase the patients’ clinical benefit as the results of a better selection of novel therapeutic that would not impair, and if possible enhance, the tumor versus normal tissue clinical ratio. OC-0220 Exploiting novel combined-modality approaches for treatment of highly aggressive pancreas carcinomas M. Orth1, L. Posselt2, S. Kirchleitner2, J. Schuster1, C. Belka1, M. Schnurr2, K. Lauber1 1 LMU Munich, Department of Radiation Oncology, Munich, Germany 2 LMU Munich, Department of Clinical Pharmacology, Munich, Germany Purpose or Objective Pancreatic ductal adenocarcinoma (PDAC) is a cancer entity with growing prevalence and very poor prognosis.

The survival rates are limited to approximately 25% of patients after one year and only 5% after five years, respectively. Standard treatment encompasses surgical resection (if possible) accompanied by radiotherapy, chemotherapy and/or palliative care. However, treatment failure is frequent, and inherent resistance towards radioand/or chemotherapy is considered as one major reason. Accordingly, novel treatment approaches are needed, which can address this resistance and which are able to create synergisms with the classic therapy modalities. Material and Methods A panel of human PDAC cell lines was subjected to clonogenic survival assays, and scores of radioresistance were extracted by principal component analysis. Next, the relative expression levels of DNA damage response (DDR) genes were analyzed by qRT-PCR, and correlation analyses were employed in order to identify potential drivers of radioresistance. Specific inhibitors targeting the respective candidates were examined in terms of their potential to sensitize PDAC cell lines towards radiotherapy. The obtained results were confirmed by RNA interference. The clinical relevance of the identified target genes was evaluated in the TCGA PDAC data set. Finally, an orthotopic PDAC model with fractionated CTbased irradiation was established in order to evaluate the therapeutic potential of our approach in vivo. Results Using a cohort of nine human PDAC cell lines, we identified several crucial components of the DNA damage response (DDR) machinery to be upregulated in the radioresistant cell lines, including ATM and DNA-PKcs. The impact of both kinases on clonogenicity was examined both by pharmacological inhibition and RNA interference. We found that inhibition and siRNA-mediated knockdown of DNA-PKcs significantly diminished the clonogenic potential of radioresistant PDAC cell lines. Using the TCGA PDAC collective, we found that expression of DNA-PKcs is elevated in about 11% of all samples and that this upregulation is associated with a striking decrease in overall survival. Currently, the in vivo efficacy of DNAPKcs inhibition in combination with fractionated radiotherapy is tested in an orthotopic mouse PDAC model. Conclusion The poor prognosis of pancreatic ductal adenocarcinoma urgently demands for the development of novel treatment approaches. We show that pharmacological inhibition of the DDR-related kinase DNA-PKcs gives rise to a novel, highly promising treatment approach which should be further explored in the future. OC-0221 High-performance radiosensitivity assay to predict post radiation overreactions G. Vogin1, L. Bodgi2, A. Canet2, S. Pereira2, J. GilletDaubin2, N. Foray3 1 Institut de Cancérologie de Lorraine & UMR 7365 CNRSUL, Academic Department of Radiation Oncology, VANDOEUVRE-LES-NANCY Cedex, France 2 Neolys Diagnostics, R&D, Lyon, France 3 Cancer Center of Lyon- UMR Inserm 1052 CNRS 5286 CLB, Radiobiology, Lyon, France Purpose or Objective Between 5 and 15% of patients treated with r adiation experience toxicity considered "unusual" that can lead to serious sequelae. Identifying those patients prior treatment would therefore have sound positive clinical implications. Retrospective analysis on skin biopsies from patients treated by radiotherapy to define a radiobiological parameter with the highest predictive performance that can be used as a reliable predictor of post-treatment toxicity. Material and Methods Immunofluorescence experiments were performed on the COPERNIC collection of 116 skin fibroblasts irradiated at 2