Marlen Haderlein ^1,2* Jens Von Der Gruen ³ Panagiotis Balermpas ³ Claus Rödel ⁴ Matthias G. Hautmann ⁵ Felix Steger ⁵ Christopher Bohr ⁶ Thomas Hehr ⁷ Carmen Stromberger ⁸ Volker Budach ⁸ Markus Schymalla ⁹ Rita Engenhart-Cabillic ⁹ Lukas Kocik ¹⁰ Hans Geinitz ¹⁰ Ursula Nestle ^11,12 Gunter Klautke ¹³ Claudia Scherl ¹⁴ Christine Gall ¹⁵ Benjamin Frey ^1,2 Philipp Schubert ^1,2 Sabine Semrau ^1,2 Oliver Ott ^1,2 Marco Kesting ¹⁶ Heinrich Iro ^17,2 Sarina Mueller ^17,2 Rainer Fietkau ^1,2

• ¹ Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Bavaria, Germany
• ² Comprehensive Cancer Center Erlangen-EMN (CCC), Erlangen, Bavaria, Germany
• ³ Department of Radiation Oncology, University Hospital Zurich, Zurich, Zurich, Switzerland
• ⁴ Klinik für Strahlentherapie und Onkologie, Universitätsklinikum Frankfurt, Frankfurt, Hesse, Germany
• ⁵ Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Regensburg, Regensburg, Bavaria, Germany
• ⁶ Department of Ear-Nose and Throat, Head and Neck Surgery, Regensburg University Hospital, Regensburg, Bavaria, Germany
• ⁷ Marienhospital Stuttgart, Stuttgart, Baden-Württemberg, Germany
• ⁸ Department of Radiation Oncology and Radiotherapy, Charité University Medicine Berlin, Berlin, Baden-Wurttemberg, Germany
• ⁹ Klinik für Strahlentherapie, Faculty of Medicine, University of Marburg, Marburg, Germany
• ¹⁰ Ordensklinikum Linz, Linz, Upper Austria, Austria
• ¹¹ Department of Radiation Oncology, Freiburg University Medical Center, Freiburg, Germany
• ¹² Clinic Maria Hilf GmbH, Moenchengladbach, Germany
• ¹³ Klinikum Chemnitz gGmbH, Chemnitz, Lower Saxony, Germany
• ¹⁴ University of Mannheim, Mannheim, Baden-Württemberg, Germany
• ¹⁵ Department of Biometry and Epidemiology, University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany
• ¹⁶ Department of Oral and Maxillofacial Surgery, University Hospital Erlangen, Erlangen, Bavaria, Germany
• ¹⁷ Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Erlangen, Erlangen, Bavaria, Germany

Background Current standard treatment concepts in head and neck squamous cell carcinoma (HNSCC) are based on former studies using 2D and 3D treatment plans. However, modern radiation techniques allow for a more precise and individual dose application. Therefore, in a clearly defined patient population de-intensified risk-adapted radiation is investigated. Methods Patients with newly diagnosed HNSCC after surgery(with resection margins≥1mm and cM0) with the following tumor stages (TNM 7thEdition) were eligible for the study: Oral cavity, oropharynx or larynx: pT1-3, pN0-pN2b, hypopharynx: pT1-2; pN1. The patients should either have a low risk of local recurrence(≤pT2, resection margin ≥5mm, no peritumoral lymphangiosis(L0) and no perineural invasion) or contralateral lymph node metastasis (≤ 3 ipsilateral lymph node metastases, in case of well-lateralized oropharyngeal or oral cavity cancer contralateral cN0, otherwise pN0). Patients were assigned to 3 different treatment regimes with reduction of the treated volume, radiation dose or both, according to tumor stage and results of surgery performed(see Fig1). Primary objective was to show LRR of <10% after 2years. Findings: 150 patients were enrolled. Tumor localisations were: n=53(35·3%) oral cavity, n=94(62·7%) oropharynx (82% HPV-positive), n=2(1·3%) Hypopharynx, n=1(0·7%) Larynx. 61 patients(41·0%) were stage IVA, 81(54·0%) stage III and 8(5·3%) stage II. Median follow up was 36 months. Cumulative incidence of 2y-LRR was 5·6%(95% CI: 1·7%-9·2%) in the whole study population and 14.1%(95%CI: 3.8%-23.2%) in patients with oral cavity cancer. Cumulative incidence of 2y-LRR in non-irradiated or dose-reduced regions was 3·5 %(95% CI: 0·4%-6·5%) After 2 years disease-free survival was 92%(95% CI: 87%-96%), overall survival was 94%(95% CI: 90%-98%) for the complete study cohort. Acute III° toxicity was as follows: dysphagia: 30%, xerostomia: 7%, mucositis 19%, dermatitis: 4%.Dysphagia and xerostomia decreases over time. After 27 months late dysphagia III° and xerostomia II° was 1% and 9%. Interpretation: The study met its primary objective. De-intensification of postoperative radiotherapy irrespective to HPV status in a pre-defined patient population is associated with a favorable toxicity profile without compromising LRR. In an unplanned subgroup analysis, a significantly increased risk of LRR was observed in patients with oral cavity cancer. In these patients, deintensified radiotherapy should be applied with caution.