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Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC., Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nilsson, Olafsdottir, Alexandersson von Döbeln, Villegas, Gagliardi, Hellström, Wang, Johansson, Gebski, Hedberg, Klevebro, Markar, Smyth, Lagergren, Al-Haidari, Rekstad, Aahlin, Wallner, Edholm, Johansson, Szabo, Reynolds, Pramesh, Mummudi, Joshi, Ferri, Wong, O’Callaghan, Lukovic, Chan, Leong, Barbour, Smithers, Li, Kang, Kong, Chao, Crosby, Bruns, van Laarhoven, van Berge Henegouwen, van Hillegersberg, Rosati, Piessen, de Manzoni and Lordick.)

Aim: Data from a local quality registry are used to model the risk of late xerostomia after radiotherapy for head and neck cancer (HNC), based on dosimetric- and clinical variables. Strengths and weaknesses of using quality registry data are explored., Methods: HNC patients treated with radiotherapy at the Karolinska University hospital are entered into a quality registry at routine follow up, recording morbidity according to a modified RTOG/LENT-SOMA scale. Other recorded parameters are performance status, age, gender, tumor location, tumor stage, smoking status, chemotherapy and radiotherapy data, including prescribed dose and organ-at-risk (OAR) dose. Most patients are entered at several time points, but at variable times after treatment. Xerostomia was modeled based on follow-up data from January 2014 to October 2018, resulting in 753 patients. Two endpoints were considered: maximum grade ≥2 (XER G≥2 ) or grade ≥3 (XER G≥3 ) late xerostomia. Univariate Cox regression was used to select variables for two multivariate models for each endpoint, one based on the mean dose to the total parotid volume (D tot ) and one based on the mean dose to the contralateral parotid (D contra ). Cox regression allows the estimation of the risk of xerostomia at different time points; models were presented visually as nomograms estimating the risk at 9, 12, and 24 months respectively., Results: The toxicity rates were 366/753 (49%) for XER G≥2 and 40/753 (5.3%) for XER G≥3 . The multivariate models included several variables for XER G≥2 , and dose, concomitant chemotherapy and age were included for XER G≥3 . Induction chemotherapy and an increased number of fractions per week were associated with a lower risk of XER G≥2 . However, since the causality of these relationships have limited support from previous studies, alternative models without these variables were also presented. The models based on the mean dose to the total parotid volume and the contralateral parotid alone were very similar., Conclusion: Late xerostomia after radiotherapy can be modeled with reasonable predictive power based on registry data; models are presented for different endpoints highly relevant in clinical practice. However, the risk of modeling indirect relationships, given the unavoidably heterogeneous registry data, needs to be carefully considered in the interpretation of the results., (Copyright © 2020 Onjukka, Mercke, Björgvinsson, Embring, Berglund, Alexandersson von Döbeln, Friesland, Gagliardi, Lenneby Helleday, Sjödin and Lax.)