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Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts., (© 2024. Springer Nature Limited.)

Introduction: The international phase II single-arm LungTech trial 22113-08113 of the European Organization for Research and Treatment of Cancer assessed the safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage NSCLC., Methods: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance for any eligible patient, SBRT (8 × 7.5 Gy) was delivered. The primary endpoint was freedom from local progression probability three years after the start of SBRT., Results: The trial was closed early due to poor accrual related to repeated safety-related pauses in recruitment. Between August 2015 and December 2017, 39 patients from six European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Six patients (19.4%) had an ultracentral tumor location. The median follow-up was 3.6 years. The rates of 3-year freedom from local progression and overall survival were 81.5% (90% confidence interval [CI]: 62.7%-91.4%) and 61.1% (90% CI: 44.1%-74.4%), respectively. Cumulative incidence rates of local, regional, and distant progression at three years were 6.7% (90% CI: 1.6%-17.1%), 3.3% (90% CI: 0.4%-12.4%), and 29.8% (90% CI: 16.8%-44.1%), respectively. SBRT-related acute adverse events and late adverse events ≥ G3 were reported in 6.5% (n = 2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4% (n = 6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively., Conclusions: The LungTech trial suggests that SBRT with 8 × 7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after a thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints, and post-SBRT interventions is crucial., Competing Interests: Disclosure Dr. Levy reports academic funding from Roche, Beigene, AstraZeneca, and Pharmamar. Dr. Adebahr was supported by the German Cancer Consortium (DKTK) and is now supported by a grant from the Federal Ministry of Education and Research (BMBF). The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Owing to major advances in the field of radiation oncology, patients with lung cancer can now receive technically individualized radiotherapy treatments. Nevertheless, in the era of precision oncology, radiotherapy-based treatment selection needs to be improved as many patients do not benefit or are not offered optimum therapies. Cost-effective robust biomarkers can address this knowledge gap and lead to individuals being offered more bespoke treatments leading to improved outcome. This narrative review discusses some of the current achievements and challenges in the realization of personalized radiotherapy delivery in patients with lung cancer., Competing Interests: Disclosure Dr. Brown reports receiving grants from CRUK Lung Cancer Centre of Excellence (institutional award). Dr. Chua reports receiving grants from the National Medical Research Council Singapore Clinician Scientist; an individual research grant from New Investigator Grant (NMRC/CS-IRG-NIG/CNIG20nov-0029); support from the Duke-NUS Medical School Khoo Pilot Award (collaborative); payment or honoraria for lectures from Varian Medical Systems and PeerVoice; support for attending meetings from Varian Medical Systems; and having participation on data safety monitoring board from AstraZeneca, Regeneron, Roche, Seagen, Merck Sharp & Dohme, Takeda. Dr. McDonald reports receiving consulting fees, payment, or honoraria for lectures from AstraZeneca. Dr. Price reports being supported by Cancer Research UK RadNET Manchester, NIHR Manchester Biomedial Research Centre, and National Institute of Health Research. Prof. Faivre-Finn reports receiving consulting fees and payment or honoraria for lectures (to the institution) and having participation on data safety monitoring (to the institution) from AstraZeneca. The remaining authors declare no conflicts of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: CONVERT was a phase 3 international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5-year outcomes of these regimens delivered with conformal techniques., Methods and Materials: CONVERT (NCT00433563) randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks), both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance., Results: Five hundred forty-seven patients were recruited at 73 centers. The median follow-up for the surviving cohort (n = 164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95% CI, 21.1-30.9) and 30.0 months (95% CI, 25.3-36.5; hazard ratio, 1.13; 95% CI, 0.92-1.38; P = .247). Performance status and tumor volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms, respectively., Conclusions: As the CONVERT trial did not demonstrate the superiority of OD RT and this regimen had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy., Materials and Methods: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes., Results: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months., Conclusion: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study., Methods: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3., Results: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease., Conclusions: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew Evison – Declarations of interest: none; Gregory Videtic – Declarations of interest: none; Corinne Faivre-Finn –Declarations of interest: none; Kevin Franks –Declarations of interest: none; Suresh Senan – Varian Medical Systems: Advisory board, Departmental research support; AstraZeneca: Advisory board, Institutional research support; BMS: Institutional research support; MSD: Advisory board, consultancy; Iain Phillips –Declarations of interest: none; Jacqueline Kruser –Dr. Kruser has received support for unrelated work from the National Institutes of Health/National Heart, Lung, and Blood Institute under grant numbers F32HL140824 and K23HL146890. Dr. Kruser’s spouse receives honoraria for lectures and speakers bureaus from Astra Zeneca. (Found online); David Palma – Dr Palma reports a Clinician-Scientist Grant from the Ontario Institute for Cancer Research, royalties from Uptodate.com, and a consultant role with equity from Need Inc, all unrelated to the current work; Timothy Kruser –Dr. Kruser sits on the speakers bureau and advisory board for AstraZeneca and serves as a Consultant for Radiologica LLC; Clive Peedell – Disclosures: Speaker fees Elekta, Varian; Clifford Robinson – Radialogica: Leadership, Stock and Other Ownership Interests; Quantaras: Stock and Other Ownership Interests, Consulting or Advisory Role; Varian Medical Systems: Consulting or Advisory Role, Research Funding; AstraZeneca: Consulting or Advisory Role; MED Serono: Consulting or Advisory Role; EmpNia: Consulting or Advisory Role; Merck: Research Funding; Noninvasive imaging and treatment system for cardiac arrhythmias WO 2017078757 A1 U.S. Provisional Application No. 62/598,162 Entitled SYSTEM AND METHOD FOR DETERMINING SEGMENTS FOR ABLATION: Patents, Royalties, Other Intellectual Property; Angela Wright – Declarations of interest: none; Lorraine McCleod – Declarations of interest: none; Percy Lee –Declarations: Varian, Viewray, AstraZeneca, Genentech, Johnson & Johnson: Consulting Fees; AstraZeneca, UK: Manuscript support for a different manuscript (“All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) No time limit for this item.”); Varian, Viewray, AstraZeneca: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Radiosurgery Society: Support for attending meeting/travel; Genentech, Viewray, AstraZeneca: Participation on a Data Safety Monitoring Board or Advisory Board; Radiosurgery Society board of director: Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid; Houda Bahig –Declarations: Research grants from Varian Medical Systems; Research grant from Astra Zeneca; Advisory boards - Sanofi & Astra Zeneca; Kevin Chua – Declarations: Advisory boards: AstraZeneca, Regeneron, Roche, Seagen, MSD, Takeda; Speaker honoraria: Varian, PeerVoice; Travel: Varian; Shakar Shiva – Declarations of interest: none; Melody Qu – Declarations of interest: none; Nazia Chaudhuri –Declarations of interest: none; Susan Harden –Declarations of interest: none; Cicely Cunningham –Declarations of interest: none; Indu S. Voruganti Maddali – Declarations of interest: none; Alexander V. Louie – Dr. Louie has received honoraria from AstraZeneca, unrelated to this review; Stephen Harrow – Declarations of interest: none., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: Anticoagulation of patients with atrial fibrillation (AF) and cancer is challenging because of their high risk for stroke and bleeding. Little is known of the variations of oral anticoagulant (OAC) prescribing in patients with AF with and without cancer., Methods: Patients with first-time AF during 2009-2019 from the Clinical Practice Research Datalink were included. Cancer diagnosis was defined as a history of breast, prostate, colorectal, lung, or hematological cancer. Competing-risk analysis was used to assess the risk of OAC prescribing in patients with AF and cancer adjusted for clinical and sociodemographic factors., Results: Of 177,065 patients with AF, 11.7% had cancer. Compared to patients without cancer, patients with cancer were less likely to receive OAC: prostate cancer (subhazard ratio [SHR], 0.95; 95% CI, 0.91-0.99), breast cancer (SHR, 0.93; 95% CI, 0.89-0.98), colorectal cancer (SHR, 0.93; 95% CI, 0.88-0.99), hematological cancer (SHR, 0.70; 95% CI, 0.65-0.75), and lung cancer (SHR, 0.44; 95% CI, 0.38-0.50). The cumulative incidence function (CIF) of OAC prescribing was lowest for patients with lung cancer and hematological cancer compared with patients without cancer. The difference between the CIF of OAC prescribing in patients with and without cancer becomes narrower in the most deprived areas. Elderly patients (aged ≥85 years) overall had the lowest CIF of OAC prescribing regardless of cancer status., Conclusions: In patients with AF, underprescribing of OAC is independently associated with certain cancer types. Patients with hematological and lung cancer are the least likely to receive anticoagulation therapy compared with patients without cancer. Underprescribing of OAC in cancer is linked to old age. Further studies of patients with AF and cancer are warranted to assess the net clinical benefit of anticoagulation in certain cancer types., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The landscape of lung radiotherapy (RT) has rapidly evolved over the past decade with modern RT and surgical techniques, systemic therapies, and expanding indications for RT. To date, 2 MRI-guided RT (MRgRT) units, 1 using a 0.35T magnet and 1 using a 1.5T magnet, are available for commercial use with more systems in the pipeline. MRgRT offers distinct advantages such as real-time target tracking, margin reduction, and on-table treatment adaptation, which may help overcome many of the common challenges associated with thoracic RT. Nonetheless, the use of MRI for image guidance and the current MRgRT units also have intrinsic limitations. In this review article, we will discuss clinical experiences to date, advantages, challenges, and future directions of MRgRT to the lung., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor (EGFR) mutations are detected in up to one third of patients with unresectable stage III non-small cell lung cancer (NSCLC). The current standard of care for unresectable stage III NSCLC is consolidation durvalumab for patients who have not progressed following concurrent chemoradiotherapy (the 'PACIFIC regimen'). However, the benefit of immunotherapy, specifically in patients with EGFR mutation-positive (EGFRm) tumors, is not well characterized, and this treatment approach is not recommended in these patients, based on a recent ESMO consensus statement. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant improvements in patient outcomes in EGFRm metastatic NSCLC. The benefits of these agents have also translated to patients with EGFRm early-stage resectable disease as adjuvant therapy. The role of EGFR-TKIs has yet to be prospectively characterized in the unresectable setting. Preliminary efficacy signals for EGFR-TKIs in unresectable EGFRm stage III NSCLC have been reported from a limited number of subgroup and retrospective studies. Several clinical trials are ongoing assessing the safety and efficacy of EGFR-TKIs in this patient population. Here, we review the current management of unresectable EGFRm stage III NSCLC. We outline the rationale for investigating EGFR-TKI strategies in this setting and discuss ongoing studies. Finally, we discuss the evidence gaps and future challenges for treating patients with unresectable EGFRm stage III NSCLC., Competing Interests: Declaration of competing interest Terufumi Kato reports consulting/advisory roles: AstraZeneca, BeiGene, Daiichi-Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; honoraria: Amgen Inc., AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceuticals Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho Pharmaceutical, Takeda; employment (spouse): Eli Lilly and company; research support (to institution): AbbVie Inc., Amgen Inc., AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, HaiHe Biopharma, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Takeda, Turning Point Therapeutics Inc. Ignacio Casarini reports local principal investigator role: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis, Roche (non-financial and for institution); principal investigator role for multiple clinical studies: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis; principal investigator role for one clinical study: Roche. Corinne Faivre-Finn reports research funding: AstraZeneca, and Elekta; travel expenses: AstraZeneca, Elekta, Peter MacCallum Cancer Centre, and CF-F’s institution; and uncompensated relationships: AstraZeneca, Elekta, and Merck Sharpe & Dohme. CF-F is supported by a grant from the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. Fiona Hegi-Johnson reports research funding: AstraZeneca; honoraria: AstraZeneca; payment or honoraria for lectures and presentations: BeiGene, Merck Sharpe & Dohme. Participation on an advisory board: AstraZeneca. FH-J is supported by the Victorian Cancer Agency. Shun Lu reports consulting/advisory roles: AstraZeneca, Boehringer Ingelheim, GenomiCare Biotechnology, Hutchison MediPharma Ltd., Pfizer, prIME Oncology, Roche, Simcere Pharmaceutical Group, Yuhan, Zai Lab; speaker’s bureau: AstraZeneca, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Roche; research funding (to institution): AstraZeneca, BeiGene, Bristol-Myers Squibb, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Hutchison MediPharma Ltd., Lilly Suzhou Pharmaceutical Co. Ltd., Roche. Mustafa Özgüroğlu reports consulting/advisory roles: Astellas (to self and institution), Janssen, Sanofi; honoraria: Astellas (to self and institution), Janssen, Novartis, Roche, Sanofi. Suresh S. Ramalingam reports consulting/advisory roles: Amgen Inc., AstraZeneca, Bristol-Myers Squibb, Genentech, Merck & Co. Inc., Takeda Inc., Tesaro; research funding: Amgen Inc., Advaxis Inc., AstraZeneca, Bristol-Myers Squibb, Genmab, Merck & Co. Inc., Takeda, Tesaro Inc. Manuel Cobo declares no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes., Materials and Methods: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression., Results: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661)., Conclusion: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: The RTOG 0617 trial presented a worse survival for patients with lung cancer treated in the high-dose (74 Gy) arm. In multivariable models, radiation level and whole-heart volumetric dose parameters were associated with survival. In this work, we consider heart subregions to explain the observed survival difference between radiation levels., Methods: Voxel-based analysis identified anatomical regions where the dose was associated with survival. Bootstrapping clinical and dosimetric variables into an elastic net model selected variables associated with survival. Multivariable Cox regression survival models assessed the significance of dose to the heart subregion, compared with whole heart v5 and v30. Finally, the trial outcome was assessed after propensity score matching of patients on lung dose, heart subregion dose, and tumor volume., Results: A total of 458 patients were eligible for voxel-based analysis. A region of significance (p < 0.001) was identified in the base of the heart. Bootstrapping selected mean lung dose, radiation level, log tumor volume, and heart region dose. The multivariable Cox model exhibited dose to the heart region (p = 0.02), and tumor volume (p = 0.03) were significantly associated with survival, and radiation level was not significant (p = 0.07). The models exhibited that whole heart v5 and v30 were not associated with survival, with radiation level being significant (p < 0.05). In the matched cohort, no significant survival difference was seen between radiation levels., Conclusions: Dose to the base of the heart is associated with overall survival, partly removing the radiation level effect, and explaining that worse survival in the high-dose arm is owing, in part, to the heart subregion dose. By defining a heart avoidance region, future dose escalation trials may be feasible., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: Consolidation durvalumab (the "PACIFIC regimen") is standard of care for patients with unresectable stage III NSCLC who have not progressed after chemoradiotherapy, on the basis of data from the phase 3 placebo-controlled PACIFIC study (NCT02125461). Nevertheless, the benefit of immunotherapy in patients with stage III EGFR-mutant (EGFRm) NSCLC is not well characterized. Here, we report a post hoc exploratory efficacy and safety analysis from a subgroup of patients with EGFRm NSCLC from the PACIFIC., Methods: Patients with stage III unresectable NSCLC and no progression after more than or equal to two cycles of platinum-based concurrent chemoradiotherapy were randomized (2:1) to receive durvalumab (10 mg/kg intravenously every 2 weeks [wk], for up to 1 y) or placebo; stratified by age, sex, and smoking history. Enrollment was not restricted by oncogenic driver gene mutation status or programmed death-ligand 1 expression. Patients with NSCLC with an EGFR mutation, determined by local testing only, were included in this subgroup analysis. The primary end points were progression-free survival (PFS; assessed by blinded independent central review) and overall survival (OS). Secondary end points included objective response rate and safety. Statistical analyses for the subgroup of patients with EGFRm NSCLC were post hoc and considered exploratory., Results: Of 713 patients randomized, 35 had locally confirmed EGFRm NSCLC (durvalumab, n = 24; placebo, n = 11). At data cutoff (January 11, 2021), median duration of follow-up for survival was 42.7 months (range: 3.7-74.3 mo) for all randomized patients in the subgroup. Median PFS was 11.2 months (95% confidence interval [CI]: 7.3-20.7) with durvalumab versus 10.9 months (95% CI: 1.9-not evaluable [NE]) with placebo; hazard ratio = 0.91 (95% CI: 0.39-2.13). Median OS was 46.8 months (95% CI: 29.9-NE) with durvalumab versus 43.0 months (95% CI: 14.9-NE) with placebo; hazard ratio = 1.02 (95% CI: 0.39-2.63). The safety profile of durvalumab was generally consistent with the overall population and known profile for durvalumab., Conclusions: PFS and OS outcomes with durvalumab were similar to placebo for patients with EGFRm tumors, with wide CIs. These data should be interpreted with caution owing to small patient numbers and lack of a prospective study that evaluates clinical outcomes by tumor biomarker status. Further research to determine the optimal treatment for unresectable stage III EGFRm NSCLC is warranted., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: The Christie NHS Foundation Trust launched their electronic patient-reported outcome measures (ePROMs) service in January 2019 in the routine clinical setting. The lung cancer questionnaires consist of 14 symptom items, adapted from the Common Terminology Criteria for Adverse Events (version 5.0) and the EuroQol EQ-5D-5L quality-of-life (QoL) tool. Patients with lung cancer are invited to complete questionnaires assessing their symptoms and QoL using an online platform., Methods: The ePROM responses and clinical, pathologic, and treatment data for patients who completed the questionnaires between January 2019 and December 2020 were extracted from electronic medical records. The symptom and QoL scores of patients who completed baseline pretreatment ePROMs and also those who completed ePROMs pre- and postpalliative lung systemic anticancer therapy (SACT) or radical thoracic radiotherapy were evaluated. Pretreatment questionnaires were analyzed according to age, Eastern Cooperative Oncology Group performance status (ECOG PS), and Adult Comorbidity Evaluation-27 (ACE-27) comorbidity score., Results: One thousand four hundred eighty patients with lung cancer were included. There were no statistically significant differences in symptoms and QoL scores between age groups. Cough ( P = .006) and EQ-5D-5L mobility scores ( P = .006) were significantly worse for patients with an ECOG PS of 0-1. Dyspnea ( P = .035), hemoptysis ( P = .023), nausea ( P = .041), mobility ( P = .004), and self-care ( P = .0420) were significantly worse for those with higher ACE-27 scores (2-3 v 0-1). Palliative SACT was associated with a significant improvement in cough ( P < .001) and hemoptysis ( P = .025), but significantly negatively affected mobility ( P = .013). Patients receiving radical thoracic radiotherapy reported a significant improvement in hemoptysis ( P = .042) but worse pain ( P = .002) and fatigue ( P = .01). Other changes in symptom and QoL scores were not significant., Conclusion: The symptoms and QoL reported at baseline and before and after both palliative SACT and radical thoracic radiotherapy are clinically relevant and meaningful. We have demonstrated that routine implementation of ePROMs into clinical practice is feasible and can inform clinical practice and future research.

Background and Purpose: We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18 F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer., Materials and Methods: Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II 'pick-the-winner' design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year., Clinicaltrials: gov:NCT01024829., Results: 150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group., Conclusion: Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available., Competing Interests: Conflict of interest: T.G. Blum reports an unrestricted grant from Stiftung Oskar-Helene-Heim (Berlin, Germany), through which staff support for the work of the current Task Force was provided. R.L. Morgan declares no competing interests. V. Durieux declares no competing interests. J. Chorostowska-Wynimko declares grants to the National Institute of Tuberculosis and Lung Diseases from Pfizer and to the Polish Respiratory Society from AstraZeneca; consulting fees from AstraZeneca, Pfizer, Amgen, Takeda, Merck Sharp & Dohme, Roche and Roche Diagnostica; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Pfizer, CelonPharma, Amgen, Takeda, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Roche Diagnostica and Amoy; support for attending meetings and/or travel from Bristol Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Pfizer and Amgen; participation on a data safety monitoring board or advisory board for AstraZeneca, Pfizer, Takeda, Merck Sharp & Dohme, Roche and Roche Diagnostica, all in the 36 months prior to manuscript submission; and is Secretary General of the European Respiratory Society and a member of the Executive Committees of the Polish Respiratory Society and the Polish Coalition for Personalized Medicine. D.R. Baldwin declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Squibb, AstraZeneca, Roche and Merck Sharp & Dohme, all in the 36 months prior to manuscript submission. J. Boyd is an employee of the European Lung Foundation. C. Faivre-Finn reports research grants from AstraZeneca and Elekta; payment or honoraria for presentations from AstraZeneca; support for attending meetings and/or travel from Elekta and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca and Merck Sharp & Dohme, all in the 36 months prior to manuscript submission. F. Galateau-Salle declares no competing interests. F. Gamarra declares no competing interests. B. Grigoriu declares support for attending meetings and/or travel from Roche and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, all in the 36 months prior to manuscript submission. G. Hardavella declares no competing interests. M. Hauptmann declares no competing interests. E. Jakobsen declares no competing interests. D. Jovanovic declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck Sharp & Dohme, Roche, Boehringer Ingelheim, WCBIP 2020 and AstraZeneca; payment for expert testimony relating to the health effects of air pollution from SO2 released by Serbia Zijin Copper mining and smelting complex and the two biggest Serbian power plants, all in the 36 months prior to manuscript submission; and is a member of the editorial boards of the Journal of Thoracic Disease and the AME Surgical Journal, and a committee member of the National Ecological Association (NEA), Serbia. P. Knaut declares no competing interests. G. Massard declares a speaker's fee from Pneumo Update Europe, in the 36 months prior to manuscript submission. J. McPhelim declares advisory board payments from AstraZeneca, Janssen-Cilag and Bristol Myers Squibb, all in the 36 months prior to manuscript submission. A-P. Meert declares no competing interests. R. Milroy declares no competing interests. R. Muhr declares no competing interests. L. Mutti declares no competing interests. M. Paesmans declares no competing interests. P. Powell is an employee of the European Lung Foundation. P.M. Putora declares research grants to their institution from AstraZeneca, Takeda and Bayer; and a speaker's fee from Janssen-Cilag, all in the 36 months prior to manuscript submission. J. Rawlinson declares travel/accommodation support from the BTOG to attend the annual meeting in Dublin as patient advocate/steering committee member; travel/accommodation support from the European Respiratory Society to attend a screening meeting in Barcelona (patient representative) and European Lung Foundation patient event at the European Respiratory Society Congress Madrid 2019; travel/accommodation support from the NCRI to attend a conference in Glasgow (consumer member); travel/accommodation support from the EORTC to attend the Patient Days event as a speaker and patient panel member; and has been a Non-Executive Director (lay member) at Sandwell and West Birmingham Clinical Commissioning Group, UK. A.L. Rich declares no competing interests. D. Rigau is a methodologist for the European Respiratory Society. D. de Ruysscher declares grants to their institution from AstraZeneca and BeiGene; payment to their institution for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca; and payment to their institution for participation on an advisory board from AstraZeneca, all in the 36 months prior to manuscript submission. J-P. Sculier declares no competing interests. A. Schepereel declares a research grant to their institution from Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol Myers Squibb and Leo Pharma; support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme and Roche; and payment for participation on a data safety monitoring board or advisory board from AstraZeneca, Bristol Myers Squibb and Merck Sharp & Dohme, all in the 36 months prior to manuscript submission. D. Subotic declares no competing interests. P. Van Schil declares consulting fees paid to their institution by AstraZeneca and Merck Sharp & Dohme; payment to their institution for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca; and travel expenses related to participation in data safety monitoring or advisory boards for the LungART Trial and the Pearls Trial, all in the 36 months prior to manuscript submission; and is the President-elect of the International Association for the Study of Lung Cancer and the Treasurer of the Belgian Association for Cardio-Thoracic Surgery. T. Tonia is a methodologist for the European Respiratory Society. C. Williams is an employee of the European Lung Foundation. T. Berghmans declares consulting fees from InhaTarget; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen; and participation on a data safety monitoring board or advisory board for Janssen and Roche, all in the 36 months prior to manuscript submission., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function., Methods: A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function., Results: A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p = 0.02, hazard ratio = 1.13, 95% confidence interval: 1.02-1.25) and mean dose to the cardiac subregion (p = 0.02, hazard ratio = 1.11 Gy -1 , 95% confidence interval: 1.02-1.21) were significantly associated with overall survival. There was a significant interaction between EF and region dose (p = 0.04) for survival, with contrast plots revealing a larger effect of region dose on survival in patients with lower EF values., Conclusions: This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: On the basis of the findings of the phase 3 PACIFIC trial (NCT02125461), durvalumab is standard of care for patients with stage III, unresectable NSCLC and no disease progression after concurrent chemoradiotherapy (cCRT). Many patients are considered unsuitable for cCRT owing to concerns with tolerability. The phase 2 PACIFIC-6 trial (NCT03693300) evaluates the safety and tolerability of durvalumab after sequential CRT (sCRT)., Methods: Patients with stage III, unresectable NSCLC and no progression after platinum-based sCRT were enrolled to receive durvalumab (1500 mg intravenously) every 4 weeks for up to 24 months. The primary end point was the incidence of grade 3 or 4 adverse events possibly related to treatment occurring within 6 months. Secondary end points included investigator-assessed progression-free survival (PFS; Response Evaluation Criteria in Solid Tumors version 1.1) and overall survival., Results: Overall, 117 patients were enrolled (59.8% with performance status >0, 65.8% aged ≥65 y, and 37.6% with stage IIIA disease). Median treatment duration was 32.0 weeks; 37.6% of patients remained on treatment at data cutoff (July 15, 2021). Grade 3 or 4 AEs occurred in 18.8% of patients. Five patients had grade 3 or 4 possibly related adverse events within 6 months (incidence: 4.3%; 95% confidence interval: 1.4-9.7), including two pneumonitis cases. Two patients (1.7%) had grade 5 AEs of any cause. Survival data maturity was limited. Median PFS was 10.9 months (95% confidence interval: 7.3-15.6), and 12-month PFS and overall survival rates were 49.6% and 84.1%, respectively., Conclusions: Durvalumab after sCRT had a comparable safety profile with that observed with durvalumab after cCRT in PACIFIC and had encouraging preliminary efficacy in a frailer population., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Retrospective studies have identified a link between the average set-up error of lung cancer patients treated with image-guided radiotherapy (IGRT) and survival. The IGRT protocol was subsequently changed to reduce the action threshold. In this study, we use a Bayesian approach to evaluate the clinical impact of this change to practice using routine 'real-world' patient data., Methods and Materials: Two cohorts of NSCLC patients treated with IGRT were compared: pre-protocol change (N = 780, 5 mm action threshold) and post-protocol change (N = 411, 2 mm action threshold). Survival models were fitted to each cohort and changes in the hazard ratios (HR) associated with residual set-up errors was assessed. The influence of using an uninformative and a skeptical prior in the model was investigated., Results: Following the reduction of the action threshold, the HR for residual set-up error towards the heart was reduced by up to 10%. Median patient survival increased for patients with set-up errors towards the heart, and remained similar for patients with set-up errors away from the heart. Depending on the prior used, a residual hazard ratio may remain., Conclusions: Our analysis found a reduced hazard of death and increased survival for patients with residual set-up errors towards versus away from the heart post-protocol change. This study demonstrates the value of a Bayesian approach in the assessment of technical changes in radiotherapy practice and supports the consideration of adopting this approach in further prospective evaluations of changes to clinical practice., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study., Materials and Methods: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage., Results: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality., Conclusion: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Purpose: CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial., Methods: Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm., Results: The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology., Conclusion: The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.

Background: There is growing interest in the collection and use of patient-reported outcome measures (PROMs) to support clinical decision making in patients with non-small cell lung cancer (NSCLC). However, an overview of research into the prognostic value of PROMs is currently lacking., Aim: To explore to what extent, how, and how robustly the value of PROMs for prognostic prediction has been investigated in adults diagnosed with NSCLC., Methods: We systematically searched Medline, Embase, CINAHL Plus and Scopus for English-language articles published from 2011 to 2021 that report prognostic factor study, prognostic model development or validation study. Example data charting forms from the Cochrane Prognosis Methods Group guided our data charting on study characteristics, PROMs as predictors, predicted outcomes, and statistical methods. Two reviewers independently charted the data and critically appraised studies using the QUality In Prognosis Studies (QUIPS) tool for prognostic factor studies, and the risk of bias assessment section of the Prediction model Risk Of Bias ASsessment Tool (PROBAST) for prognostic model studies., Results: Our search yielded 2,769 unique titles of which we included 31 studies, reporting the results of 33 unique analyses and models. Out of the 17 PROMs used for prediction, the EORTC QLQ-C30 was most frequently used (16/33); 12/33 analyses used PROM subdomain scores instead of the overall scores. PROMs data was mostly collected at baseline (24/33) and predominantly used to predict survival (32/33) but seldom other clinical outcomes (1/33). Almost all prognostic factor studies (26/27) had moderate to high risk of bias and all four prognostic model development studies had high risk of bias., Conclusion: There is an emerging body of research into the value of PROMs as a prognostic factor for survival in people with NSCLC but the methodological quality of this research is poor with significant bias. This warrants more robust studies into the prognostic value of PROMs, in particular for predicting outcomes other than survival. This will enable further development of PROM-based prediction models to support clinical decision making in NSCLC., (© 2022. The Author(s).)

Toxicity concerns from thoracic radiation therapy in the treatment of lung cancers have changed substantially over the past few decades. Survival in the treatment of lung cancer has markedly improved and the introduction of advanced radiation and imaging techniques to treatment planning and delivery has made reducing toxicity possible. Phase 3 dose-escalation trials have revealed that excess dose to critical organs within the thorax can negatively impact overall survival. We summarize the existing literature on the known toxicities of thoracic radiation therapy, summarize the technological advances that have made toxicity reduction possible, and provide an overview of emerging technologies and biomarkers that are being evaluated to assess future toxicity reductions., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Objectives: Exercise has been reported to alleviate disease as well as treatment impact in patients with lung cancer. Nevertheless, there is limited information available regarding the perception of lung cancer dedicated healthcare professionals' and their advice on exercise., Materials and Methods: An online survey exploring healthcare professionals' practice patterns, perceptions, barriers, and facilitators of exercise in patients with lung cancer was conducted within members of the EORTC Lung Cancer Group (LCG)., Results: One hundred forty-one healthcare providers completed the survey, mainly medical and radiation oncologists. Overall, 63% of the study participants declared that they frequently assessed exercise level in their patients, and 43% of them reinforced the importance of exercise. However, only 10% referred patients to an exercise program or specialist. Although the majority of the respondents had a positive perception regarding the benefits and safety of exercise (even in patients with advanced disease and/or bone metastasis), two-thirds of clinicians reported not having adequate training about exercise counselling. Moreover, 53% reported to lack of knowledge of guidelines referring to exercise in patients with cancer. Several obstacles and facilitators to improve exercise promotion in lung cancer care were identified., Conclusion: Healthcare providers recognize the relevance and feasibility of exercise as part of cancer treatment intervention, but specific pathways to do the referral are frequently missing. Future structured and well-designed strategies and initiatives are needed to support an effective referral in order to implement exercise interventions routinely in clinical practice., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Lung cancer radiotherapy increases the risk of cardiotoxicity and heart radiation dose is an independent predictor of poor survival. This study describes heart doses and strategies aiming to reduce exposure., Materials and Methods: A systematic review of lung cancer dosimetry studies reporting heart doses published 2013-2020 was undertaken. Doses were compared according to laterality, region irradiated, treatment modality (stereotactic ablative body radiotherapy (SABR) and non-SABR), planning technique, and respiratory motion management., Results: For 392 non-SABR regimens in 105 studies, the average MHD was 10.3 Gy (0.0-48.4) and was not significantly different between left and right-sided tumours. It was similar between IMRT and 3DCRT (10.9 Gy versus 10.6 Gy) and lower with particle beam therapy (proton 7.0 Gy; carbon-ion 1.9 Gy). Active respiratory motion management reduced exposure (7.4 Gy versus 9.3 Gy). For 168 SABR regimens in 35 studies, MHD was 4.0 Gy (0.0-32.4). Exposure was higher in central and lower lobe lesions (6.3 and 5.8 Gy respectively). MHD was lowest for carbon ions (0.5 Gy) compared to other techniques. Active respiratory motion management reduced exposure (2.4 Gy versus 5.0 Gy). Delineation guidelines and Dose Volume Constraints for the heart varied substantially., Conclusions: There is scope to reduce heart radiation dose in lung cancer radiotherapy. Consensus on planning objectives, contouring and DVCs for the heart may lead to reduced heart doses in the future. For IMRT, more stringent optimisation objectives may reduce heart dose. Active respiratory motion management or particle therapy may be considered in situations where cardiac dose is high., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The current standard of care for patients with newly diagnosed limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy (CCRT). The prognosis remains poor due to the aggressiveness and high risk of progression or relapse of SCLC even if an initial response is achieved. Therefore, there is an urgent unmet clinical need in this population. The multicenter, phase 3, randomized, placebo-controlled, double-blind KEYLYNK-013 study evaluates the addition of pembrolizumab to CCRT followed by pembrolizumab with or without olaparib in participants with previously untreated limited-stage SCLC. (ClinicalTrials.gov: NCT04624204)., Methods: Eligible participants aged ≥18 years with newly diagnosed, pathologically confirmed, limited-stage (ie, stage I-III) SCLC will be randomized 1:1:1 to CCRT (ie, etoposide plus carboplatin or cisplatin for 4 cycles and standard thoracic radiotherapy) plus pembrolizumab (Groups A and B) or CCRT plus placebo (Group C). In the absence of disease progression, participants will receive pembrolizumab plus placebo (Group A), pembrolizumab plus olaparib (Group B), or placebo (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by blinded independent central review and overall survival., Results: Enrollment began in December 2020 and is ongoing at approximately 150 sites., Conclusions: KEYLYNK-013 will provide valuable information on the efficacy and safety of pembrolizumab plus CCRT and pembrolizumab with or without olaparib post CCRT in participants with limited-stage SCLC., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT., Method: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency., Results: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors., Conclusion: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted., Competing Interests: Conflict of interest statement None of the authors has any conflict of interest to declare concerning the current study. Some of the authors acknowledge public research support in the acknowledgement., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation., Competing Interests: Disclosure AP received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi Sankyo, eCancer, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme (MSD), Merck KGaA, Novartis, Pfizer, Roche/Genentech, Takeda, outside the submitted work. NL reports unrelated institutional research funding received from Amgen, Array, AstraZeneca, Bayer, BMS, Lilly, EMD Serono, Guardant Health, MSD, Pfizer, Roche, Takeda and unrelated personal fees (CME lectures, consulting) received from Bayer, Boehringer Ingelheim, BMS, Canadian Agency for Drugs and Technologies in Health, EMD Serono, MSD, Novartis, Sanofi Genzyme. SPo reports personal fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Janssen, Lilly, Merck KGaA, Novartis, Roche, Takeda, Seattle Genetics, Turning Point Therapeutics, GlaxoSmithKline, outside the submitted work. KK reports personal fees from AstraZeneca, Roche, during the conduct of the study. MJA reports personal fees from AstraZeneca, Takeda, Roche, Alpha Pharmaceutical, Amgen, Lilly, ONO, MSD, Merck, outside the submitted work. MEA reports personal fees from Biocartis, Invivoscribe, Janssen Global Services, BMS, AstraZeneca, Roche, Merck, RMEI Medical Education, Clinical Care Options, PeerView Institute for medical education, outside the submitted work. OA reports personal fees from Pfizer, grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Lilly, Merck, BMS, grants and personal fees from Roche, outside the submitted work. DP reports personal fees from AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, AbbVie, Janssen, outside the submitted work; and clinical trials research (as principal investigator or co-investigator): AstraZeneca, AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen. FdM reports grants and personal fees from AstraZeneca, grants from Boehringer, personal fees from Roche, BMS, Novartis, MSD, Pfizer, Takeda, outside the submitted work. AMD reports personal fees from Roche, Eli Lilly, Pfizer, Pharmamar, Takeda, Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Jansen, Chiesi, grants and personal fees from Amgen, personal fees from Bayer, Sanofi, outside the submitted work. RD reports personal fees from Pfizer, personal fees and non-financial support from Roche, non-financial support from AstraZeneca, personal fees from Novartis, Boehringer Ingelheim, Foundation Medicine, Karyopharm, outside the submitted work. CFF reports grants and other from AstraZeneca, other from MSD, grants and other from Elekta, during the conduct of the study. JF reports personal fees from Blueprint Medicines, Novartis, Janssen, AstraZeneca, outside the submitted work. EF reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, GlaxoSmithKline, Janssen, Medscape, Merck KGaA, MSD, Novartis, PeerVoice, Pfizer, prIME Oncology, Puma Biotechnology, Roche, Sanofi Genzyme, Springer, Takeda, Touch Medical, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, personal fees from CME Outfitters, BeiGene, Medical Trends, Peptomyc, Regeneron, from Syneos Health, outside the submitted work; and Grifols: independent member of the board. GC reports consultation fees from Pfizer, Roche, AstraZeneca, BMS, Daichii Sankyo, Seagen, Gilead, Novartis, Lilly, Ellipsis, Merck. RH reports consultation fees from AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Bolt Biotherapeutics, BMS, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Foundation Medicine, Inc., Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, HiberCell, Inc., I-Mab Biopharma, Immune-Onc Therapeutics, Immunocore, Infinity Pharmaceuticals, Johnson & Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Inc., Oncocyte Corp., Oncternal Therapeutics, Pfizer, Refactor Health, Inc., Ribbon Therapeutics, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Inc., Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems, Inc., WindMIL Therapeutics, Xencor, Inc., research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company, and participation on board of Immunocore Holdings Limited, Junshi Pharmaceuticals. PAJ reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Loxo Oncology, grants and personal fees from Eli Lilly, personal fees from SFJ Pharmaceuticals, Voronoi, grants and personal fees from Daiichi Sankyo, personal fees from Biocartis, Novartis, Sanofi, grants and personal fees from Takeda Oncology, personal fees from Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, grants from Revolution Medicines, grants from PUMA, grants from Astellas, outside the submitted work. In addition, PAJ is a co-inventor on a DFCI patent on EGFR mutations and receives postmarketing royalties from Lab Corp. TJ reports personal fees from Pfizer, AstraZeneca, BMS, Merck, MSD, Takeda, Boehringer Ingelheim, Roche, Ignyta, Novartis, Bayer, Amgen, Gilead, Puma Pharmaceuticals, outside the submitted work. TM reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, personal fees from Pfizer, during the conduct of the study; personal fees from BMS, grants and personal fees from Ono, MSD, personal fees from Novartis, grants and personal fees from Taiho, personal fees from Takeda, Amgen, Invitae, Merck Biopharma, Thermo Fisher, grants from Bridge Biotherapeutics, grants and personal fees from Ethicon, outside the submitted work. TM reports personal fees and other from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd, Amgen, Amoy Diagnostics Co. Ltd, grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, Boehringer Ingelheim, grants, personal fees and other from BMS, personal fees and other from Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd, other from geneDecode, personal fees and other from Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, Lilly, Loxo Oncology, Lunit USA, Inc., personal fees from MD Health (Brazil), Medscape/WebMD, grants, personal fees and other from Merck Serono, MSD, personal fees and other from Mirati Therapeutics Inc., personal fees from MoreHealth, grants, personal fees and other from Novartis, personal fees and other from OrigiMed, personal fees from PeerVoice, Physicians' Education Resource, P. Permanyer SL, grants, personal fees and other from Pfizer, Inc., personal fees from PrIME Oncology, personal fees and other from Puma Biotechnology Inc., personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, grants, personal fees and other from Takeda, personal fees from Touch Medical Media, other from Virtus Medical Group, personal fees and other from Yuhan Corporation, other from AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, grants from Clovis Oncology, grants, personal fees and other from SFJ Pharmaceuticals, grants from Xcovery, personal fees and other from Curio Science, personal fees from Inivata, Berry Oncology, grants and personal fees from G1 Therapeutics Inc., other from Aurora, personal fees from Qiming Development (HK) Ltd, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd, Shanghai BeBirds Translation & Consulting Co., Ltd, Liangyihui Network Technology Co., Ltd, Taiho, personal fees and other from Gilead Sciences, Inc, Vertex Pharmaceuticals, personal fees from Covidien LP, outside the submitted work. NN reports personal fees from MSD, grants and personal fees from Qiagen, Biocartis, Incyte, Roche, BMS, Merck, Thermo Fisher, AstraZeneca, personal fees from Sanofi, Eli Lilly, Bayer, ArcherDx, grants and personal fees from Illumina, personal fees from Amgen, outside the submitted work. LPA reports grants from MSD, AstraZeneca, Pfizer, BMS, personal fees from Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint, BMS, Mirati, Janssen, other from Genomica, Altum sequencing, outside the submitted work. SR reports personal fees from AstraZeneca, BMS, Amgen, GlaxoSmithKline, Merck, Takeda, Eisai, Lilly, outside the submitted work. LS reports grants and personal fees from AstraZeneca, grants from Novartis, personal fees from Janssen, grants and personal fees from Genentech, personal fees from Takeda, Pfizer, grants from Boehringer Ingelheim, outside the submitted work. JV reports honoraria for invited speaker from AstraZeneca, BMS, MSD, and Novartis; participation on advisory board of AstraZeneca, BMS, Boehringer Ingelheim, Daichi Sankyo, MSD, Pfizer, and Roche; grant from MSD. IIW reports grants and personal fees from Genentech/Roche, Bayer, BMS, AstraZeneca, Pfizer, HTG Molecular, personal fees from Asuragen, grants and personal fees from Merck, GlaxoSmithKline, Guardant Health, personal fees from Flame, grants and personal fees from Novartis, Sanofi, personal fees from Daiichi Sankyo, grants and personal fees from Amgen, personal fees from Oncocyte, MSD, Platform Health, grants from Adaptive, Adaptimmune, EMD Serono, Takeda, Karus, Johnson & Johnson, 4D, Iovance, Akoya, outside the submitted work. JW reports personal fees from Amgen, AstraZeneca, Bayer, Blueprint, grants and personal fees from BMS, personal fees from Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, grants and personal fees from Janssen, personal fees from Lilly, Loxo, MSD, grants and personal fees from Novartis, Pfizer, personal fees from Roche, Seattle Genetics, Takeda, outside the submitted work. YLW reports personal fees from AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, Sanofi, Novartis, Takeda; grants from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui and Roche, outside the submitted work. JCHY reports personal fees and other from Amgen, grants, personal fees and other from AstraZeneca, personal fees and other from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, other from Eli Lilly, personal fees and other from Merck KGaA, Darmstadt, Germany, MSD, Novartis, personal fees from Ono Pharmaceuticals, Pfizer, personal fees and other from Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, other from Johnson & Johnson, Glaxo, Puma Technology, outside the submitted work. YY reports and contracted studies with ArcherDx, Chugai Pharma and Thermo Fisher Science; honoraria for lectures from MSD, Chugai Pharma, AstraZeneca, Pfizer, Roche/Ventana, Agilent/Dako, Thermo Fisher Science, ArcherDx, Novartis, Eli Lilly, Amgen and Sysmex; participation on advisory board of MSD, Chugai Pharma, AstraZeneca, Novartis, Amgen, Takeda and Daiichi-Sankyo. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, BMS, grants from Lilly, grants and personal fees from MSD, Novartis, outside the submitted work. SPe received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines Corporation, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she received honoraria (all fees to institution). All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non-small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned., Methods: Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method., Results: Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS., Conclusion: These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting., Competing Interests: David R. SpigelLeadership: ASCO (Inst)Consulting or Advisory Role: Genentech/Roche (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Takeda (Inst), Evelo Therapeutics (Inst), Bayer (Inst), EMD Serono (Inst), Molecular Templates (Inst), Amgen (Inst), Curio Science (Inst), Intellisphere (Inst), Ipsen (Inst), Jazz Pharmaceuticals (Inst), Mirati Therapeutics (Inst), Puma Biotechnology (Inst), Sanofi/Aventis (Inst), Exelixis (Inst), Novocure (Inst), Regeneron (Inst), Lilly (Inst), Janssen (Inst), Evidera (Inst)Research Funding: Genentech/Roche (Inst), Novartis (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), AstraZeneca (Inst), University of Texas Southwestern Medical Center—Simmons Cancer Center (Inst), Merck (Inst), G1 Therapeutics (Inst), Neon Therapeutics (Inst), Takeda (Inst), Nektar (Inst), Celldex (Inst), Clovis Oncology (Inst), Daiichi Sankyo (Inst), EMD Serono (Inst), Astellas Pharma (Inst), GRAIL (Inst), Transgene (Inst), Aeglea Biotherapeutics (Inst), Ipsen (Inst), BIND Therapeutics (Inst), Eisai (Inst), ImClone Systems (Inst), Immunogen (Inst), Janssen Oncology (Inst), MedImmune (Inst), Molecular Partners (Inst), Agios (Inst), GlaxoSmithKline (Inst), Tesaro (Inst), Cyteir (Inst), Apollomics (Inst), Novocure (Inst), Elevation Oncology (Inst), Calithera Biosciences (Inst), Arcus Biosciences (Inst), Arrys Therapeutics (Inst), Bayer (Inst), BeiGene (Inst), BioNTech (Inst), Blueprint Medicines (Inst), Boehringer Ingelheim (Inst), Denovo Biopharma (Inst), Hutchison MediPharma (Inst), Incyte (Inst), Kronos Bio (Inst), Loxo Oncology (Inst), Macrogenics (Inst), Molecular Templates (Inst), Oncologie (Inst), Pfizer (Inst), PTC Therapeutics (Inst), PureTech (Inst), Razor Genomics (Inst), Repare Therapeutics (Inst), Rgenix (Inst), Tizona Therapeutics Inc (Inst), Verastem (Inst)Travel, Accommodations, Expenses: AstraZeneca, Genentech, Novartis Corinne Faivre-FinnTravel, Accommodations, Expenses: AstraZeneca Jhanelle E. GrayHonoraria: Merck Sharp & Dohme, Axiom Healthcare Strategies, InivataConsulting or Advisory Role: Novartis, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, EMD Serono, Lilly, AstraZeneca, Sanofi, Merck Sharp & Dohme, Janssen Scientific AffairsResearch Funding: Array BioPharma (Inst), Merck (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Genentech/Roche (Inst), G1 Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Ludwig Institute for Cancer Research (Inst)Travel, Accommodations, Expenses: Merck Sharp & Dohme, Inivata, Merck, EMD Serono, Novartis David VicenteHonoraria: AstraZenecaConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme Oncology, Roche/Genentech, Pfizer, AstraZeneca, Boehringer IngelheimTravel, Accommodations, Expenses: AstraZeneca David PlanchardHonoraria: Prime Oncology, PeerVoiceConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche, Pfizer, Merck Sharp & Dohme Oncology, Celgene, MedImmune, BeiGene, Samsung, AbbVie, Janssen, Daiichi Sankyo/Astra ZenecaResearch Funding: AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Lilly (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Sanofi/Aventis (Inst), Taiho Pharmaceutical (Inst), Daiichi Sankyo (Inst), AbbVie (Inst), Janssen (Inst) Johan F. VansteenkisteHonoraria: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Merck Sharp & Dohme Oncology (Inst), Roche (Inst), Lilly (Inst), Daiichi-Sankyo (Inst)Consulting or Advisory Role: Novartis (Inst), Boehringer Ingelheim (Inst), AstraZeneca (Inst), Merck Sharp & Dohme Oncology (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Daiichi-Sankyo (Inst)Research Funding: Merck Sharp & Dohme (Inst) Marina C. GarassinoHonoraria: Merck Sharp & Dohme Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Novartis, Takeda, Roche, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, RegeneronSpeakers' Bureau: AstraZeneca, Takeda, Merck Sharp & Dohme Oncology, Celgene, Incyte, Roche, Bristol Myers Squibb, Otsuka, LillyResearch Funding: Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), AstraZeneca (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Merck (Inst), Incyte (Inst), Takeda (Inst), Spectrum Pharmaceuticals (Inst), Blueprint Medicines (Inst), Lilly (Inst), AstraZeneca (Inst), Ipsen (Inst), Janssen (Inst), Exelixis (Inst), MedImmune (Inst), Sanofi (Inst), Pfizer (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Rina HuiHonoraria: Merck Sharp & Dohme, Novartis, Roche, AstraZeneca, Bristol Myers Squibb, Lilly, Pfizer, Seattle Genetics, Oncosec, MerckConsulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Roche, Bristol Myers Squibb, Novartis, Lilly, Pfizer, Seattle Genetics, Oncosec, MerckResearch Funding: AstraZeneca (Inst), Lilly (Inst), Merck Sharp & Dohme (Inst), Roche (Inst), Seattle Genetics (Inst), OncoSec (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Novartis Xavier QuantinHonoraria: Bristol Myers Squibb France, AstraZeneca, AmgenTravel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme Oncology Andreas RimnerHonoraria: More HealthConsulting or Advisory Role: AstraZeneca, Merck, Boehringer IngelheimResearch Funding: Varian Medical Systems (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), AstraZeneca (Inst), Merck (Inst) Yi-Long WuHonoraria: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, Merck Sharp & Dohme Oncology, Bristol Myers Squibb/China, Hengrui PharmaceuticalConsulting or Advisory Role: AstraZeneca, Roche, Boehringer Ingelheim, TakedaResearch Funding: Boehringer Ingelheim (Inst), Roche (Inst), Pfizer (Inst) Mustafa ÖzgüroğluHonoraria: Astellas Pharma, Novartis, Janssen Oncology (Inst)Consulting or Advisory Role: Merck Sharp & Dohme Oncology, AstraZenecaSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Ki H. LeeConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, Lilly Terufumi KatoEmployment: Lilly (I)Honoraria: Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Merck Sharp & Dohme, Novartis, Takeda, Daiichi Sankyo, Merck SeronoConsulting or Advisory Role: AstraZeneca, Merck Sharp & Dohme, Lilly, Pfizer, Merck SeronoResearch Funding: Chugai Pharma (Inst), Merck Sharp & Dohme (Inst), Pfizer (Inst), Taiho Pharmaceutical (Inst), AstraZeneca (Inst), Lilly (Inst), AbbVie (Inst), Ono Pharmaceutical (Inst), Regeneron (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Amgen (Inst), Merck Serono Maike de WitConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Ipsen, AbbVie, Jazz PharmaceuticalsSpeakers' Bureau: AstraZeneca, Ipsen, Janssen, Merck Sharp & Dohme, SanofiResearch Funding: AstraZeneca (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Janssen (Inst), Merck Sharp & Dohme (Inst), Boehringer Ingelheim (Inst), Pierre Fabre (Inst), Ipsen (Inst), Amgen (Inst), Genzyme (Inst), Pfizer (Inst), Takeda (Inst), Noona Healthcare (Inst), AbbVie (Inst), Nucana (Inst), MorphoSys (Inst)Travel, Accommodations, Expenses: Astellas Pharma, AstraZeneca, Takeda, Pfizer Takayasu KurataHonoraria: AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Lilly, Boehringer Ingelheim, Merck Sharp & Dohme OncologyResearch Funding: Merck Sharp & Dohme Oncology (Inst), AstraZeneca (Inst), Lilly (Inst), Ono Pharmaceutical (Inst), Novartis (Inst), Takeda (Inst), Bristol Myers Squibb (Inst) Martin ReckConsulting or Advisory Role: Lilly, Merck Sharp & Dohme Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, AbbVie, Amgen, Mirati Therapeutics, Samsung Bioepis, Sanofi/RegeneronSpeakers' Bureau: Roche/Genentech, Lilly, Merck Sharp & Dohme Oncology, Merck Serono, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics, Sanofi/Aventis Byoung C. ChoLeadership: Gencurix, Interpark BioStock and Other Ownership Interests: Theravance, Gencurix, Bridgebio, Kanaph Therapeutics, Cyrus therapeutics, Interpark BioConsulting or Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Yuhan, Pfizer, Janssen, Takeda, Merck Sharp & Dohme, Ono Pharmaceutical, Lilly, Medpacto, Blueprint Medicines, Kanaph Therapeutics, Bridgebio, Cyrus Therapeutics, Guardant Health, Joseah BiopharmaResearch Funding: Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GI Innovation, Lilly, Blueprint Medicines, Interpark BioPatents, Royalties, Other Intellectual Property: Champions OncologyOther Relationship: DAAN Biotherapeutics Suresh SenanHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, Merck Sharp & Dohme Oncology, BeiGene, PfizerResearch Funding: ViewRay (Inst), AstraZeneca (Inst), Varian Medical Systems (Inst), Bristol Myers Squibb (Inst) Jarushka NaidooHonoraria: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, Daiichi Sankyo/Lilly, TakedaConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Roche/Genentech, Daiichi Sankyo/Lilly, Takeda, Pfizer, Kaleido BiosciencesResearch Funding: Merck (Inst), AstraZeneca (Inst), Roche/Genentech (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune Helen MannEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Michael NewtonEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Piruntha ThiyagarajahEmployment: AstraZeneca/MedImmune, Reckitt Benckiser (I)Stock and Other Ownership Interests: AstraZeneca/MedImmune Scott J. AntoniaConsulting or Advisory Role: Bristol Myers Squibb, Merck, Memgen, Achilles Therapeutics, Amgen, Celsius Therapeutics, EMD Serono, G1 Therapeutics, GlaxoSmithKline, Glympse Bio, RAPT Therapeutics, Samyang, Venn Therapeutics, Tarus TherapeuticsPatents, Royalties, Other Intellectual Property: Oncolytic VirusTravel, Accommodations, Expenses: RAPT Therapeutics, Celsius Therapeutics, Amgen, Achilles TherapeuticsNo other potential conflicts of interest were reported.

Background: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC., Materials and Methods: Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models., Results: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status., Conclusions: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable., Competing Interests: Disclosure SS reports participating on advisory boards for AstraZeneca, Celgene, Merck Sharp & Dohme, BeiGene, Eli Lilly, and Varian Medical Systems; and institutional research grants from AstraZeneca, Varian Medical Systems, and ViewRay Inc. MÖ reports receiving personal fees from Janssen, Astellas, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi, AstraZeneca, and MSD; and reports receiving a research grant from Janssen. DD reports receiving institutional research support from AstraZeneca, Genentech, Guardant Health, Janssen Research and Development, Bristol-Myers Squibb, G1 Therapeutics, Merck & Co, Inc., Novartis, AbbVie, ARMO Biosciences, Immunomedics, Eli Lilly, Merus NV, and Daiichi Sankyo. AV reports receiving personal fees for participating in a speakers’ bureau for AstraZeneca. DV reports receiving honoraria from AstraZeneca; receiving institutional research support from AstraZeneca, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; undertaking a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MDS Oncology, Pfizer, and Roche/Genentech; and receiving travel/accommodation/expenses from AstraZeneca, Pfizer, Merck Sharp & Dohme, and Roche. SM reports receiving institutional research support from Takeda Pharmaceuticals; and receiving travel/accommodations/expenses from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, and Ono Pharmaceutical. RH reports participating on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Oncosec, Pfizer, Seagen, and Roche; receiving honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Oncosec, Pfizer, Seagen, and Roche; receiving research funding (paid to the institution) from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novartis, Onosec, Roche, and Seagen; and receiving travel, accommodations, and expenses from Novartis. CF-F reports receiving honoraria from AstraZeneca; participating in a speaker’s bureau and an advisory board for AstraZeneca (fees paid to institution); is a scientific committee member/chair for AstraZeneca; and reports receiving research funding and travel, accommodations, or expenses from AstraZeneca and Elekta. LP-A reports being board member of Genomica; participating in a leadership role for ALTUM Sequencing; participating in a speaker’s bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merk Serono, MSD Oncology, Pfizer, and Roche/Genentech; receiving honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Incyte, Ipsen, Eli Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, Sysmex, and Takeda; receiving research funding (paid to the institution) from AstraZeneca, Bristol-Myers Squibb, Kura Oncology, Merck Sharp and Dohme, and PharmaMar; and receiving travel, accommodations, or expenses from Roche, AstraZeneca, AstraZeneca Spain, Bristol-Myers Squibb, Merck Sharp and Dohme, Eli Lilly, Pfizer, and Takeda. YLW reports receiving institutional research support from Roche, Pfizer, and Boehringer Ingelheim; receiving consultancy fees from AstraZeneca, Boehringer Ingelheim, Takeda, Roche, and Merck; and receiving honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Hengrui Pharmaceutical, MSD Oncology, Eli Lilly, Roche, Pierre Fabre, Pfizer, Sanofi, and Merck. HM is an employee of AstraZeneca and holds stock or stock options in AstraZeneca. PAD is a former employee of AstraZeneca and holds stock or stock options in AstraZeneca. SJA reports a consulting or advisory role for AstraZeneca, Achilles Therapeutics, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, CBMG, Celsius Therapeutics, EMD Serono, G1 Therapeutics, GlaxoSmithKline, Glympse Bio, Memgen, Merck, RAPT Therapeutics, Samyang, Tarus Therapeutics, and Venn Therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study., Materials and Methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages., Results: Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually., Conclusions: While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals' HRQoL, symptoms and toxicity in treatment decision-making., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Immune-mediated adverse events (imAEs), including all-cause immune-mediated pneumonitis, were reported in approximately 25% of patients in the placebo-controlled, phase III PACIFIC trial of durvalumab monotherapy (for up to 12 months) in patients with unresectable, stage III NSCLC and no disease progression after concurrent chemoradiotherapy; only 3.4% of patients experienced grade 3/4 imAEs. With broad application of the PACIFIC regimen (consolidation durvalumab after chemoradiotherapy), now standard-of-care in this setting, there is a need to better characterize the occurrence of imAEs with this regimen., Methods: We performed descriptive, post-hoc, exploratory analyses to characterize the occurrence of imAEs (pneumonitis and non-pneumonitis) in PACIFIC in terms of: incidence, severity, and timing; clinical management and outcomes; and associations between the occurrence of imAEs and (1) all-cause AEs and (2) baseline patient, disease, and treatment characteristics., Results: Any-grade immune-mediated pneumonitis (9.4%) and non-pneumonitis imAEs (10.7%) occurred infrequently and were more common with durvalumab versus placebo. Grade 3/4 immune-mediated pneumonitis (1.9%) and non-pneumonitis imAEs (1.7%) were uncommon with durvalumab, as were fatal imAEs (0.8%; all pneumonitis). The most common non-pneumonitis imAEs with durvalumab were thyroid disorders, dermatitis/rash, and diarrhea/colitis. Dermatitis/rash had the shortest time to onset (from durvalumab initiation), followed by pneumonitis; dermatitis/rash had the longest time to resolution, followed by thyroid disorders. Most patients with immune-mediated pneumonitis (78.4%) and non-pneumonitis imAEs (56.3%) had these events occur ≤ 3 months after initiating durvalumab. ImAEs were well managed with administration of systemic corticosteroids, administration of endocrine replacement therapy, and interruption/discontinuation of durvalumab. Time elapsed from completion of prior radiotherapy to trial randomization (<14 vs. ≥ 14 days) did not impact either incidence or severity of imAEs. Durvalumab had a manageable safety profile broadly irrespective of whether patients experienced imAEs., Conclusion: The risk of imAEs should not deter use of the PACIFIC regimen in eligible patients, as these events are generally well managed through appropriate clinical intervention., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure SP has received honoraria and consultant fees from AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, Novartis, Takeda, Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), EMD Serono, Bayer, Blueprint, Daiichi Sankyo, Guardant Health, Janssen, GlaxoSmithKline (GSK), BeiGene, Incyte, Eli Lilly, Seattle Genetics and Amgen; received institutional research funding from AstraZeneca, Roche, Boehringer Ingelheim, Clovis, Celgene, Novartis, Takeda, Ariad, BMS, MSD, Daiichi Sankyo, Guardant Health, Janssen, Epizyme, GSK, Mirati, Trizel and Turning Point Therapeutics. PB has received institutional research funding from AstraZeneca, BMS and MSD; holds non-remunerated consulting and advisory board roles for BMS, MSD, Pfizer, Epizyme, Trizel and Daiichi. IO holds an advisory board role for AstraZeneca; has received speakers fee from Roche and an institutional research grant from Medtronic and Roche. AS has an advisory board role for BMS, MSD, AstraZeneca and Roche and has received an institutional research grant from BMS. CFF has received institutional honoraria from AstraZeneca and institutional research funding from AstraZeneca and Elekta. AGN has received honoraria and consultant fees from Merck, BMS, AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, Novartis, Eli Lilly, AbbVie and Oncologica; has received institutional research funding from Pfizer and has produced educational content for AstraZeneca, Pfizer, UpToDate and European Society of Oncology. NG has received honoraria and consultant fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Roche and Trizell; has received institutional research funding from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Roche and Trizell; has received hospitality/travel expenses from AstraZeneca, BMS, Roche and has an immediate family member who is an employee of AstraZeneca. AKN has received honoraria and consultant fees from AstraZeneca, Boehringer Ingelheim, MSA Pharma, Trizell, Roche, Douglas Pharmaceuticals, Atara Biotherapeutics, Seagen, PharmAbcine, BMS and UpToDate; has received institutional research funding from AstraZeneca and Douglas Pharmaceuticals. MR has received honoraria for consultancy and lectures from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Merck, Mirati, MSD, Lilly, Novartis, Pfizer, Regeneron, Roche and Sanofi Bioepis.

Introduction: Recent studies suggest that immune-related cells can be recruited for anti-tumor functions as well as tumor progression and the interplay between systemic inflammation and local immune response may play a major role in the development and progression of various cancers including lung cancer. Inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) can be used as surrogate biomarkers of host immune status. In this work, associations between neutrophils, lymphocytes, platelets, NLR, PLR, SII and overall survival (OS) are investigated in two cohorts of non-small cell lung cancer (NSCLC) patients treated with fractionated radiotherapy (RT) and stereotactic body radiation therapy (SBRT) and a cohort of small cell lung cancer (SCLC) patients treated with fractionated RT., Material and Methods: Data from 2513 lung cancer patients were retrospectively analyzed. Baseline NLR, PLR, and SII (NLR × platelet count) were calculated from full blood test prior to RT initiation. Cox proportional hazards regression analyses were used to evaluate the association between systemic inflammation markers and known clinical factors with OS., Results: The two-year OS was 42%, 63%, and 62% in the NSCLC fractionated RT, SBRT, and SCLC cohort. NLR (per 1 unit: hazard ratio [HR]: 1.04, p  < 0.05) and SII (per 100 × 10 9 /L: HR: 1.01, p  < 0.05) remained the strongest independent factors of OS in multivariable Cox analyses, correcting for clinical factors in early-stage and locally advanced NSCLC and SCLC patients treated with RT., Discussion: This single-center large-cohort study suggests that baseline NLR and SII are independent prognostic biomarkers associated with OS in locally advanced and early-stage NSCLC patients treated with either curative-intent fractionated RT or SBRT and SCLC patients treated with curative-intent fractionated RT. External validation is warranted to evaluate the utility of these biomarkers for patients' stratification and adapting new treatment approaches.

Background: In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment., Methods: Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0-2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683., Findings: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with 18 F-fluorodeoxyglucose ( 18 F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group., Interpretation: Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using ( 18 F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC., Funding: French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League., Competing Interests: Declaration of interests CLP reports grants to the institution from Amgen, AstraZeneca, Eli Lilly, Medscape, and Nanobiotix; grants to the institution for participation in advisory boards for Roche; and grants to the institution for speaker fees from PriMEOncology, all outside the submitted work. NP reports grants from Pfizer and Varian, all outside the submitted work. FB reports personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly Oncology, Roche, Novartis, Merck, Merck Sharp & Dohme, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. UN reports consulting fees, honoraria, and participation in advisory boards for AstraZeneca. PB reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck; support for meetings and travel from Merck Sharp & Dohme; and participation in advisory boards for Merck. ED reports personal financial interests from Astra-Zeneca, Ipsen, Merck Sharp & Dohme, Novartis, and Roche, all outside the submitted work. GZ reports personal fees from AstraZeneca, BMS, Boehringer, and MSD; and non-financial support and funding for international meeting attendance from Abbvie, AstraZeneca, MSD, Pfizer, Roche, and Takeda, all outside the submitted work. EP reports personal financial interests from AstraZeneca, Bristol-Myers Squibb, Roche, and Takeda; and non-financial support from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme, all outside the submitted work. ALav reports travel and accommodation grants from Bristol-Myers Squibb; and a consulting role for AstraZeneca, all outside the submitted work. CF-F reports grants from AstraZeneca and Elekta, all outside the submitted work. PAT reports financial support for teaching lectures and advisory boards from AstraZeneca and Ethicon Endosurgery, all outside the submitted work. OM reports financial support for participation in advisory boards AstraZeneca and MSD, all outside the submitted work. AB reports consultancy fees from Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020., Materials and Methods: Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression., Results: In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease., Conclusions: The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Small cell lung cancer (SCLC) is an aggressive form of lung cancer associated with an increased risk of develping brain metastases (BM), which are a significant cause of morbidity and mortality. Prophylactic cranial irradiation (PCI) was first introduced in the 1970s with the aim of reducing BM incidence and improving survival and quality of life (QoL). Prospective clinical trials and meta-analyses have demonstrated its effectiveness in reducing BM incidence and improving survival, across all stages of the disease following response to induction chemotherapy. Despite its long history, "unknowns" surrounding PCI use still exist and there are particular subgroups of patients for which its use remains controversial. PCI is known to cause neurocognitive toxicity which can have a significant impact on a patient's QoL. Strategies to minimise this, including the use of hippocampal avoidance radiotherapy techniques, neuroprotective drugs and stereotactic radiosurgery in place of whole brain radiotherapy for the treatment of BM, are under evaluation. This review offers a summary of the key PCI trials published to date and the current treatment recommendations based on available evidence. It also discusses the key questions being addressed in ongoing clinical trials and highlights others where there is currently a knowledge gap and therefore where further data are urgently required., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer., Methods: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed., Results: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors., Conclusion: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: So far, the impact of intra-thoracic anatomical changes (ITACs) on patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is unknown. Studying these is important, as ITACs have the potential to impact the workflow and reduce treatment quality. The aim of this study was to assess and categorise ITACs, as detected on cone beam computed tomography scans (CBCT), and their subsequent impact upon treatment in lung cancer patients treated with SABR., Materials and Methods: CBCTs from 100 patients treated with SABR for early non-small cell lung cancer were retrospectively reviewed. The presence of the following ITACs was assessed: atelectasis, infiltrative change, pleural effusion, baseline shift and gross tumour volume (GTV) increase and decrease. ITACs were graded using a traffic light protocol. This was adapted from a tool previously developed to assesses potential target undercoverage or organ at risk overdose. The frequency of physics or clinician review was noted. A linear mixed effects model was used to assess the relationship between ITAC grade and set-up time (time from first CBCT to beam delivery)., Results: ITACs were observed in 22% of patients. Twenty-one per cent of these were categorised as 'red', implying a risk of underdosage to the GTV. Most were 'yellow' (51%), indicating little impact upon planning target volume coverage of the GTV. Physics or clinician review was required in 10% of all treatment fractions overall. Three patients needed their treatment replanned. The mixed effect model analysis showed that ITACs cause a significant prolongation of set-up time (Χ 2 (3) = 9.22, P = 0.02)., Conclusion: Most ITACs were minor, but associated with unplanned physics or clinician review, representing a potentially significant resource burden. ITACs also had a significant impact upon set-up time, with consequences for the wider workflow and intra-fraction motion. Detailed guidance on the management of ITACs is needed to provide support for therapeutic radiographers delivering lung SABR., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Aims: The neutrophil-lymphocyte ratio (NLR) and the absolute lymphocyte count (ALC) have been proposed as prognostic markers in non-small cell lung cancer (NSCLC). The objective of this study was to examine the association of NLR/ALC before and after curative-intent radiotherapy for NSCLC on disease recurrence and overall survival., Materials and Methods: A retrospective study of consecutive patients who underwent curative-intent radiotherapy for NSCLC across nine sites in the UK from 1 October 2014 to 1 October 2016. A multivariate analysis was carried out to assess the ability of pre-treatment NLR/ALC, post-treatment NLR/ALC and change in NLR/ALC, adjusted for confounding factors using the Cox proportional hazards model, to predict disease recurrence and overall survival within 2 years of treatment., Results: In total, 425 patients were identified with complete blood parameter values. None of the NLR/ALC parameters were independent predictors of disease recurrence. Higher pre-NLR, post-NLR and change in NLR plus lower post-ALC were all independent predictors of worse survival. Receiver operator curve analysis found a pre-NLR > 2.5 (odds ratio 1.71, 95% confidence interval 1.06-2.79, P < 0.05), a post-NLR > 5.5 (odds ratio 2.36, 95% confidence interval 1.49-3.76, P < 0.001), a change in NLR >3.6 (odds ratio 2.41, 95% confidence interval 1.5-3.91, P < 0.001) and a post-ALC < 0.8 (odds ratio 2.86, 95% confidence interval 1.76-4.69, P < 0.001) optimally predicted poor overall survival on both univariate and multivariate analysis when adjusted for confounding factors. Median overall survival for the high-versus low-risk groups were: pre-NLR 770 versus 1009 days (P = 0.34), post-NLR 596 versus 1287 days (P ≤ 0.001), change in NLR 553 versus 1214 days (P ≤ 0.001) and post-ALC 594 versus 1287 days (P ≤ 0.001)., Conclusion: NLR and ALC, surrogate markers for systemic inflammation, have prognostic value in NSCLC patients treated with curative-intent radiotherapy. These simple and readily available parameters may have a future role in risk stratification post-treatment to inform the intensity of surveillance protocols., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure A-MCD reports receipt of honoraria for participation in advisory boards and/or lectures from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, Bristol Myers Squibb (BMS), Amgen, Novartis, Merck Sharp & Dohme (MSD), Takeda and PharmaMar; research funding from BMS, AbbVie and Amgen. MF reports receipt of advisory board honoraria to institution from BMS, Takeda, AstraZeneca, Boehringer Ingelheim, MSD and Roche. AA reports receipt of honoraria for participation in advisory boards from AstraZeneca, Roche, MSD, BMS, Lilly, Takeda and Bayer; research grant from BMS. BB reports receipt of grants/research support to institute from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline (GSK), Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE Immunotherapeutics, Pfizer, PharmaMar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma and Tolero Pharmaceuticals. CF-F reports participation in advisory boards for AstraZeneca; research funding from MSD and AstraZeneca. LEH reports research funding to institution from Roche, Boehringer Ingelheim and AstraZeneca; advisory board honoraria to institution from BMS, Lilly, Roche, Pfizer, Takeda, MSD, Amgen and Boehringer Ingelheim; speaker fees from MSD; travel/conference reimbursement from Roche and BMS; participation in mentorship program funded by AstraZeneca; fees for educational webinars from Quadia; fees to institution for interview sessions from Roche. SL reports consulting activities for MSD, AstraZeneca, BMS, Bayer and Eli Lilly. SP reports receipt of honoraria to institute for consultancy, advisory boards and/or lectures from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Mirati, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional financial support for clinical trials from Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, Roche, Illumina, MSD, Merck Serono, Novartis and Pfizer. NR reports receipt of speaker honoraria from MSD, BMS, Roche, Boehringer Ingelheim, Guardant Health, Pfizer, AbbVie, Ipsen, Novartis, AstraZeneca, Lilly, Takeda and Amgen; fees for organising educational events from Amgen and Roche; advisory panel honoraria from MSD, BMS, Roche, Boehringer Ingelheim, Guardant Health, Pfizer, AbbVie, Ipsen, Novartis, AstraZeneca, Lilly, Takeda and Amgen; sponsorship to attend scientific meetings from Boehringer Ingelheim, MSD and Roche; research grants from Novartis and Pfizer. CMR reports consultancy for AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros and Vavotek; serves on scientific advisory boards for Bridge Medicines and Harpoon Therapeutics. DDR reports receipt of research grants to institute from BMS, AstraZeneca and Boehringer Ingelheim; advisory board honoraria to institute from BMS, AstraZeneca, Boehringer Ingelheim and Philips; funding to institute for investigator-initiated study from Olink. PEVS reports board membership of IASLC; treasurer of BACTS; fees to institution for serving as an external expert for AstraZeneca, MSD and National Cancer Institute, France. JV reports receipt of advisory board honoraria and/or lecture fees from Boehringer Ingelheim, AstraZeneca, MSD, Novartis, Roche, Pfizer and BMS; research grant to institute from MSD. MR reports receipt of honoraria for lectures and consultancy from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Samsung; funding for academic research from BMS and Boehringer Ingelheim.

Outcomes of non-small cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD n = 587) and interstitial lung disease (ILD n = 34) treated with curative-intent radiotherapy were retrospectively investigated. Presence of ILD but not decreased forced expiratory volume in 1-second correlated with poor overall survival. Increased breathlessness and oxygen requirements after radiotherapy were observed in severe/very severe COPD and ILD., Competing Interests: Declaration of Competing Interest C. Faivre-Finn has declared research grants from AstraZeneca, MSD and Elekta and sits on the advisory boards of AstraZeneca and Pfizer. D. Woolf has declared travel grants, consultancy and speaker fees from AstraZeneca and travel grants from Roche. None of the other co-authors have any relevant conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Stereotactic body radiation therapy (SBRT) is an effective and well-tolerated treatment for medically inoperable patients with early stage NSCLC. SBRT is a noninvasive treatment involving the delivery of ablative radiation doses with high precision in the course of a few treatments. Relative to conventionally fractionated radiation, SBRT achieves superior local control and survival. SBRT use has increased dramatically in the past 15 years and is currently considered the standard of care in cases of inoperable early stage NSCLC. It is being increasingly applied to more complex patient populations at higher risk of treatment-related toxicity. In these more complex patients, there is an increasing need to balance patient and treatment factors in selecting the optimal patients for SBRT. Here, we review several challenging clinical scenarios often encountered in thoracic multidisciplinary tumor boards., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Introduction: Optimal treatment for 'potentially resectable' stage III-N2 non-small cell lung cancer (NSCLC) requires multimodality treatment: local treatment (surgery or radiotherapy) and systemic anticancer therapy. There is no clear evidence of superiority for survival between the two approaches and little research has explored quality of life (QOL). This study will inform the design of a phase III randomised trial of surgery versus no surgery as part of multimodality treatment for stage III-N2 NSCLC with QOL as a primary outcome., Methods and Analysis: Patient participants will be randomised to receive multimodality treatment (1) with surgery OR (2) without surgery. The Quintet Recruitment Intervention will be used to maximise recruitment. Eligible patients will have 'potentially resectable' N2 NSCLC and have received a multidisciplinary team recommendation for multimodality treatment. Sixty-six patients and their carers will be recruited from 8 UK centres. Patient/carer QOL questionnaires will be administered at baseline, weeks 6, 9, 12 and month 6. Semistructured interviews will be conducted. Quantitative data will be analysed descriptively and qualitative data will be analysed using framework analysis., Ethics and Dissemination: Ethical approval has been obtained. Results will be disseminated via publications, national bodies and networks, and patient and public involvement groups., Trial Registration: NCT04540757., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study compared MRI to CBCT for the identification and registration of lymph nodes (LN) in patients with locally advanced (LA)-NSCLC, to assess the suitability of targeting LNs in future MR-image guided radiotherapy (MRgRT) workflows., Method: Radiotherapy radiographers carried out Visual Grading Analysis (VGA) assessment of image quality, LN registration and graded their confidence in registration for each of the 24 LNs on CBCT and two MR sequences, MR1 (T2w Turbo Spin Echo) and MR2 (T1w DIXON water only image)., Results: Pre-registration image quality assessment revealed MR1 and MR2 as significantly superior to CBCT in terms of image quality (p ≤ 0.01). No significant differences were noted in interobserver variability for LN registration between CBCT, MR1 and MR2. Observers were more confident in their MR registrations compared to their CBCT based LN registrations (p ≤ 0.02)., Summary: Interobserver setup correction variability was not found to be significantly different between CBCT and MR. Image quality and registration confidence were found to be superior for MRI sequences. This is a promising step towards MR-guided radiotherapy for the treatment of LA-NSCLC., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Purpose . 4D-CT is routine imaging for lung cancer patients treated with stereotactic body radiotherapy. No studies have investigated optimal 4D phase selection for radiomics. We aim to determine how phase data should be used to identify prognostic biomarkers for distant failure, and test whether stability assessment is required. A phase selection approach will be developed to aid studies with different 4D protocols and account for patient differences. Methods . 186 features were extracted from the tumour and peritumour on all phases for 258 patients. Feature values were selected from phase features using four methods: (A) mean across phases, (B) median across phases, (C) 50% phase, and (D) the most stable phase (closest in value to two neighbours), coined personalised selection. Four levels of stability assessment were also analysed, with inclusion of: (1) all features, (2) stable features across all phases, (3) stable features across phase and neighbour phases, and (4) features averaged over neighbour phases. Clinical-radiomics models were built for twelve combinations of feature type and assessment method. Model performance was assessed by concordance index (c-index) and fraction of new information from radiomic features. Results . The most stable phase spanned the whole range but was most often near exhale. All radiomic signatures provided new information for distant failure prediction. The personalised model had the highest c-index (0.77), and 58% of new information was provided by radiomic features when no stability assessment was performed. Conclusion . The most stable phase varies per-patient and selecting this improves model performance compared to standard methods. We advise the single most stable phase should be determined by minimising feature differences to neighbour phases. Stability assessment over all phases decreases performance by excessively removing features. Instead, averaging of neighbour phases should be used when stability is of concern. The models suggest that higher peritumoural intensity predicts distant failure., (Creative Commons Attribution license.)