ESTRO 36 Abstract Book

S212 ESTRO 36 _______________________________________________________________________________________________

lesion compared to other cancers for observation and tissue access, and because radiotherapy (RT) has provided a dominant approach as a primary treatment for these lesions. Current principles are governed by strong observational studies that described outcomes determined by overall treatment time in addition to RT dose and fractionation, and the hazard associated with accelerated proliferation. Subsequently clinical trials and their combination in individual patient meta-analyses confirmed these principles (e.g. MARCH, 2006). At the same time the same investigators have shown an added benefit to addition of concurrent chemotherapy (CTx) compared to standard fractionated RT alone (MACH-NC 2000, 2009). In essence, the combination of RT with CTx needs to be considered in unison, since outcomes today are frequently immutably linked to the application of both approaches. Following these studies significant evolution in a variety of areas has taken place. These include the emergence of HPV-related disease on the one hand and a developing significant sub-population of elderly patients who may be unable to tolerate intensive treatments used for younger patients and whose biology may differ. In addition, new treatment approaches have emerged as well, including potential combination of systemic agents with altered RT fractionation (where increased efficacy appears to be present), use of induction CTx, the use of biotherapies, the introduction of trans-oral surgical approaches (including robotic approaches that may also require additional application of adjuvant RT) and the nascent introduction of immunotherapy. For these reasons, while the focus of this talk is on radiobiology, and predominantly in HPV-negative tumors, it remains necessary to address principles of combination with other agents and approaches. For example, exploration of biomarkers in the microenvironment of surgical wounds may influence outcome of post-surgical adjuvant RT +/- CTx. Understanding RT-CTx interaction requires an understanding of the principles of spatial cooperation, synergy, and independent cell kill, including ways to exploit biological phenomena, such as apoptosis, hypoxia, or directly enhancing the direct cell kill through influence on DNA repair or on double strand breakage. A sustained search for biomarkers of response to agents that may influence RT outcomes is ongoing as exemplified by ERCC1 in the case of Cisplatin and for hypoxia, the description of hypoxia gene signatures is undergoing validation in the context of prognostic and predictive impact and the pre- therapeutic value of identifying those who may benefit from hypoxic modification of RT. An additional adverse biological modifier of RT outcome is represented by smoking exposure which confers adverse survival outcome overall within a complicated matrix of activity including adverse influence on the host through additional co- morbidity, causation of the cancer that may be adversely effected as a function of the intensity of tobacco exposure, or may influence the response to RT in current smokers who continue to smoke during RT. Finally, beyond smoking, other tumor-host microenvironment interaction exists. The most significant interest in this area today is the emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) interaction in inhibiting anticancer T-cell immunity with the possibility of generating durable responses and extended overall survival using targeted therapy. Much interest has been generated for a range of possible HNC scenarios in the context of RT. Approaches under consideration include modification of RT volumes, RT and CTx interaction with immune check point inhibitors and application of these combinations in different risk subsets, and the continued search for ways to exploit the rare instance of RT induced immune-mediated systemic response, a phenomenon termed the ‘ abscopal effect’ . For the latter, local RT may induce regression of metastatic cancer at distant sites which have not been irradiated through induction of adaptive immune responses. This effect governs such

clinical trial questions as reduction of the intensity of treatment to regions that traditionally have been managed with conventional elective doses of RT or for the management of oligometastases. Also, elderly patients require novel approaches and there is considerable evidence that aging affects the immune system and anti- tumor response in the elderly, particularly through T cell function. Combining standard RT with immune modulation is an attractive strategy in the elderly due to their poorer anti-tumor T cell function and the favorable toxicity profile of emerging immunotherapy approaches. Trials addressing these approaches are currently in design. SP-0398 Novel developments in the radiobiology of HPV-positive head and neck tumours S. Nuyts 1 1 University Hospital Gasthuisberg, Leuven, Belgium Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that is often the result of tobacco and/or alcohol abuse or infection with high-risk Human papillomaviruses (HPV). Worldwide, an increase in HPV related oropharyngeal carcinoma’s is seen. Despite the fact that the HPV positive HNSCC form a distinct clinical entity with better treatment outcome, all HNSCC are currently treated uniformly with the same treatment modality. However, it is expected that the results of ongoing randomized studies will reshape radio- chemotherapy schedules for this tumour group. At present, biologic basis of these different outcomes and their therapeutic influence are an area of intense investigation. The radiobiological differences between HPV+ and HPV− head and neck tumours and resulting treatment possibilities will be discussed from the perspective of the 5 Rs. Over the last couple of years several hypotheses have been put forward correlating radiotherapy response to micro– environmental (immune system and hypoxia) and tumour intrinsic factors. It has been hypothesized that the immune system plays a more important role in clearance of HPV related HNSCC compared to HPV- HNSCC due to the expression of viral proteins. On the other hand the presence of high-titer serum antibodies to these viral proteins indicates the presence of immune tolerance and opportunities for immunotherapeutic approaches. One of the most studied environmental factors in relation to radiotherapy response is hypoxia, which is known to result in radiation resistance. Some studies suggest a possible influence of hypoxia in radiation sensitization in HPV+ HNSCC, whilst others suggest a more ambiguous role for tumour hypoxia. Moreover, factors influencing the intrinsic radiotherapy response such as the role of cancer stem cells, differences in DNA repair capacity and influence of HPV on cell cycle and cell death pathways will be discussed. In this presentation, we will thus summarize the molecular basis for different radiotherapy response based on HPV status, novel treatment opportunities and possible biomarkers for HPV positive HNSCC. OC-0399 Transcriptome analyses of the radiation response in HNSCC cells with different radiation sensitivity J. Heß 1,2 , A. Michna 1 , U. Schötz 2,3 , M. Selmansberger 1 , H. Zitzelsberger 1,2 , K. Unger 1,2 , K. Lauber 2,3 1 Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Research Unit Radiation Cytogenetics, Muenchen, Germany 2 Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer", Neuherberg, Germany 3 Ludwig-Maximilians-University, Department of