Original Research Article Prospectively scored pulmonary toxicities in non-small cell lung cancer: Results from a randomized phase II dose escalation trial Christina M. Lutz a,⇑ , Marianne M. Knap a , Lone Hoffmann a , Ditte S. Møller a , Olfred Hansen b , Carsten Brink b , Tine Schytte b , Christa H. Nyhus c , Tine McCulloch d , Svetlana Borissova e , Markus Alber f , Azza A. Khalil a a Department of Oncology, Aarhus University Hospital, Aarhus, Denmark b Department of Oncology, Odense University Hospital, Odense, Denmark c Department of Oncology, Vejle Hospital, Vejle, Denmark d Department of Oncology, Aalborg Hospital, Aalborg, Denmark e Department of Oncology, Herlev Hospital, Herlev, Denmark f Heidelberg Institute for Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany article info Article history: Received 9 June 2020 Revised 19 November 2020 Accepted 21 November 2020 Available online 26 November 2020 Keywords: Prospective Radiation pneumonitis Locally-advanced non-small cell lung cancer abstract Purpose: Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investi- gated. Methods: Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo- radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A–59pts) and 66 Gy/33fx (B–58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP  G2. Results: Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5. 8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP  G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP  G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP  G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivari- able logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. Conclusion: No statistical difference between the high- and low dose arm was found in the risk of devel- oping RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model. Ó 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 1. Introduction The current standard treatment of locally-advanced non-small cell lung cancer (LA-NSCLC) consists of concomitant chemo- radiotherapy (CRT) at 60–66 Gy in 30–33 fractions (fx). However, both local control and overall survival are poor [1,2], calling for drastic advancements in treatment. During the past decades, sev- eral attempts of intensifying RT have been launched. These include increase in radiation dose and decrease in overall treatment time [3–6]. Beyond RT, adjuvant immunotherapy (Duvalumab) follow- ing CRT has shown promising progression-free and overall survival in the phase III PACIFIC trial [7,8]. Unfortunately, any treatment intensification is restricted by the severe and sometimes lethal tox- icities observed in the standard treatment [2,9]. Severe pulmonary toxicities often have a measurable impact on the quality of life of patients after treatment [10,11]. The most prominent pulmonary toxicity in RT for lung cancer is radiation pneumonitis (RP). RP occurs within nine months after RT. The risk of RP has been linked to a variety of both clinical and dosimetric factors. The most widely acknowledged are age, smoking status, chemotherapy, previously https://doi.org/10.1016/j.ctro.2020.11.013 2405-6308/Ó 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ⇑ Corresponding author at: Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. E-mail address: chrilutz@rm.dk (C.M. Lutz). Clinical and Translational Radiation Oncology 27 (2021) 8–14 Contents lists available at ScienceDirect Clinical and Translational Radiation Oncology journal homepage: www.elsevier.com/locate/ctro