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and subcutaneous xenograft models; and shows marked radiosensitisation in tumour regrowth delay experiments. This work has led to the establishment of a proof-of- principle, window of opportunity clinical trial in non- small cell lung cancer patients. This study will utilise functional imaging data, along with putative circulating and tissue markers of hypoxia to assess whether standard clinical doses of atovaquone are able to reduce tumour hypoxia. 2) Buparlisib (BKM120), a highly specific pan class-1 PI3K inhibitor, has been shown to reduce tumour hypoxia in vivo, due to a reduction in OCR, as well as by ‘vascular normalisation’. A window-of-opportunity study combining Buparlisib with palliative thoracic radiotherapy has recently been completed. 18 F-Misonidazole PET-CT scans were obtained pre- and post Buparlisib treatment to assess whether this drug is able to reduce hypoxia in non- small cell lung cancer patients. An outline of this imaging data will be presented. SP-0339 Targeting hypoxia with DNA repair inhibitors R. Syljuasen 1 1 Norwegian Radium Hospital/ Oslo University Hospital, Department of Radiation Biology- Institute for Cancer ResearchSyljuåsen, Oslo, Norway Abstract text Tumor hypoxia represents a major obstacle to radiotherapy due to the oxygen effect. On the other hand, hypoxia is a tumor specific feature that may be exploited to achieve tumor selective treatment. Here, I will review how inhibitors of DNA repair and DNA damage signaling may selectively kill hypoxic cells, sparing the surrounding normal tissue. For example, hypoxia-induced replication stress or hypoxia-mediated downregulation of DNA repair proteins can cause increased effects of such inhibitors. Secondly, I will focus on our previous and new results with inhibitors of the ATR, Chk1 and Wee1 checkpoint kinases (VE822, AZD6738, MK1775, AZD7762, UCN01). These results show either similar or increased effects of these inhibitors in cancer cells grown at hypoxic compared to normoxic conditions. SP-0340 Model-based clinical validation of proton therapy in head and neck cancer. A. Lin 1 , J.C. Rwigema 2 , J. Langendijk 3 , J. Lukens 1 , S. Swisher-McClure 1 , J. Langendijk 3 1 University of Pennsylvania, Radiation Oncology, Philadelphia, USA 2 Mayo Clinic- Scottsdale, Radiation Oncology, Scottsdale, USA 3 University Medical Centre- Groningen, Radiation Oncology, Groningen, The Netherlands Many patients with head and neck cancer are cured after undergoing definitive multimodality therapy. Despite technological advances and improvements in radiotherapy delivery, many of these patients experience severe or permanent toxicity that negatively impacts quality of life. Single-institution data have suggested advantages of proton beam therapy (PBT) over intensity- modulated radiotherapy (IMRT), and randomized trials are ongoing to provide level I evidence establishing the clinical benefit of PBT. However, performing comparative randomized trials for new technology is increasingly challenging in part due to limited resources, high cost, and difficulties with patient accrual. Therefore, alternative comparative approaches have been proposed Abstract text Purpose Symposium: Proton therapy in head and neck cancer: patient selection, validation and future directions

to allow appropriate guidance in treatment selection, based on modeling clinical outcome in different patients. A model-based strategy may be a cost-effective strategy to quantify clinical gains with PBT via estimation of potential reduction normal tissue complication probability (NTCP). Such an approach may be optimal in informing patient eligibility for a chosen therapy to enhance clinical outcomes and cost efficiency. The subject of this presentation is to present and discuss a clinical validation of a multivariable NTCP model in patients treated for oropharynx cancer with PBT, and to compare outcomes against similarly-treated patients with IMRT. We also will present and discuss the possible implications of such findings, and how it may inform patient selection and prospective studies as it relates to proton therapy. Methods This study was a joint collaboration between 2 institutions (University Medical Centre of Groningen and the University of Pennsylvania), limited to patients with advanced-stage oropharynx cancer treated with curative intent (PBT, n=30; IMRT, n=175). NTCP models were developed using multivariable logistic regression analysis with backward selection. In the PBT treated patients, an alternative IMRT plan was also made, to serve as a reference to determine the benefit of PBT in terms of NTCP. The models were then applied to the PBT treated patients to compare predicted and observed clinical outcomes. Five, clinically-relevant, binary endpoints were analyzed at 6 months post-treatment: dysphagia ≥ grade 2, dysphagia ≥ grade 3, xerostomia ≥ grade 2, salivary duct inflammation ≥ grade 2, and feeding tube dependence. Corresponding toxicity grading was based on CTCAEv4. Paired t-tests and Wilcoxon rank tests were used to compare mean NTCP results for endpoints between PBT and IMRT. Results The NTCP models developed based on outcomes from all patients were applied to those receiving PBT. For patients receiving PBT, no significant differences were observed between the expected and observed prevalences. In addition, the NTCP-values were calculated for the alternative IMRT plans for all PBT treated patients, revealing significantly higher NTCP- values for the IMRT plans. PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6 months post treatment, with the largest absolute differences in rates of > grade 2 dysphagia and xerostomia. Conclusion At 6-month follow-up, this model-based approach demonstrates significant improvements in treatment- related toxicity with PBT compared to IMRT for oropharyngeal cancer. This study demonstrates the value of NTCP model based approaches in comparing predicted patient outcomes when randomized data are not available. This study also brings up questions on whether randomized data is necessary, and if so, how such a model-based approach could be incorporated into prospective trials. SP-0341 Advanced selection procedures for proton therapy in head and neck cancer patients. D. Scandurra 1 1 UMCG, Radiation Oncology, Groningen, The Netherlands Abstract text In the Netherlands, head and neck cancer is not a standard indication for proton therapy referral; there must first be a demonstrable benefit compared to photon therapy. This benefit can consist of: an expected reduction in treatment-related side-effects as determined by published and validated normal tissue complication probability (NTCP) models, and/or an increased target dose or coverage due to limitations