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Radiotherapy &Oncology Journal of the European SocieTy for Radiotherapy and Oncology Journal of the European SocieTy for Radiotherapy and Oncology

Volume 132 Supplement 1 (2019) olu e 132 Supple e t 1 (2019)

7th ICHNO International Congress on innovative approaches in Head and Neck Oncology Radiotherapy &Oncology Journal of the European SocieTy for Radiotherapy and Oncology Radiotherapy & Oncology is available online: For ESTRO e bers: http://www.thegreenjournal.co For institutional libraries: http://www.sciencedirect.co 14–16 March 2019 Barcelona, Spain Radiotherapy & Oncology is available online: For ESTRO members: http://www.thegreenjournal.com For institutional libraries: http://www.sciencedirect.com

Volume 132 Supplement 1 (2019)

Radiotherapy & Oncology is available online: For ESTRO members: http://www.thegreenjournal.com For institutional libraries: http://www.sciencedirect.com

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7TH ICHNO CONTENT

THURSDAY 14 MARCH 2019 Keynote lecture

New insights into the molecular landscape of Head and Neck cancer.............................................Abs. 1 New insights into the immune landscape of Head and Neck cancer ...............................................Abs. 2 Debate This house believes that radiomics will not change clinical practice. .......................................... Abs. 3-4 Proffered papers Proffered papers 1........................................................................................................... Abs. 5-10 Late breaking news Late breaking news ........................................................................................................ Abs. 11-12 Keynote lecture TNM8 :How has the dust settled one year later? ......................................................................Abs. 13 Symposium 1 Immuno-oncology . ........................................................................................................ Abs. 14-16 SNUC: a sustainable concept? ..............................................................................................Abs. 17 Pushing the limits in Head and Neck robotic surgery ................................................................Abs. 18 Proffered papers Proffered papers 2......................................................................................................... Abs. 19-24 Symposium 2 New developments in radiation therapy. ........................................................................... Abs. 25-28 Interactive tumour board session Oropharynx Poster discussion Poster discussion ........................................................................................................... Abs. 29-32 Symposium 3 New techniques in surgery .............................................................................................. Abs. 33-35 SATURDAY 16 MARS 2019 Keynote lecture Integration of imaging and radiotherapy innovation: Head and Neck radiotherapy applications ...... Abs. 36 Symposium 4 How to improve survivorship? .......................................................................................... Abs. 37-39 Proffered papers Proffered papers 3 ......................................................................................................... Abs. 40-45 Debate This house believes that immunotherapy is going to replace chemotherapy .................................... Abs. 46-47 Conference remarks Concluding remarks Posters Multidisciplinary management . ........................................................................................ Abs. 48-85 Innovative treatments .................................................................................................. Abs. 86-100 Biology, HPV and molecular targeting . ...........................................................................Abs. 101-112 Imaging and radiomics ................................................................................................Abs. 113-131 Supportive care, quality of life, rehabilitation ..................................................................Abs. 132-149 Minimal invasive and reconstructive surgery ......................................................................... Abs. 150 Epidemiology and prevention . ......................................................................................Abs. 151-158 Salivary gland, skull base, skin and thyroid cancers .........................................................Abs. 159-173 Special requirements for elderly patients . ......................................................................Abs. 174-178 Immunodiagnosis and immunotherapy ...........................................................................Abs. 179-184 FRIDAY 15 MARCH 2019 Keynote lecture

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vivo T cell suppression assays, we identified a particular subset of MDSC with high suppressive activity. A high frequency of this subset in the peripheral blood was associated with poor survival. Finally, we employed whole mount staining of surgical specimens, followed by ultramicroscopy and 3-D reconstruction to unravel the true three-dimensional “landscape” of the tumor immune microenvironment. Using this technology, we decoded the functional interaction of tumor-associated neutrophils with T cells in situ. We identified intratumoral hot spots of interaction, which had prognostic relevance. Our data provide a rationale for the co-targeting of myeloid cells and T cells in HNC immunocombination therapy.

Keynote lecture: Keynote lecture 1: New insights into the molecular landscape of Head and Neck cancer SP-001 New insights into the molecular landscape of Head and Neck cancer R. Brakenhoff 1 1 Vu University Medical Center, Otolaryngology-Head and Neck Surgery- tumor biology section- Cancer Center Amsterdam, Amsterdam, The Netherlands Abstract text Head and neck squamous cell carcinomas (HNSCC) develop in the mucosal lining of the upper aerodigestive tract. Despite the fact that the disease develops in a single tissue in a relatively small anatomical region, it is remarkably heterogeneous. At present two separate disease entities are distinguished: HNSCCs caused by human papillomavirus (HPV) infection and those that do not contain HPV. However, large scale genomics research have revealed additional levels of heterogeneity between tumors in head and neck cancer that are gradually changing the molecular landscape. Implementation of these molecular insights in clinical care is hampered at present by small sample size of the studies, differences in technical platforms exploited, variation in tumor-stroma composition of the analysed specimen, and the computational approaches applied. However even with the newest single cell techniques these molecular tumor classifications can be repeated and seem robust. These developments demand adaptation of the classical genetic progression models that initially determined the concepts of carcinogenesis. They do provide an opportunity for better stratification of patients for prognosis and personalized treatment approaches. Although the high-throughput genomics of head and neck cancer revealed these intriguing new insights, these studies did not provide a wide array of novel therapeutic leads. Head and neck cancer is a disease of tumor suppressor gene inactivation, and particularly cell cycle control is frequently abrogated. Also beta-catenin signalling appears to play a role but not according to the classical Wnt pathway. More detailed research of these genes and pathways as well as their role in carcinogenesis, together with functional genetic screens using RNA interference and CRISPR genome editing will reveal the new promising therapeutic leads that are so urgently awaited. SP-002 Immune landscape in Head and Neck cancer S. Brandau 1 1 Universitätsklinikum Essen, HNO-Klinik, Essen, Germany Abstract text Patients with progressing head and neck cancer (HNC) experience significant changes in circulating immune cells. In addition, most HNC tissues are heavily infiltrated by distinct subsets of immune cells, which influence tumor biology and disease progression. We have investigated the immunobiology of this disease with a focus on the interaction of myeloid cells and T cells. We found distinct alterations in circulating myeloid-derived suppressor cells (MDSC) and T cells in patients with HPV-negative versus HPV-positive tumors. Based on multi-color FACS and ex Keynote lecture: Keynote lecture 2: New insights into the immune landscape of Head and Neck cancer

Debate: Debate 1: This house believes that radiomics will not change clinical practice

SP-003 For the motion V. Gregoire 1 1 Centre Léon Bérard, Radiation Oncology, Lyon, France SP-004 Against the motion P. Lambin 1 1 MaastrichtUniversity, Radiation Oncology|The D-Lab, Maastricht, The Neterlands

Proffered papers 1

OC-005 Preoperative vs. postoperative radiotherapy in treatment of oral cavity cancer – The ARTSCAN 2 study C. Kristin 1 , Z. Björn 2 , N. Per 3 , K. Elisabeth 4 , B. Eva 4 , S. Karin 2 , R. Johan 5 , K. Stefan 6 , G. Maria 4 , S. Johanna 1 , J. Wennerberg 1 1 Lund University Hospital, ORL/H&N Surgery, Lund, Sweden; 2 Umeå Universitetssjukhus, Oncology, Umeå, Sweden; 3 Lund University Hospital, Radiation Physics, Lund, Sweden; 4 Lund University Hospital, Oncology, Lund, Sweden; 5 Örebro University Hospital, Oncology, Örebro, Sweden; 6 Örebro University Hospital, ORL/Head and Neck Surgery, Örebro, Sweden Purpose or Objective A longstanding controversy in the combined modality treatment of resectable squamous cell carcinoma of the oral cavity is the timing of radiotherapy (RT); before or after surgery? Very limited clinical data are at hand and there is not enough evidence to conclude any advantage of either of the two methods regarding tumour-control and side-effects. In the previous ARTSCAN trial, patients with resectable oral cancers treated with 68 Gy accelerated fractionation (AF) RT preoperatively showed a strong trend towards better outcome than patients given preoperative conventional fractionation, (CF) RT. To further investigate this preoperative AF was compared with the ‘’gold standard”, post operative CF RT, in a randomized controlled trial, ARTSCAN 2. This trial aimed both to investigate the earlier finding of superior tumour-response to AF RT vs CF RT and to challenge the question of pre- vs. postoperative RT. The study was performed on behalf of the ARTSCAN-study Group.

Debate: Debate 1: This house believes that radiomics will not change clinical practice

Proffered papers 1

7th ICHNO 7 th ICHNO Conference International Conference on innovative approaches in Head and Neck Oncology 14 – 16 March 2019 Barcelona, Spain __________________________________________________________________________________________ page 7

international guidelines (CTVn-IG). A radical identical dose was prescribed to the primary tumor. Both real and virtual treatments were calculated with RapidArc software by Varian®. Dosimetric data to the different organs-at-risk (OAR) were compared between the two plans. Response was evaluated at 3 months by PET/CT. Follow-up neck CT scans were performed at 6, 12, 18 and 24 months. Results Lymphatic migration was observed in all of the 44 patients. Four patients (9%) presented a unpredicted lymphatic drainage and 21 patients (48%) had only a unilateral drainage. The volumes of CTVn-LS and PTVn-LS (median volumes of 91.8 cc and 219.1 cc, respectively) were systematically smaller than CTVn-LS and PTVn-IG (median volumes of 188.3 cc and 405.3 cc, respectively). This led to a significant dose decrease in identified OAR, particularly to the controlateral parotid gland, controlateral submandibular gland, inferior constrictor muscle for oral/oropharynx tumors and superior constrictor muscle for larynx/hypopharynx tumors (Table 1). At a median follow-up of 42 months, 3 patients experienced a regional relapse: 2 in an irradiated area (4.5%) and 1 in a non-irradiated area (2.3%). Currently, 4 patients had a local reccurence and 6 patients died (2 patients from geriatric degradation and 4 patients experienced fatal local relapse).

Material and Methods ARTSCAN 2, an open multicentre randomised controlled comparative phase III study aimed to evaluate loco- regional tumour control (LRC), overall survival (OS) and QoL in patients with oral cancer with combined modality treatment, started to enroll 2007. Patients were randomized 1:1 between the two trial arms: AF RT (68 Gy in 4.5 weeks) prior to surgery vs. surgical resection followed by CF RT (60 Gy to histopathological low risk patients and 66 Gy+ weekly cisplatin to high risk patients). Results A total of 250 patients were randomized, whereof 240 were eligible for analysis; 120 in each arm. Median follow up was 4.7 years. LRC at two years was 83% for preop. AF RT and 79% for postop. CF RT (p=0.80; logrank). OS at 2 years was 73 % for preop AF RT and 78 % for post op CF RT (p=0.12; logrank). Asexpected acute mucosal side-effects were more pronounced in patients with preop AF RT compared to patients treated with postop CF RT. Late side-effects were slightly worse for some QoL parameters in patients treated with preoperative AF RT. Conclusion This study does not support that preop AF improves outcome in oral cavity cancer compared with the ”gold standard”, postoperative CF RT. The intense treatment schedule and the higher dose increased the severity of acute and possibly late side effects. In the choice between treatment options not only survival, but also QoL and health economics must be considered. OC-006 Individualized prophylactic irradiation based on sentinel lymph node(s) identification in cN0 HNSCC E. Longton 1 , G. Lawson 2 , B. Bihin 3 , S. Deheneffe 1 , I. Mathieu 4 , F. Hanin 4 , T. Vander Borght 5 , M. Laloux 6 , J. Daisne 1 1 CHU UCL Namur-site Sainte-Elisabeth, Radiation oncology, Namur, Belgium; 2 CHU UCL Namur- site Godinne-, Head and Neck Surgery, Yvoir, Belgium; 3 Namur Research Institute for Life Sciences Narilis, Unit of Biostatistics, Namur, Belgium; 4 CHU UCL Namur- site Sainte-Elisabeth, Nuclear Medicine, Namur,Belgium; 5 CHU UCL Namur- site Godinne-, Nuclear medicine, Yvoir, Belgium; 6 CHU UCL Namur- site Sainte- Elisabeth, Maxillofacial Surgery, Namur, Belgium Purpose or Objective Due to a risk of occult nodal metastases in clinically node- negative (CN0) head and neck squamous cell carcinoma (HNSCC) patients, prophylactic and often bilateral neck irradiation is mandatory. However, it leads to a large irradiation of healthy tissue and could miss unexpected nodal basins drained by the tumor. This prospective, non- randomized, interventional phase II study investigated how sentinel lymph node (SLN) mapping by SPECT/CT may help to individualize prophylactic neck irradiation and its potential impact on radiation-related toxicities and tumor control. The final results are presented. Material and Methods Forty-four patients with newly diagnosed cN0 squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx were included and treated with upfront (chemo)radiotherapy with a curative intent. After simulation, all patients were imaged in treatment position with SPECT/CT after 99m Tc nanocolloid injection around the tumor. The neck levels containing up to four hottest SLN were selected for prophylactic irradiation (CTVn-LS). A comparative virtual planning was performed by including the levels selected on the basis of the current

Conclusion SLN mapping using SPECT/CT allowed to significantly reduce the prophylactically irradiated neck volumes in cN0 HNSCC patients. This resulted in a significant dose decrease in OAR, especially in patients presenting a unilateral lymphatic drainage, while uncompromising the oncological outcome. OC-007 Radiologic extranodal extension portends worse outcome in TNM-8 cT1-T2N1 HPV+ oropharyngeal cancer S.H.S.Huang 1 , E. Yu 2 , A. Billfalk-Kelly 3 , J. Su 4 , J. Waldron 3 , E. Bartlett 2 , A. Bayley 3 , S. Bratman 3 , J. Cho 3 , M. Giuliani 3 , A. Hope 3 , A. Hosni 3 , J. Kim 3 , J. Ringash 3 , A. Hansen 5 , J. De Almeida 6 , L. Tong 3 , W. Xu 4 , B. O'Sullivan 3 1 Princess Margaret Cancer Centre, 2B-Radiation Therapy, Toronto, Canada; 2 Princess Margaret Cancer Centre, Department of Medical Imaging, Toronto, Canada; 3 Princess Margaret Cancer Centre, Department of Radiation Oncology, Toronto, Canada; 4 Princess Margaret

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OC-008 Fast tumor regression detected by weekly MRI allows for adaptive (chemo) radiation for Head and Neck cancer C.Terhaard 1 , B. Peltenburg 1 , R. De Bree 2 , N. Raaijmakers 1 , J.W. Dankbaar 3 , F. Pameijer 4 , M. Philippens 1 1 UMC Utrecht, Radiation Oncology Department, Utrecht, The Netherlands; 2 UMC Utrecht, Department of Head and Neck surgical Oncology, Utrecht, The Netherlands; 3 UMC Utrecht, Radiology Department, Utrecht, The Netherlands; 4 UMC Utrecht, Radiology Department, Utrecht, The Netherlands Purpose or Objective The effect of (chemo)radiotherapy on head and neck squamous cell carcinoma can be visualized using MRI. Adaptation of radiotherapy treatment plans might be possible based on changes in tumor volume during treatment, using MRI guided treatment. Furthermore, different patterns of volume changes might be an indicator of radiosensitivity and could possibly predict treatment failure. Therefore the objective of this study is to follow treatment response with T2 weighted images of head and neck cancer and to adapt based on this tumor regression. Material and Methods Twenty patients with stage II, III or IV oropharyngeal, laryngeal or hypopharyngeal squamous cell carcinoma were included. Two patients had HPV positive tumors. Treatment consisted of radiotherapy, with or without concurrent chemotherapy. All patients underwent MRI prior to and in week 2, 3, 4 and 5 of the radiotherapy treatment.Imaging was obtained with the patient positioned in the radiotherapy mask. Tumor delineation was performed on T2 weighted MR images with fat- suppression (mDIXON) for the baseline and each subsequent images. Relative volume changes compared to the baseline were determined. A follow up of at least 3 months was available for all patients. Results During (chemo)radiotherapy tumors generally reduced in size with each passing week. On average the tumors were only 50% of their original size at the end of the third week of treatment. At the end of the fifth week only on average 20% of the original tumor volume was visible on T2 weighted images (fig 1). In one patient, tumor visibly increased in size from the third week onward. This was the only patient with a local recurrence within 3 months after treatment (fig 2). However, in some cases, tumors were increasingly in time harder to differentiate from nonmalignant tissues in the treatment area. Fig 1. Change in tumor volume of all patients (black). Red line shows the average tumor change across all patients. Purple line identifies the patient with an increasing tumor volume starting in the third week and an eventual local recurrence. Fig 2. T2 weighted MRI images of the patient with a local recurrence within 3 months after treatment. The patient was diagnosed with a T4aN3bM0 hypopharyngeal carcinoma. A) Pretreament MRI with the tumor visible at the right side of the hypopharynx. B) Week 2 of radiotherapy. C) Week 3 of radiotherapy. D) Week 4 of radiotherapy. E) Week 5 of radiotherapy. F) T2 weighted MRI a time of local recurrence (3 months after radiotherapy).

Cancer Centre, Department of Biostatistics, Toronto, Canada; 5 Princess Margaret Cancer Centre, Division of Medical Oncology, Toronto, Canada; 6 Princess Margaret Cancer Centre, Otolaryngology - Head & Neck Surgery, Toronto, Canada Purpose or Objective The 8 th edition TNM (TNM-8) cT1-2N1 HPV+ oropharyngeal cancer (OPC) is generally considered early stage with excellent prognosis. This study aims to identify adverse radiologic nodal features that may portend poorer prognosis in a subset of this population. Material and Methods All TNM-8 cT1-T2N1 HPV+ OPC patients (pts) treated with definitive IMRT in 2008-2015 were included. Tumor HPV status was ascertained by p16 staining. Pre-IMRT CT/MR were reviewed by a designated head and neck radiologist blinded to treatment outcomes. Number and level of radiologically involved lymph node (LN), extranodal extension (rENE: LN with an unequivocal ‘ill-defined’ border), retropharyngeal LN (RPLN), and lower neck (Level 4 or 5b) LNs were recorded. Inter- and intra-rater (after 3-month interval) concordance for rENE were assessed in a randomly selected cohort (n=45). Disease-free survival (DFS), locoregional control (LRC), and distant control (DC) were compared between those with (rENE+) vs without (rENE–). Univariable (UVA) and multivariable analysis (MVA) with step-wise modal selection identified prognostic factors for DFS. Results We excluded 28/308 pts due to unavailable pre-IMRT CT/MR, leaving 280 eligible for analysis [rENE+: 45 (16%); rENE–: 235 (84%)]. The Kappa scores were 0.89 (95% CI: 0.74-1.00) for inter-rater and 0.82 (0.62-1.00) for intra- rater concordance on rENE. Both rENE+ and rENE– cohorts had similar distribution in age (p=0.88), gender (p=0.26), and T category (p=0.40), and presence of RPLN (p=0.07). Proportion of systemic agent usage was similar between rENE+ and rENE respectively (chemotherapy: 29 vs 136; EGFR inhibitor: 1 vs 29) (p=0.13). The rENE+ cohort had a higher number of LNs per pt [median: 6 (1-20) vs 2 (1-15), p<0.001] and was more likely to have necrotic LNs [33 (73%) vs 132 (56%), p=0.046]. Median follow-up was 4.8 years. Although LRC was high in both cohorts [93% (78-98) vs 97% (94-99), p=0.34], the rENE+ group had inferior 5- year DC [78% (59-88) vs 95% (91-97), p<0.001)] and DFS [58% (43-77) vs 90% (86-94), p<0.001]. MVA identified rENE+ as the strongest independent adverse prognostic factor for DFS [HR 4.3 (95% CI 2.3-8.1), p<0.001]. T2 (vs T1) category [HR 2.1 (1.0-4.2), p=0.039], smoking pack- years (continuous) [HR 1.02 (1.0-1.03), p=0.013], and addition of systemic agents [HR 0.4 (0.2-0.8), p=0.005] were also prognostic. RPLN, LN number (continuous), and lower neck LN were significant in UVA but not MVA. Conclusion Data from this contemporary TNM-8 cT1-T2N1 HPV+ OPC cohort suggests that the presence of rENE is associated with reduced DC and DFS, whereas the number of radiographically evident LNs is not an independent predictor for DFS. While these results are derived in a high- volume head and neck cancer centre, external validation in a more general setting is desirable before consideration of rENE inclusion in the refinement of future editions of the HPV+ OPC TNM stage classification.

Material and Methods Two-hundred and twenty-nine consecutive patients with locally recurrent head-and-neck cancer treated with CIR between 2010 and 2017 were analyzed retrospectively regarding progression free survival (PFS), overall survival (OS), pattern of failure and toxicity. Acute (initial 90 days after CIR) and late toxicity were assessed using NCI CTCAE v4.03. Results The median age at treatment start was 59 years (range 22 – 89 years) and the median time between initial irradiation and CIR was 3.9 years (range 0.3 – 46.5 years). On average, patients received 3 (range 1 – 8) tumor-specific treatments before CIR. 54% of primary tumors were adenoid cystic carcinomas (ACC), 25% were squamous cell carcinomas, 7% were adenocarcinomas and 14% were other tumor entities. Most common tumor sites were salivary glands (24%), nasopharynx (23%), paranasal sinus (21%), oral cavity (10%) and oropharynx (8%). The median planning target volume of CIR was 128.9 ccm (range 13.3 – 925.0 ccm), patients received a median dose of 51 Gy (RBE) (range 30 – 66 Gy (RBE) in 3 Gy(RBE) fractions and the median cumulative applied lifetime dose after CIR was 132.8 BED2Gy (range 88.8 – 155.0 BED2Gy). Median local PFS after CIR was 18.9 months (95% CI 14.2 – 23.6 months) and median overall survival after CIR was 24.8 months (95% CI 20.5 – 29.0 months). 94% of local recurrences after CIR were in-field. Associated with increased local control after CIR in the multivariate analysis were a median dose of 51 Gy(RBE) or higher (HR 0.46; 95% CI 0.24 – 0.90; p=0.022), a radiotherapy interval of at least 12 months (HR 0.26; 95% CI 0.11 – 0.62; p=0.002) and patients with ACC (HR 0.48; 95% CI 0.29 – 0.79; p=0.004). Serious acute toxicity (≥grade 3) after CIR included dysphagia °III (n=3; 1.3%), fistula °III (n=1; 0.4%), impaired hearing °III (n=1; 0.4%) and laryngeal edema °IV (n=2; 0.9%). One patient with multiple previous surgeries and a 7.5 cm large tumor infiltrating the base of skull and the temporal lobe died during CIR (18 Gy (RBE) of 51 Gy (RBE) applied) due to bacterial meningitis. 13 patients received a gastric feeding tube before treatment, 3 patients during treatment. Late toxicities of grade 3 or higher (n=13; 11.5%) included fistula °III (n=1; 0.9%), osteonecrosis °III (n=1; 0.9%), impaired hearing (n=5; 4.4%), optic nerve disorder °III / IV (n=2; 1.8% / n=2; 1.8%), brain necrosis °IV (n=1; 0.9%) and carotid blowout °IV (n=1; 0.9%). Conclusion CIR in patients with locally recurrent or progressive head- and-neck cancer is a feasible and effective treatment option with acceptable toxicity and good local control, representing a valuable alternative to surgical salvage and palliative chemotherapy in selected patients. Further studies are merited to confirm these findings. OC-010 Local recurrence of nasopharyngeal carcinomas – outcomes after reirradiation A. Ruffier-Loubière 1 , Y.G. Tao 1 , F. NGuyen 1 , A. Moya- Plana 2 , C. Even 2 , C. Berthold 1 , O. Casiraghi 3 , S. Temam 2 , P. Blanchard 1 1 Inst. de Cancérologie Gustave-Roussy, Oncology- Radiotherapy, Villejuif CEDEX, France; 2 Inst. de Cancérologie Gustave-Roussy, Head and Neck Cancer, Villejuif CEDEX, France; 3 Inst. de Cancérologie Gustave- Roussy, Pathology, Villejuif CEDEX, France Purpose or Objective Local control of nasopharyngeal carcinomas (NPC) following intensity modulated radiotherapy has improved over 2D or 3D radiotherapy, with less than 10% of local

Conclusion During (chemo)radiotherapy, MRI T2 weighted images can be used to delineate tumor volume. Generally tumors decrease in size during treatment. It may be possible to decrease the dose to healthy tissues by adapting radiotherapy plans based on the changes. It may even be possible to predict local status after treatment, however this is subject of ongoing investigation. The availability of the MR-linac makes treatment adaptation based on daily T2 weighted MR imaging possible. OC-009 Carbon-ion reirradiation for recurrent Head and Neck cancer: A single-institutional experience T. Held 1,2 , P. Windisch 1,2 , S. Akbaba 1,2 , K. Lang 1,2 , D. Bernhardt 1,2 , P. Plinkert 3 , K. Freier 4 , S. Kargus 4 , S. Rieken 1,2,5 , K. Herfarth 1,2,5 , J. Debus 1,2,5,6,7,8 , S. Adeberg 1,2,7,8 1 Heidelberg University Hospital, Department of Radiation Oncology, Heidelberg, Germany; 2 HIRO, Heidelberg Institute of Radiation Oncology, Heidelberg, Germany; 3 Heidelberg University Hospital, Department of Otorhinolaryngology, Heidelberg, Germany; 4 Heidelberg University Hospital, Department of Oral and Maxillofacial Surgery, Heidelberg, Germany; 5 HIT, Heidelberg Ion-Beam Therapy Center, Heidelberg, Germany ; 6 NCT, National Center for Tumor Diseases, Heidelberg, Germany; 7 German Cancer Research Center, German Cancer Consortium DKTK partner site Heidelberg, Heidelberg, Germany; 8 German Cancer Research Center, Clinical Cooperation Unit Radiation Oncology, Heidelberg, Germany Purpose or Objective To assess the feasibility and safety of carbon-ion reirradiation (CIR) in therapy-refractory patients with recurrent or progressive head-and-neck cancer (HNC).

page 10 7 th ICHNO Conference International Conference on innovative approaches in Head and Neck Oncology 14 – 16 March 2019 Barcelona, Spain __________________________________________________________________________________________ 7th ICHNO

recurrences. Reirradiation and surgery are the main “curative” options for local recurrences. However the risk of severe toxicity following reirradiation is high, and a nomogram predicting the risk of relapse and grade 5 toxicity after reirradiation was recently published (Li et al, J Clin Oncol 2018). The goal of this analysis was to review the outcomes and toxicity following NPC local reirradiation performed at Gustave Roussy Cancer Campus since 2005, and externally validate the published nomogram. Material and Methods The charts of all patients having received radiotherapy for a non-metastatic NPC between 2005 and 2018 were reviewed. Patient and tumor characteristics, as well as outcomes, were retrospectively reviewed. A leave one out cross validated receiver operator characteristics curve was performed to evaluate the discriminatory performance of the nomogram. Results Out of 346 NPC patients treated with radiotherapy over this time period, 35 had received a second course of radiotherapy and were included in the analysis. They were mostly male (75%), median age was 54 years, and 20% had retained a chronic grade 3 or higher toxicity as a result of the first course of radiotherapy. Local recurrences were classified as rT3T4 in 50% of the cases. The median interval between the first and second courses of radiotherapy was 78 months. 43% of the patients received concurrent chemotherapy and 37% induction chemotherapy. The median dose of reirradiation was 62 Gy. Two third of the patients had received IMRT or proton therapy as reirradiation technique. After a median follow-up of 54 months after the end of reirradiation, 7 patients had suffered a grade 5 toxicity, including 6 with a vascular blowout. These treatment- related deaths occurred early after reirradiation, with a median time to occurrence shorter than 6 months. 85% of patients presented at some point in follow-up a grade 3 or higher toxicity altering their quality of life, including cranial nerve palsies, hearing impairment or temporal brain necrosis. Overall survival rates were 56% at 2 years and 40% at 5 years. The published nomogram was not predictive of overall survival or grade 5 toxicity in our patient cohort (areas under the ROC curves of 0.58 and 0.55, respectively). Conclusion Reirradiation is an effective treatment for local recurrence of NPC,but is associated with a high rate of severe toxicity, including 20% of treatment-related deaths. Nomograms predicting survival and toxicity would be helpful in selecting patients for reirradiation, although they should be externally validated prior to clinical use in non-endemic areas. OC-011 New insights from the De-ESCALate HPV trial H. Mehanna 1 , M. Robinson 2 , A. Hartley 3 , A. Kong 1 , B. Foran 4 , T. Fulton-Lieuw 5 , M. Dalby 5 , P. Mistry 5 , M. Sen 6 , L. O'Toole 7 , J. Dunn 5 1 University of Birmingham, Institute of Head and Neck Studies and Education, Birmingham, United Kingdom; 2 University of Newcastle, Pathology, Newcastle, United Kingdom; 3 University Hospitals Birmingham, Oncology, Birmingham, United Kingdom; 4 Weston Park Hospital, Oncology, Sheffield, United Kingdom; 5 University of Warwick, Clinical Trials Unit, Late breaking news: Late breaking news

Coventry, United Kingdom; 6 St James's Institute of Oncology, Oncology, Leeds, United Kingdom; 7 Castle Hill Hospital, Queen's Centre for Oncology, Hull, United Kingdom Purpose or Objective To elucidate the risk factors associated with worse survival from cetuximab, compared to cisplatin. In De-ESCALate HPV, an international, multi-centre, randomised, controlled trial, patients with low-risk HPV+OPSCC were randomised to receive radiotherapy (70G in 35F) and either cisplatin (3 doses of 100 mg/m 2 ) or cetuximab (400 mg/m 2 loading dose followed by weekly 250 mg/m 2 ). There were no differences between the cisplatin and cetuximab arms in the reported severe or all grade toxicity. Importantly, however, there was a significant difference in the 2-year overall survival and in the time to recurrence between cisplatin and cetuximab. Material and Methods We undertook new proportional hazard modelling analyses of the survival data to examine factors associated with poor survival from cetuximab. Results Overall, there was a statistically significant difference in the 2-year overall survival between cisplatin and cetuximab (97.5% vs 89.4%, log-rank p=0.001; hazards ratio=4.99, 95% CI 1.70-14.7). All patient factors (age, T/N stage, smoking, performance status, HPV-DNA-ISH) appear to be associated with worse survival with cetuximab compared to cisplatin (Figure 1). In particular, patients with TNM8 stage III (T4 or N3) disease showed larger 2-year OS detriment when treated with cetuximab (67.1% (42.5-83.1%), compared to cisplatin (93.3% (95%CI 75.9-98.3%, Log rank p=0.03), HR=4.83 (95%CI 1.00-23.31, Fig 2). When considering the cetuximab-treated group only, all patient factors (age, T/N stage, performance status, HPV- ISH), appeared to be associated with progressively worse survival, except smoking. Smokers appeared to have better 2-year OS (92.0% (82.9% to 96.3%)) than non- smokers (87.0% (77.1% to 92.8%)) when treated with cetuximab. This may be due to smoking resulting in more EGFR upregulation. Conclusion There was significant detriment from the use of cetuximab instead of cisplatin in terms of tumour control across all patient characteristics and groups, and especially TNM8 Stage III patients. Patients treated with cetuximab appeared to have better survival if they smoked than non- smokers. Cisplatin and radiotherapy remain the standard of care in this setting.

Table 1

Keynote lecture: Keynote lecture 3: TNM8: How has the dust settled one year later?

SP-013 TNM8: How has the dust settled one year later? B. O'Sullivan 1 , R. Wu 1 , s.h. Huang 1 , w. Xu 2 , V. Gregoire 3 , S. Patel 4 , J. Brierley 1 , W. Lydiatt 5 1 Princess Margaret Cancer centre / University of Toronto, Tadiation Oncology, Toronto, Canada; 2 Princess Margaret Cancer centre / University of Toronto, Tadiation Oncology, Toronto Biostatistics, Toronto, Canada; 3 Centre Léon Bérard, Radiation Oncology, Lyon, France; 4 Memorial Sloan Kettering Cancer Center, Head and Neck Service, New York, USA; 5 Methodist Estabrook Cancer Center / Creighton University, Head and Neck Surgery, Nebraska, USA Abstract text The TNM classification is an anatomic-based classification that stratifies cancer patients according to prognosis, facilitating treatment decision-making and patient discussions. It is also essential for clinical trial eligibility and stratification, research, cancer registry activities, as well as cancer control and policy development. To maintain relevance, the 8 th edition head and neck cancer (HNC) TNM (TNM8) includes important modifications. These reflect biologic and clinical behavior (e.g. HPV- mediated oropharyngeal cancer (OPC)), improvements in assessment and treatment (e.g. nasopharyngeal carcinoma), and evolving knowledge about prognostic factors (e.g. depth of invasion in oral cavity cancers (OCSCC), extra-nodal extension for non-virally mediated HNC, and size criteria for non-Merkel cell cutaneous carcinoma). One year following implementation of TNM8, we reflect on challenges and users’ experience in transitioning to the new classification. This discussion includes an ongoing international survey from an unselected population of authors (n= 206 so far) of recent HNC Medline indexed publications to appreciate understanding and adoption of TNM8, and guide implementation of future TNM updates. Notably 30% still use both TNM7 and TNM8 due to existing clinical trials and treatment guidelines, but almost all (93%) support separate systems for HPV-positive vs HPV–negative OPC. Primary concerns centred around the N-classifications generally, and implementation of depth of invasion in OCSCC and extra-nodal extension in non-viral HNC. Only 22% felt that HPV+ OPC should receive de-intensified treatment based on TNM8. Most of the survey were clinicians who felt that TNM plays a central role in clinical care but generally seemed to under-appreciate many additional purposes of staging (including research, cancer registration and global control activities). Two thirds consider that enhanced educational resources would increase understanding and adoption of the current version, and that accessibility to resources needs improvement. The operational challenges and views mentioned herein need to be considered in future changes to the HNC TNM.

Figure: Overall survival for patients with T4 or N3 disease, by trial group. N=58

The 2-year survival rate with 95% confidence interval is 93.3% (75.9% to 98.3%) in the Cisplatin and Radiotherapy arm and 67.1% (42.5% to 83.1%) in the Cetuximab and Radiotherapy arm. Log-rank p-value= 0.03; HR: 4.83, 95% CI: 1.00 to 23.31

Symposium: Symposium 1: Immuno-oncology

SP-012 Pembrolizumab in the first line treatment of recurrent and/or metastatic head and neck cancer B. Burtness USA

SP-014 Immuno-score J. Galome France

Abstract not received

page 12 7 th ICHNO Conference International Conference on innovative approaches in Head and Neck Oncology 14 – 16 March 2019 Barcelona, Spain __________________________________________________________________________________________ 7th ICHNO

of SMARCB1 (INI1) (7) is currently retained under the umbrella of SNUC as it is still not clear whether it represents a distinct entity. Using next-generation sequencing, IDH2 mutations at R172 were recently identified in 30% to 50% of SNUCs (8, 9). Further studies have shown that IDH2 mutations can also be found in poorly-differentiated sinonasal carcinomas other than SNUC and that they frequently co-exist with MYC amplifications (9). Notably, the identification of IDH mutations in poorly differentiated sinonasal carcinomas and SNUC has also significant therapeutic implications, as mutant IDH inhibitors have shown promise in the treatment of other malignancies. In conclusion, SNUC remains a poorly understood sinonasal malignancy, but in the next future molecular studies are likely to provide new perspectives for its diagnosis and treatment. References 1) Frierson HF Jr, et al. Am J Surg Pathol. 1986;10:771-9. 2) Mills SE. Endocr Pathol. 1996;7:329-343. 3) Jeng YM, et al. Am J Surg Pathol. 2002;26:371-6. 4) Franchi A, et al. Am J Surg Pathol. 2002;26:1597-604. 5) Lewis JS Jr, et al. (2017) In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (eds) WHO classification of head and neck tumours. IARC, Lyon, pp 18-20. 6) Stathis A, et al. Cancer Discov. 2016;6:492-500. 7) Agaimy A, et al. Am J Surg Pathol 2017;41:458-471. 8) Jo VY, et al. Mod Pathol 2017;30:650-659 9)Dogan S, et al. J Pathol. 2017;242:400-408.

SP-015 Current status of immunotherapy in Head and Neck cancer L. Licitra Italy

Abstract not received

SP-016 Integration

immunotherapy

with

radiotherapy in Head and Neck cancer P. Huber Germany

Abstract not received

Keynote lecture: Keynote lecture 4: SNUC: a sustainable concept?

SP-017 SNUC: a sustainable concept? A. Franchi 1 1 University of Pisa, Department of Translational Research, Pisa, Italy Abstract text Sinonasal undifferentiated carcinoma (SNUC) was first described as a distinct entity by Frierson and coworkers in 1986 (1), as a highly aggressive carcinoma devoid of glandular and squamous differentiation, and histologically consisting of nests, trabeculae, and sheets of medium- sized cells with small to moderate amounts of eosinophilic cytoplasm. A high mitotic rate, tumor necrosis, and prominent vascular permeation were characteristic. Although it was initially thought to represent a large cell variant of neuroendocrine carcinoma, it is now considered a separate entity from the group of sinonasal neuroendocrine tumors (2). More importantly, it was stressed that SNUC has to be separated from nasopharyngeal-type undifferentiated carcinoma and olfactory neuroblastoma, for their better prognosis and response to treatment (3, 4). Still in the recent 4th edition of the WHO classification of head and neck tumors (5), from the histopathologic point of view SNUC remains a diagnosis of exclusion, requiring separation from several other epithelial and non-epithelial high-grade sinonasal malignancies. However, due to the lack of specific criteria, it is likely that the diagnosis of SNUC may have been applied to a heterogeneous group of carcinomas, thus possibly representing a final common pathway of dedifferentiation for a variety of sinonasal epithelial neoplasms. More recently, the refinement in diagnostic criteria and the availability of new molecular markers has led to the separation of specific tumor types from this group of tumors. The first one has been NUT carcinoma, which is a poorly differentiated carcinoma often showing squamous differentiation and presenting a rearrangement of the nuclear protein in testis ( NUTM1 ) gene on chromosome 15q14. In most cases, the partner gene of the fusion is BRD4 (bromodomain-containing protein 4) on 19p13.1, and less frequently BRD3 or WHSC1L1 . NUT carcinoma is a highly aggressive tumor with a median survival <1 year, but the evidence of clinical response to targeted treatments with bromodomain inhibitors underscores the importance of its distinction from other poorly differentiated carcinomas of the sinonasal tract (6). The recently described subset of undifferentiated carcinomas with rhabdoid histologic features and loss

Keynote lecture: Keynote lecture 5: Pushing the limits in Head and Neck robotic surgery

SP-018 Pushing the limits in Head and Neck robotic surgery C. Simon Switzerland

Abstract not received

Proffered papers: Proffered papers 2

OC-019 What is the optimal cut-off of depth of invasion for elective neck dissection in oral cavity cancer? Abstract withdrawn OC-020 Sentinel lymph node biopsy for early stage oral cancer; experience of 3 Dutch Head and Neck centers I. Den Toom 1,2 , K. Boeve 3,4 , R. Van Es 1 , B. De Keizer 5 , S. Van Weert 2 , S. Willems 6 , M. Witjes 3 , E. Bloemena 7,8 , R. Leemans 2 , R. De Bree 1 1 UMC Utrecht, Head and Neck Surgical Oncology, Utrecht, The Netherlands; 2 Amsterdam UMC, Otolaryngology-Head and Neck Surgery, Amsterdam, The Netherlands ; 3 University Medical Center Groningen, Oral and Maxillofacial Surgery, Groningen, The Netherlands ; 4 University Medical Center Groningen, Pathology and Medical Biology, Groningen, The Netherlands ; 5 UMC Utrecht, Radiology and Nuclear Medicine, Utrecht, The Netherlands ; 6 UMC Utrecht, Pathology, Utrecht, The Netherlands ; 7 Amsterdam UMC/Academic Centre for Dentistry ACTA, Oral and Maxillofacial Surgery / Oral Pathology, Amsterdam, The Netherlands ; 8 Amsterdam UMC, Pathology, Amsterdam, The Netherlands

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