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Background: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy., Methods: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded., Results: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group., Conclusions: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.)., (Copyright © 2024 Massachusetts Medical Society.)

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with American Joint Committee on Cancer-Union for International Cancer Control TNM eighth edition stages II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus among panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include the following: (1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision-making of a multispecialty team of expert providers; (2) biomarker testing for rNSCLC; (3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; (4) equipoise regarding the optimal management of patients with stage II between upfront surgery followed by adjuvant therapy and neoadjuvant or perioperative strategies; and (5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups., Competing Interests: Disclosure Dr. Spicer reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Roche, Regeneron, and Pfizer; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, and Merck Sharp & Dohme; honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pfizer; meeting support from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; data safety monitoring board for AstraZeneca; and receipt of other services from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. Dr. Cascone reports receiving speaker fees and/or honoraria from the American Society for Clinical Oncology Post, AstraZeneca, Bio Ascend, Bristol-Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medical, PeerView, Physicians' Education Resource, Society for Immunotherapy of Cancer, and Targeted Oncology; advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Mark Foundation for Cancer Research, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, and Regeneron; and institutional research funding from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Dr.Ahn reports receiving consulting fees from AstraZeneca, Alpha Pharmaceuticals, Genxin, and Pfizer; and honoraria from Takeda, Roche, Merck, Merck Sharp & Dohme, AstraZeneca, Amgen, Boronoi, Arcus, Daiichi Sankyo, Bayer, and Janssen, outside the submitted work. Dr.Dacic reports receiving consulting fees from AstraZeneca, Genentech, and Medscape, outside the submitted work. Dr. Felip reports receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, and Daiichi Sankyo; honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; travel support from AstraZeneca, Janssen, and Roche; and other from Grifols as an independent member of the board, outside the submitted work. Dr. Forde reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Novartis, Regeneron, and BioNTech; consulting fees from Ascendis, AstraZeneca, Bristol-Myers Squibb, Curevac, Novartis, Regeneron, G1, Genlux, Genentech, Gritstone, Merck, Janssen, F Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, and Tavotek. Dr. Higgins reports receiving grants or contracts from Jazz Pharmaceuticals, RefleXion Medicalx; consulting fees from AstraZeneca and Janssen; positions on the NRG Oncology Board of Directors and RTOG Foundation Board of Directors; and stock or stock options in Picture Health. Dr. Kris reports receiving grant or contracts from BerGenBio, Merus, AstraZeneca, Mirati, Pfizer, Janssen, Sanofi, and Novartis; honoraria from Pfizer and AstraZeneca; and personal fees from AstraZeneca and Roche/Genentech, outside the submitted work. Dr. Mitsudomi reports receiving grants or contracts from Boehringer Ingelheim, AstraZeneca, Chugai, Pfizer, Ono, Daiichi Sankyo, and Eli Lilly; consulting fees from AstraZeneca, Novartis, Chugai, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Thermo Fisher, Roche Diagnostics, Bristol-Myers Squibb, Ono Pharmaceuticals, Taiho, Takeda, Janssen, Daiichi Sankyo, and Regeneron; honoraria from AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Daiichi Sankyo, Thermo Fisher, Merck Sharp & Dohme, Bristol-Myers Squibb, Ono Pharmaceuticals, Invitae, Guardant, Novartis, Amgen, Merck biopharma, and Kyorin; data safety monitoring board for Taiho Pharmaceutical, outside the submitted work. Dr. Provencio reports receiving grants or contracts from Bristol-Myers Squibb, AstraZeneca, Roche, Janssen, and Takeda; consulting fees from Bristol-Myers Squibb, Roche, AstraZeneca, Merck Sharp & Dohme, and Takeda; honoraria from Bristol-Myers Squibb, Takeda, Roche, AstraZeneca, and Merck Sharp & Dohme; and meeting attendance support from Merck Sharp & Dohme, Roche, and Bristol-Myers Squibb, outside the submitted work. Dr. Senan reports receiving grants or contracts from AstraZeneca, Merck Sharp & Dohme, and Bristol-Myers Squibb; consulting fees from AstraZeneca and Bristol-Myers Squibb; honoraria from AstraZeneca; advisory board participation for AstraZeneca and Merck Sharp & Dohme; and membership on ETOP scientific committee, outside the submitted work. Dr. Solomon reports receiving travel support from IASLC to attend meeting related to manuscript; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Merck Sharp & Dohme, Pfizer, Roche, GlaxoSmithKline, Janssen, and Amgen; honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and GlaxoSmithKline; unpaid leadership roles at the IASLC, Thoracic Oncology Group of Australasia, and Cancer Council of Victoria. Dr. Tsao reports receiving travel support from IASLC to attend meeting related to manuscript; grants or contracts from AstraZeneca, Bayer, and Lily; consulting fees from AstraZeneca, Bayer, Amgen, AbbVie, Regeneron, Sanofi, Daiichi Sankyo, and Lily; honoraria from AbbVie and Sanofi; and board of directors for IASLC. Dr. Tsuboi reports receiving grant from AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Novartis Japan, BMG KK, MiRXES, and Johnson & Johnson Japan; honoraria from Amgen KK, Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme KK, Bristol-Myers Squibb KK, Daiichi Sanko KK, and Novalis; advisory committee participation for Chugai Pharmaceutical Co., Ltd., and AstraZeneca KK; and Board of Directors for Japan Lung Cancer Society (JLCS), Bronchology Committee Chair for JLCS, and Educational Committee working group chair for IASLC, outside the submitted work. Dr. Wakelee reports receiving grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; advisory board participation for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership positions on the IASLC Board of Directors and ECOG-ACRIN executive committee. Dr. Wu reports receiving grants and contracts form AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Henqrui, and Roche; honoraria from AstraZeneca, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi; and unpaid leadership role for Chinese Thoracic Oncology Group. Dr. Yang reports receiving personal fees and other from Amgen, Bayer Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; grants, personal fees, and other from AstraZeneca; other from Eli Lilly; personal fees from Ono Pharmaceuticals and Pfizer; and other from JNJ, Puma Technology, Gilead, and GlaxoSmithKline, outside the submitted work. Dr. Zhou reports receiving consulting fees from Innovent Biologics, Hengrui, Qila, and TopAlliance Biosciences; honoraria from Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart. Dr. Kelly reports receiving grants from AstraZeneca, during the conduct of the study; grants and personal fees from Genentech and Bristol-Myers Squibb; and personal fees from AstraZeneca, outside the submitted work. 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.)

Competing Interests: FLS has received research funding from AstraZeneca and institutional honoraria from Astrazeneca. SS has received research funding from AstraZeneca and honoraria from MSD, AstraZeneca, and BMS.

Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC., Methods: This single-arm, phase-II trial enrolled operable T3-4N0-2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy., Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3-4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8 + T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8 + CD39 + T cells and lower HLA-DR + Tregs., Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0-2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs., Trial Registration Number: NCT04245514., Competing Interests: Competing interests: The authors have disclosed the following conflicts of interest: DEO-L received grants from Janssen and Curium, honoraria from EANM, EAU, ESMO, and Curium, travel support from EANM, ESMO, EAU, and Bayer, and serves on a Bayer advisory board. CD received institutional fees for advisory roles with BMS, AstraZeneca, and MSD. SMSH has research contracts with several pharmaceutical companies and received honoraria from Janssen. IB’s institution received support from BMS, AstraZeneca, and Boehringer Ingelheim, and he received honoraria from AstraZeneca, MSD, and BMS. FLS received a research grant from ViewRay and honoraria from AstraZeneca. SS’s institution received grants from Varian, ViewRay, and AstraZeneca; he received consulting fees and honoraria from AstraZeneca and MSD, and serves on advisory boards for AstraZeneca and MSD. TDdG’s institution received grants from Idera Pharmaceuticals, consulting fees from LAVA Therapeutics and Mendus, and she holds stock in LAVA Therapeutics. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Use of stereotactic ablative radiotherapy (SABR) for central lung tumors can result in up to a 35% incidence of late pulmonary toxicity. We evaluated an automated scoring method to quantify post-SABR bronchial changes by using artificial intelligence (AI)-based airway segmentation., Materials and Methods: Central lung SABR patients treated at Amsterdam UMC (AUMC, internal reference dataset) and Peter MacCallum Cancer Centre (PMCC, external validation dataset) were identified. Patients were eligible if they had pre- and post-SABR CT scans with ≤ 1 mm resolution. The first step of the automated scoring method involved AI-based airway auto-segmentation using MEDPSeg, an end-to-end deep learning-based model. The Vascular Modeling Toolkit in 3D Slicer was then used to extract a centerline curve through the auto-segmented airway lumen, and cross-sectional measurements were computed along each bronchus for all CT scans. For AUMC patients, airway stenosis/occlusion was evaluated by both visual assessment and automated scoring. Only the automated method was applied to the PMCC dataset., Results: Study patients comprised 26 from AUMC, and 33 from PMCC. Visual scoring identified stenosis/occlusion in 8 AUMC patients (31 %), most frequently in the segmental bronchi. After airway auto-segmentation, minor manual edits were needed in 9 % of patients. Segmentation for a single scan averaged 83sec (range 73-136). Automated scoring nearly doubled detected airway stenosis/occlusion (n = 15, 58 %), and allowed for earlier detection in 5/8 patients who had also visually scored changes. Estimated rates were 48 % and 66 % at 1- and 2-years, respectively, for the internal dataset. The automated detection rate was 52 % in the external dataset, with 1- and 2-year risks of 56 % and 61 %, respectively., Conclusion: An AI-based automated scoring method allows for detection of more bronchial stenosis/occlusion after lung SABR, and at an earlier time-point. This tool can facilitate studies to determine early airway changes and establish more reliable airway tolerance doses., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Stereotactic ablative radiotherapy (SABR) is increasingly used for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) and for pulmonary metastases. In patients with ES-NSCLC, SABR is highly successful with reported 5-year local control rates of approximately 90%. However, the assessment of local control following lung SABR can be challenging as radiological changes arising from radiation-induced lung injury (RILI) can be observed in up to 90% of patients. These so-called 'benign' radiological changes evolve with time and are often asymptomatic. Several radiological and metabolic features have been explored to help distinguish RILI from local recurrences (LR). These include the Response Evaluation Criteria for Solid Tumors (RECIST), high-risk features (HRF's) and maximum standardized uptake value (SUVmax) on FDG-PET-CT. However, use of some of these approaches have poor predictive values and low specificity for recurrence. A proposed new workflow for the evaluation of post-lung SABR radiological changes will be reviewed which uses the presence of so-called 'actionable radiological features' to trigger changes to imaging schedules and identifies the need for a multidisciplinary board review. Furthermore, this critical review of post-lung SABR imaging will highlight current challenges, new insights, and unknowns in this field., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Louie Alexander has received honoraria from AstraZeneca for speaker's bureau and advisory board participation, unrelated to the present work. Palma David reports a Clinician-Scientist Grant from the Ontario Institute for Cancer Research, royalties from Uptodate.com, and has a consultant role with equity from Need Inc, all unrelated to the present work. Senan Suresh has received honoraria from ViewRay Inc and the Department of Radiation Oncology at the Amsterdam University Medical Center has funded research agreements with ViewRay Inc. and Varian Medical Systems, unrelated to the present work. All other authors declare no conflicts of interest., (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: In inoperable stage III NSCLC, the standard of care is chemoradiotherapy and adjuvant durvalumab (IO) for 12 months. Pneumonitis is the commonest toxicity leading to discontinuation of IO. A failure to distinguish between expected radiation-induced changes, IO pneumonitis and infection can lead to unnecessary durvalumab discontinuation. We investigated the use of a structured multidisciplinary review of CT-scans, radiation dose distributions and clinical symptoms for the diagnosis of IO pneumonitis., Methods: A retrospective study was conducted at an academic medical center for patients treated for stage III NSCLC with chemoradiotherapy and adjuvant durvalumab between 2018 and 2021. An experienced thoracic radiologist reviewed baseline and follow-up chest CT-scans, systematically scored radiological features suspected for pneumonitis using a published classification system (Veiga C, Radioth Oncol 2018), and had access to screenshots of radiation dose distributions. Next, two experienced thoracic oncologists reviewed each patients' case record, CT-scans and radiation fields. A final consensus diagnosis incorporating views of expert clinicians and the radiologist was made., Results: Among the 45 included patients, 14/45 (31.1%) had a pneumonitis scored in patient records and durvalumab was discontinued in 11/45 cases (24.4%). Review by the radiologist led to a diagnosis of immune-related pneumonitis only in 6/45 patients (13.3%). Review by pulmonary oncologists led to a diagnosis of immune-related pneumonitis in only 4/45 patients (8.9%). In addition a suspicion of an immune-related pneumonitis was rejected in 3 separate patients (6.7%), after the thoracic oncologists had reviewed the patients' radiation fields., Conclusions: In patients treated using the PACIFIC regimen, multidisciplinary assessment of CT-scans, radiation doses and patient symptoms, resulted in fewer diagnoses of immune-related pneumonitis (8.9%). Our study underscores the challenges in accurately diagnosing either IO-related or radiation pneumonitis in patients undergoing adjuvant immunotherapy after chemoradiotherapy and highlights the need for multidisciplinary review in order to avoid inappropriate cessation of adjuvant IO., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: In stage III non-small cell lung cancer (NSCLC), curative treatment approaches used to include neoadjuvant therapy followed by surgery, and definitive chemoradiotherapy followed by consolidation durvalumab (CRT-ICI). Surgical strategies included either neoadjuvant chemotherapy (CTx-surg) or chemoradiotherapy (CRT-surg). We studied the outcomes of these three radical intent strategies in the Netherlands Cancer Registry (NCR) for patients diagnosed from 2017 to 2021., Materials and Methods: Patients with clinical stage III NSCLC (TNM edition 8) were identified in the NCR after excluding patients with known driver mutations, ECOG performance status >=2, N3-disease and those undergoing sequential chemoradiotherapy or single modality/palliative treatments. Overall survival (OS) was calculated from date of surgery or start of durvalumab., Results: Treatments delivered were CRT-ICI (n = 1016 patients), CRT-surg (n = 166) and CTx-surg (n = 111). The surgical series comprised 224 lobectomies, 21 bilobectomies and 32 pneumonectomies, with a 90-day postoperative mortality rate of 3.3 %. Use of CRT-surg decreased steeply after 2018, when durvalumab became fully reimbursed, and use of CRT-ICI increased. Three-year OS was better following CRT-surg (78.7 %) compared to CTx-surg (66.7 %) or CRT-ICI (63.2 %). After controlling for age, ECOG performance status and histology, the hazard ratios for CRT-surg and CTx-surg were 0.66 (95 % CI 0.47-0.91) and 0.82 (95 % CI 0.58-1.17), respectively, compared to CRT-ICI., Conclusion: Population survivals after curative strategies for clinical stage III NSCLC in The Netherlands exceed those reported historically for both surgical and non-surgical approaches. Use of surgery decreased from 2018 following the formal reimbursement of durvalumab. While variations in case-mix hamper comparison between curative treatment strategies, there is a clear need for randomized studies in subgroups with potentially resectable disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CD reports research grants from AstraZeneca and Bristol-Myers Squibb, consulting fees from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme. IB reports research grants from AstraZeneca, Bristol-Myers Squibb and Boehringer Ingelheim, consulting fees from AstraZeneca, Bristol-Myers Squibb and Boehringer Ingelheim. SS reports participating on advisory boards for AstraZeneca, Merck Sharp & Dohme, and Varian Medical Systems; and institutional research grants from AstraZeneca, Varian Medical Systems, and ViewRay. RD declares 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. Published by Elsevier B.V.)

The findings of two well conducted trials that randomised 1803 patients with a peripheral non-small cell lung cancer measuring ≤ 2 cm to a lobar to sub-lobar resection have established the latter as a new standard of care. It is important for non-surgical oncologists to appreciate the details of study design and outcomes of both studies, given the possible impact they have for considerations of stereotactic ablative radiotherapy (SABR) for operable patients with early-stage NSCLC. Differences in overall survival between the study populations highlight the impact of confounding factors like smoking history and comorbidities on reported outcomes. For example, despite low post-operative mortality rates in both trials, the 5-year disease-free survival rate in the CALGB 140503 trial was only approximately 60 % with either surgical procedure. Both phase III trials required guideline recommended nodal staging, which does not reflect real world surgical practice, and which may limit the generalisability of the reported findings to local institutional outcomes. Furthermore, the emergence of other malignancies was recorded in 15-18 % of study patients during follow-up, and patients who underwent sub-lobar resections had a better long-term survival associated with a higher likelihood of undergoing additional curative treatments. These findings from the JCOG0802 and the CALGB 140503 will encourage more interest in enrolling patients into ongoing trials comparing surgical resection with SABR., 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.)

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for patients with early-stage lung cancer who are inoperable. However, SABR causes benign radiation-induced lung injury (RILI) which appears as lesion growth on follow-up CT scans. This triggers the standard definition of progressive disease, yet cancer recurrence is not usually present, and distinguishing RILI from recurrence when a lesion appears to grow in size is critical but challenging. In this study, we developed a tool to do this using scans with apparent lesion growth after SABR from 68 patients. We performed bootstrapped experiments using radiomics and explored the use of multiple regions of interest (ROIs). The best model had an area under the receiver operating characteristic curve of 0.66 and used a sphere with a diameter equal to the lesion's longest axial measurement as the ROI. We also investigated the effect of using inter-feature and volume correlation filters and found that the former was detrimental to performance and that the latter had no effect. We also found that the radiomics features ranked as highly important by the model were significantly correlated with outcomes. These findings represent a key step in developing a tool that can help determine who would benefit from follow-up invasive interventions when a SABR-treated lesion increases in size, which could help provide better treatment for patients., (© 2024. The Author(s).)

Background: In patients with locally advanced unresectable non-small cell lung cancer (NSCLC), durvalumab, an anti-programmed cell death ligand-1 (PD-L1) antibody, has shown improved overall survival when used as consolidation therapy following concurrent chemoradiotherapy (CRT). However, it is unclear whether CRT itself upregulates PD-L1 expression. Therefore, this study aimed to explore the changes in the uptake of the anti PD-L1 antibody [ 89 Zr]Zr-durvalumab in tumors and healthy organs during CRT in patients with NSCLC., Methods: Patients with NSCLC scheduled to undergo CRT were scanned 7±1 days after administration of 37±1 MBq [ 89 Zr]Zr-durvalumab at baseline, 1-week on-treatment and 1 week after finishing 6 weeks of CRT. First, [ 89 Zr]Zr-durvalumab uptake was visually assessed in a low dose cohort with a mass dose of 2 mg durvalumab (0.13% of therapeutic dose) and subsequently, quantification was done in a high dose cohort with a mass dose of 22.5 mg durvalumab (1.5% of therapeutic dose). Tracer pharmacokinetics between injections were compared using venous blood samples drawn in the 22.5 mg cohort. Visual assessment included suspected lesion detectability. Positron emission tomography (PET) uptake in tumoral and healthy tissues was quantified using tumor to plasma ratio (TPR) and organ to plasma ratio, respectively., Results: In the 2 mg dose cohort, 88% of the 17 identified tumor lesions were positive at baseline, compared with 69% (9/13) for the 22.5 mg cohort. Although the absolute plasma concentrations between patients varied, the intrapatient variability was low. The ten quantitatively assessed lesions in the 22.5 mg cohort had a median TPR at baseline of 1.3 (IQR 0.7-1.5), on-treatment of 1.0 (IQR 0.7-1.4) and at the end of treatment of 0.7 (IQR 0.6-0.7). On-treatment, an increased uptake in bone marrow was seen in three out of five patients together with a decreased uptake in the spleen in four out of five patients., Conclusions: This study successfully imaged patients with NSCLC with [ 89 Zr]Zr-durvalumab PET before and during CRT. Our data did not show any increase in [ 89 Zr]Zr-durvalumab uptake in the tumor 1-week on-treatment and at the end of treatment. The changes observed in bone marrow and spleen may be due to an CRT-induced effect on immune cells., Trial Registration Number: EudraCT number: 2019-004284-51., Competing Interests: Competing interests: SMSH is on the advisory board and/or received institutional research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche and Takeda. DV received institutional research support from Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Boehringer Ingelheim, Roche and Aplagon. SS is on the advisory board of AstraZeneca, receives institutional research support and a speakers fee from AstraZeneca. SS is on the advisory board of Bristol-Myers Squibb and receives institutional research support from Bristol-Myers Squibb. CWM-vdHvO is advisor for GEHealthcare and Eli Lilly and received institutional research support from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, G1 Therapeutics and Bristol-Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Magnetic resonance imaging (MR)-guided radiotherapy permits continuous intrafraction visualization and use of automatic triggered beam delivery, with use of smaller planning target volumes (PTV). We report on long-term clinical outcomes following MR-guided single fraction (SF) lung SABR on a 0.35 T linac., Materials and Methods: Details of patients treated with SF-SABR for lung tumors were accessed from an ethics approved institutional database. A breath-hold 3D MR simulation scan was performed using a true FISP sequence, followed by a breath-hold 3D CT scan. The gross tumor volume (GTV) was first contoured on the breath-hold CT scan, which was then compared with contours on the 3D MR scan, before the GTV was finalized. SABR plans used step-and-shoot IMRT beams to a PTV derived by adding a 5 mm margin to the breath-hold GTV, and a 3 mm gating window was used. SABR was delivered during repeated breath-holds, using automatic beam gating with continuous visualization of the GTV in a sagittal MR plane., Results: Between 2018-2022, 50 consecutive patients were treated, and 69% had a primary non-small cell lung cancer. Median PTV was 11.2 cc (range 3.9-53.5); 80% of GTV's were located ≤2.5 cm from the chest wall. Prescribed doses were 34 Gy (in 58%), 30 Gy (32%), or between 20-28 Gy (10%). After a median follow-up of 18.1 months (95% CI 12.8-23.5), the 2-year survival was 82% (89% for primary NSCLC and 62% for metastases). After a median follow-up of 16.1 months (95% CI 11.2-21.1), local recurrences developed in 2 patients (4%). The 3-year local control rate was 97%, and just 1 patient developed grade ≥3 toxicity (chest wall pain)., Conclusion: MR-guided SF-SABR delivery to lung tumors on a 0.35 T linac, using repeated breath-holds with automatic beam gating, achieves good tumor control and low toxicity., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: This joint guideline by American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) was initiated to review evidence and provide recommendations regarding the use of local therapy in the management of extracranial oligometastatic non-small cell lung cancer (NSCLC). Local therapy is defined as the comprehensive treatment of all known cancer-primary tumor, regional nodal metastases, and metastases-with definitive intent., Methods: ASTRO and ESTRO convened a task force to address 5 key questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions address clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease. Recommendations were based on a systematic literature review and created using ASTRO guidelines methodology., Results: Based on the lack of significant randomized phase 3 trials, a patient-centered, multidisciplinary approach was strongly recommended for all decision-making regarding potential treatment. Integration of definitive local therapy was only relevant if technically feasible and clinically safe to all disease sites, defined as 5 or fewer distinct sites. Conditional recommendations were given for definitive local therapies in synchronous, metachronous, oligopersistent, and oligoprogressive conditions for extracranial disease. Radiation and surgery were the only primary definitive local therapy modalities recommended for use in the management of patients with oligometastatic disease, with indications provided for choosing one over the other. Sequencing recommendations were provided for systemic and local therapy integration. Finally, multiple recommendations were provided for the optimal technical use of hypofractionated radiation or stereotactic body radiation therapy as definitive local therapy, including dose and fractionation., Conclusions: Presently, data regarding clinical benefits of local therapy on overall and other survival outcomes is still sparse for oligometastatic NSCLC. However, with rapidly evolving data being generated supporting local therapy in oligometastatic NSCLC, this guideline attempted to frame recommendations as a function of the quality of data available to make decisions in a multidisciplinary approach incorporating patient goals and tolerances., Competing Interests: Disclosures All task force members’ disclosure statements were reviewed before being invited and were shared with other task force members throughout the guideline's development. Those disclosures are published within this guideline. Where potential conflicts were detected, remedial measures to address them were taken. Tom Boike: APEx reviewer (honoraria), Boston Scientific (speaker's bureau); Anne-Marie Dingemans: Amgen (advisory board, research), Bayer, Boehringer Ingelheim, Lilly, PharmaMar, Roche, Sanofi (all advisory boards), AstraZeneca, Chiesi, Janssen, Pfizer, Takeda (all honoraria), EORTC Lung Cancer Group (chair); Jill Feldman (patient representative): AstraZeneca, Blueprint Medicines, Janssen, Novartis (all honoraria), EGFR Resisters (cofounder), IASLC Patient Advocate Committee (chair); Daniel Gomez: AstraZeneca (consultant and research), GRAIL (consultant), Johnson & Johnson (consultant), Medtronic (advisory board), Medical Learning Group (honoraria–ended 8/2021), Varian (consultant and research); Matthias Guckenberger (co-chair): European Thoracic Oncology Platform (research), Varian (research-ended 12/2020), ViewRay (institutional research), ESTRO (president); Paul Hesketh (American Society of Clinical Oncology representative): UpToDate (consultant – editor); Puneeth Iyengar (co-chair): AstraZeneca (advisory board-ended 12/2020), National Cancer Institute/NRG Oncology (research – PI); Salma Jabbour: Advarra (consultant – DSMB), IMX Medical and Merck (consultant), Novocure (consultant-ended 4/2022), Beigene and Merck (institutional research grant), Syntactx (consultant – adjudication committee), International Journal of Radiation Oncology, Biology, and Physics (deputy editor), NCI Radiation Research Program, Upper GI Work Group (co-chair); Mirjana Josipovic: Danish National Research Center for Radiation Therapy (research), Varian (institutional research); Yolande Lievens: AstraZeneca (institutional research), Belgium College for Physicians in Radiation Oncology, (deputy chair-ended 10/2021), Belgium College of Oncology & AntiCancer Fund (board member), European Cancer Organization (Ex-officio executive committee member-ended 3/2022), ESTRO (former president), UGent Chair on ESTRO value-based health care (promotor, institutional research); Fiona McDonald: AstraZeneca (institutional research), Cancer Research United Kingdom (research – PI), Merck (institutional research), IASLC Advanced Radiotherapy Committee (chair), ESTRO ACROP Guidelines Committee (chair), UK SABR Consortium (chair); Bradford Perez: BMS (consultant, research-ended 12/2021), G1 Therapeutics (consultant–ended 4/2021); Umberto Ricardi: BrainLab (institutional research), ESTRO (past president); Enrico Ruffini: AstraZeneca (honoraria), European Society of Thoracic Surgeons (past president), IASLC (steering committee and chair, Thymic subcommittee); Dirk De Ruysscher: AstraZeneca and BMS (research and institutional advisory board), BeiGene (institutional research), Celgene, Merck/Pfizer, Roche/Genentech, Seattle Genetics (all institutional advisory boards), EORTC Lung Oligometastases committee (chair); Suresh Senan: AstraZeneca (advisory board – DSMB), BMS (consultant–ended 6/2022), BeiGene (advisory board-ended 3/2021), Merck (consultant), Varian and ViewRay (institutional research); Joachim Widder: Elekta and Raysearch (institutional research); Hina Saeed (Guideline Subcommittee representative),Clinical and Translational Radiation Oncology (editor); Bryan Schneider (American Society of Clinical Oncology representative), ASCO Guideline advisory group (co-chair), NCCN Immune Checkpoint Inhibitor-Related Toxicities guideline (vice chair). Sean All, Mark Berry, and Lisa Bradfield reported no disclosures., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Introduction: In patients with unresectable stage III non-small cell lung cancer, high-dose chemoradiotherapy (CRT) followed by consolidation durvalumab improves the 5-year overall survival compared to CRT alone. The feasibility and safety of salvage surgery for such patients who subsequently develop locoregional failure (LRF) is unclear. We evaluated our institutional experience with radical-intent salvage surgery in this patient population., Materials and Methods: Details of patients undergoing salvage surgery for locoregional failure after CRT and durvalumab were identified from an institutional surgical database. Each patient's case underwent multidisciplinary discussion at initial disease presentation, and again at time of progression., Results: Ten patients underwent salvage surgery for LRF after prior concurrent (n = 9) or sequential (n = 1) platinum-based high-dose chemo-radiotherapy followed by durvalumab. Consolidation durvalumab was completed in 4 patients, and discontinued in 6, due to either toxicity or disease progression. Median time between end of radiotherapy to detection of LRF was 19 months (range 6-75). Seven patients underwent a lobectomy, 1 a bilobectomy and 2 patients a pneumonectomy. Postoperative morbidity (Clavien-Dindo grade III-V) and 90-day mortality were 10% and 0%, respectively. Median follow-up after surgery was 7 months (range 1-25) during which 2 patients died (both 9 months post-operatively), one due to distant progression, and one of sepsis/bleeding. Eight patients are alive at 1-23 months post-surgery, with 6 showing no evidence of disease., Conclusions: Our results suggest that salvage pulmonary resection can be performed safely in selected patients with LRF following chemoradiotherapy and durvalumab. This radical-intent treatment option merits consideration by multidisciplinary lung tumor boards., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Stereotactic body radiation therapy (SBRT) of central lung tumors with photon or proton therapy has a risk of increased toxicity. Treatment planning studies comparing accumulated doses for state-of-the-art treatment techniques, such as MR-guided radiotherapy (MRgRT) and intensity modulated proton therapy (IMPT), are currently lacking., Purpose: We conducted a comparison of accumulated doses for MRgRT, robustly optimized non-adaptive IMPT, and online adaptive IMPT for central lung tumors. A special focus was set on analyzing the accumulated doses to the bronchial tree, a parameter linked to high-grade toxicities., Methods: Data of 18 early-stage central lung tumor patients, treated at a 0.35 T MR-linac in eight or five fractions, were analyzed. Three gated treatment scenarios were compared: (S1) online adaptive MRgRT, (S2) non-adaptive IMPT, and (S3) online adaptive IMPT. The treatment plans were recalculated or reoptimized on the daily imaging data acquired during MRgRT, and accumulated over all treatment fractions. Accumulated dose-volume histogram (DVH) parameters of the gross tumor volume (GTV), lung, heart, and organs-at-risk (OARs) within 2 cm of the planning target volume (PTV) were extracted for each scenario and compared in Wilcoxon signed-rank tests between S1 & S2, and S1 & S3., Results: The accumulated GTV D 98% was above the prescribed dose for all patients and scenarios. Significant reductions (p < 0.05) of the mean ipsilateral lung dose (S2: -8%; S3: -23%) and mean heart dose (S2: -79%; S3: -83%) were observed for both proton scenarios compared to S1. The bronchial tree D 0.1cc was significantly lower for S3 (S1: 48.1 Gy; S3: 39.2 Gy; p = 0.005), but not significantly different for S2 (S2: 45.0 Gy; p = 0.094), compared to S1. The D 0.1cc for S2 and S3 compared to S1 was significantly (p < 0.05) smaller for OARs within 1-2 cm of the PTV (S1: 30.2 Gy; S2: 24.6 Gy; S3: 23.1 Gy), but not significantly different for OARs within 1 cm of the PTV., Conclusions: A significant dose sparing potential of non-adaptive and online adaptive proton therapy compared to MRgRT for OARs in close, but not direct proximity of central lung tumors was identified. The near-maximum dose to the bronchial tree was not significantly different for MRgRT and non-adaptive IMPT. Online adaptive IMPT achieved significantly lower doses to the bronchial tree compared to MRgRT., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

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.

The introduction of immune checkpoint inhibitors has dramatically changed the treatment landscape and improved survival for many patients with thoracic malignancies. Although some patients may experience prolonged survival benefit with immune checkpoint inhibitors, a majority do not experience disease control or benefit, supporting the need for research and development of improved approaches for facilitating immune recognition. Additionally, many patients will experience toxicity with the current approaches to immunotherapy, supporting the need for developing treatment strategies with less risk of adverse events. An extensive array of different strategies are currently under investigation, including novel combinations of checkpoint inhibitors or immunotherapies; novel agents beyond checkpoint inhibitors (e.g., bispecific antibodies, vaccine strategies, cytokine therapies); and different approaches for use of radiation to augment systemic immunotherapy agents. With each strategy, researchers are evaluating the potential for augmenting antitumor responses and ensuring more sustained antitumor effects. This article highlights areas of active research, reviewing the rationale for different investigative strategies, as well as currently available clinical data.

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: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands., Material and Methods: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015-2017) was obtained from the Netherlands Cancer Registry (NCR)., Results: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015-2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from ≤ 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1)., Conclusion: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of ≤ 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Surgery is the preferred treatment for patients with early-stage non-small cell lung cancer (NSCLC) while stereotactic body radiation therapy (SBRT) may be applied in patients with major comorbidity or high age. We evaluated the association between age and treatment utilization for early-stage NSCLC in patients diagnosed in 2015-2016 in three European countries., Patients and Methods: Information was retrieved from population-based registries in England, Norway and the Netherlands. Treatment patterns and two-year overall survival rates for 105,124 patients with clinical stage I were analysed by age-group., Results: Surgical resection rates were higher in Norway (55%) and England (53%) than in the Netherlands (47%), and decreased with increasing age. SBRT use was highest in the Netherlands (41%), followed by Norway (29%) and England (12%). In the Netherlands, SBRT was the prevailing treatment in patients aged 70 years or older. In octogenarians, the proportion not receiving curative intent treatment was 53% in England, versus 35% in Norway and 22% in the Netherlands. Two-year survival rates were better for surgery than for SBRT and slightly better in Norway., Conclusion: In patients aged 70 years or older, the proportion not receiving any curative treatment remains substantial, and differs significantly between countries. Measures to address these disparities are needed., Competing Interests: Declaration of Competing Interest Dr. Senan reports grants from Varian Medical Systems, grants from ViewRay Inc., grants and personal fees from AstraZeneca, outside the submitted work. Other authors had nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The neoadjuvant use of immune checkpoint inhibitors (ICIs) in resectable non-small-cell lung cancer (NSCLC) is currently an area of active ongoing research. The place of neoadjuvant ICIs in the treatment guidelines needs to be determined. We carried out a systematic review of published data on neoadjuvant ICIs in resectable NSCLC to study its efficacy and safety., Patients and Methods: A literature search was carried out using the MEDLINE (PubMed) and Embase databases to retrieve articles and conference abstracts of clinical trials measuring the efficacy [major pathological response (MPR) and pathological complete response (pCR)] and safety (failure to undergo resection, surgical delay, treatment-related adverse events (trAEs) grade ≥3) of neoadjuvant immunotherapy in resectable NSCLC until July 2021., Results: Nineteen studies with a total of 1066 patients were included in this systematic review. Neoadjuvant immunotherapy was associated with improved pathological response rates, especially in combination with chemotherapy. Using mono ICI, dual therapy-ICI, chemoradiation-ICI, radiotherapy-ICI, and chemo-ICI, the MPR rates were 0%-45%, 50%, 73%, 53%, and 27%-86%, respectively. Regarding pCR, the rates were 7%-16%, 33%-38%, 27%, 27%, and 9%-63%, respectively. Safety endpoints using monotherapy-ICI, dual therapy-ICI, chemoradiation-ICI, radiotherapy-ICI, and chemo-ICI showed a failure to undergo resection in 0%-17%, 19%-33%, 8%, 13%, and 0%-46%, respectively. The trAEs grade ≥3 rates were 0%-20%, 10%-33%, 7%, 23%, and 0%-67%, respectively., Conclusion: In patients with resectable NSCLC stage, neoadjuvant immunotherapy can improve pathological response rates with acceptable toxicity. Further research is needed to identify patients who may benefit most from this approach, and adequately powered trials to establish clinically meaningful benefits are awaited., Competing Interests: Disclosure SS reports grants and personal fees from AstraZeneca; personal fees from MSD, BeiGene, and Celgene; grants and nonfinancial support from Varian Medical Systems; and grants from ViewRay Inc. IB reports grants from BMS and AstraZeneca. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Radiation therapy is a cornerstone of modern lung cancer treatment alongside surgery, chemotherapy, immunotherapy and targeted therapies. Advances in radiotherapy techniques have enhanced the accuracy of radiation delivery, which has contributed to the evolution of radiation therapy into a guideline-recommended treatment in both early-stage and locally advanced nonsmall cell lung cancer. Furthermore, although radiotherapy has long been used for palliation of disease in advanced lung cancer, it is increasingly having a role as a locally ablative treatment in patients with oligometastatic disease.This review provides an overview of recent developments in radiation techniques, particularly for non-radiation oncologists who are involved in the care of lung cancer patients. Technical advances are discussed, and findings of recent clinical trials are highlighted, all of which have led to a changing perception of the role of radiation therapy in multidisciplinary care., Competing Interests: Conflict of interest: T. Finazzi reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: F.L. Schneiders has nothing to disclose. Conflict of interest: S. Senan reports grants and personal fees from AstraZeneca and Varian Medical Systems, grants from ViewRay Inc., and personal fees from MSD and Celgene, outside the submitted work., (Copyright ©ERS 2021.)

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized., Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method., Results: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively., Conclusion: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Background and Purpose: Current nomograms predicting survival prognosis after stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) are based on peripherally located tumors. However, patients with a central lung tumor tend to be older, the tumor is often larger and fraction-schedules are risk-adapted. Therefore, we developed and externally validated a nomogram to predict overall survival (OS) in patients having centrally located early-stage NSCLC treated with SBRT., Materials and Methods: Patients who underwent SBRT for centrally located NSCLC were identified and baseline characteristics were obtained. A nomogram was built to predict 6-month, 1-, 2- and 3-year OS using Cox proportional hazards model. The model building procedure was validated using bootstrap sampling. To determine generalizability, external validation was performed on a cohort of patients with central NSCLC treated with SBRT from another center. Discriminatory ability was measured with the concordance index (C-index) and calibration plots were used to compare Kaplan-Meier-estimated and nomogram-predicted OS., Results: The nomogram was built on data of 220 patients and consisted of the following variables: PTV, age, WHO performance status, tumor lobe location and ultracentral location. The C-index of the nomogram (corrected for optimism) was moderate at 0.64 (95% confidence interval (CI) 0.59-0.69). Calibration plots showed favorable predictive accuracy. The external validation showed acceptable validity with a C-index of 0.62 (95% CI 0.61-0.64)., Discussion: We developed and externally validated the first nomogram to estimate the OS-probability in patients with centrally located NSCLC treated with SBRT. This nomogram is based on 5 patient and tumor characteristics and gives an individualized survival prediction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Treatment patterns in patients with stage III non-small cell lung cancer (NSCLC) vary considerably between countries, for reasons that are not well understood. We studied factors influencing treatment decision-making at thoracic multidisciplinary tumor boards (MDT's) and outcome for patients treated between 2015-2017, at a regional network comprising 5 hospitals., Materials and Methods: Details of all patients, including comorbidities, with stage III NSCLC were collected in an ethics-approved database. Weekly MDT's were conducted. The preferred radical intent treatments (RIT) for suitable patients were assumed to be concurrent chemoradiotherapy and/or surgery and other therapies were non-radical intent treatments (n-RIT)., Results: Of 197 patients identified, 95 % were discussed at an MDT. RIT were recommended in 61 % of patients, but only 48 % finally received RIT. The estimated median OS was significantly better for patients undergoing RIT (28.3 months, CI-95 % 17.3-39.3), versus those who did not (11.2 months, CI-95 % 8.0-14.3). Patient age ≥70 years and a WHO-PS ≥2 were the most important predictors of not recommending RIT. Deaths due to progressive lung cancer within 2 years were observed in 36, 26 and 29 % of patients who received RIT, sequential chemoradiotherapy or radical radiotherapy. Corresponding comorbidity related deaths within 2 years were 3, 12 and 38 %., Conclusion: A large number of patients who underwent MDT review were considered too old or not fit for RIT. More effective and better tolerated systemic treatments are required for patients presenting with stage III NSCLC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) accounts for approximately one in five cancer-related deaths, and management requires increasingly complex decision making by health care professionals. Many centers have therefore adopted a multidisciplinary approach to patient care, using the expertise of various specialists to provide the best evidence-based, personalized treatment. However, increasingly complex disease staging, as well as expanded biomarker testing and multimodality management algorithms with novel therapeutics, have driven the need for multifaceted, collaborative decision making to optimally guide the overall treatment process. To keep up with the rapidly evolving treatment landscape, national-level guidelines have been introduced to standardize patient pathways and ensure prompt diagnosis and treatment. Such strategies depend on efficient and effective communication between relevant multidisciplinary team members and have both improved adherence to treatment guidelines and extended patient survival. This article highlights the value of a multidisciplinary approach to diagnosis and staging, treatment decision making, and adverse event management in NSCLC. IMPLICATIONS FOR PRACTICE: This review highlights the value of a multidisciplinary approach to the diagnosis and staging of non-small cell lung cancer (NSCLC) and makes practical suggestions as to how multidisciplinary teams (MDTs) can be best deployed at individual stages of the disease to improve patient outcomes and effectively manage common adverse events. The authors discuss how a collaborative approach, appropriately leveraging the diverse expertise of NSCLC MDT members (including specialist radiation and medical oncologists, chest physicians, pathologists, pulmonologists, surgeons, and nursing staff) can continue to ensure optimal per-patient decision making as treatment options become ever more specialized in the era of biomarker-driven therapeutic strategies., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Introduction: The PACIFIC trial demonstrated that durvalumab significantly improved progression-free and overall survival (PFS/OS), versus placebo, in patients with Stage III NSCLC and stable or responding disease following concurrent, platinum-based chemoradiotherapy (CRT). A range of CT and RT regimens were permitted, and used, in the trial. We report post-hoc, exploratory analyses of clinical outcomes from PACIFIC according to CRT-related variables., Methods: Patients were randomized 2:1 (1-42 days post-CRT) to up to 12 months durvalumab (10 mg/kg intravenously every 2 weeks) or placebo. Efficacy and safety were analyzed in patient subgroups defined by the following baseline variables: platinum-based CT (cisplatin/carboplatin); vinorelbine, etoposide, or taxane-based CT (all yes/no); total RT dose (<60 Gy/60-66 Gy/>66 Gy); time from last RT dose to randomization (<14 days/≥14 days); and use of pre-CRT induction CT (yes/no). Treatment effects for time-to-event endpoints were estimated by hazard ratios (HRs) from unstratified Cox-proportional-hazards models., Results: Overall, 713 patients were randomized, of whom 709 received treatment in either the durvalumab (n/N = 473/476) or placebo arms (n/N = 236/237). Durvalumab improved PFS, versus placebo, across all subgroups (median follow up, 14.5 months; HR range, 0.34-0.63). Durvalumab improved OS across most subgroups (median follow up, 25.2 months; HR range, 0.35-0.86); however, the 95 % confidence interval (CI) of the estimated treatment effect crossed one for the subgroups of patients who received induction CT (HR, 0.78 [95 % CI, 0.51-1.20]); carboplatin (0.86 [0.60-1.23]); vinorelbine (0.79 [0.49-1.27]); and taxane-based CT (0.73 [0.51-1.04]); and patients who were randomized ≥14 days post-RT (0.81 [0.62-1.06]). Safety was broadly similar across the CRT subgroups., Conclusion: Durvalumab prolonged PFS and OS irrespective of treatment variables related to prior CRT to which patients with Stage III NSCLC had previously stabilized or responded. Limited patient numbers and imbalances in baseline factors in each subgroup preclude robust conclusions., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Risk information in patient decision aids (PDAs) is often difficult for older patients to process. Providing audiovisual and narrative information may enhance the understanding and use of health-related information. We studied the effects on patients' information processing and use of audiovisual and narrative information of an early-stage non-small-cell lung cancer treatment decision aid explaining surgery and stereotactic ablative radiotherapy. We further investigated differences between older and younger patients., Methods: We conducted a 2 (modality: textual v. audiovisual) × 2 (narration style: factual v. narrative) online experiment among cancer patients and survivors ( N = 305; M age = 62.42, SD = 11.68 y). Age was included as a potential modifier: younger (<65 y) versus older (≥65 y) age. We assessed 1) perceived cognitive load, 2) satisfaction with information, 3) comprehension, 4) information recall, and 5) decisional conflict. Analysis of variance was used for data analysis., Results: Irrespective of patient age, audiovisual information (compared with textual information) led to lower perceived cognitive load, higher satisfaction with information, and lower decisional conflict (subscale Effective Decision). Narrative information (compared with factual information) led to reduced decisional conflict (subscale Uncertainty) but only in younger patients. Combining audiovisual information with factual information also resulted in lower perceived cognitive load in younger patients as compared with older patients., Limitations: Patients who actually face the decision, especially older patients, might be more motivated to process our decision-aid information than the present study participants who responded to a hypothetical situation online., Conclusions: Providing participants with audiovisual information, irrespective of their age, improved their processing and use of information in a decision aid. Narratives did not clearly benefit information processing.

Background: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence., Methods/design: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets., Discussion: The INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0-1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events., Trial Registration: Netherlands Trial Registration (NTR): NL8435 , Registered 03 March 2020.

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic., Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC., Results: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided., Conclusion: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression., Patients and Methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians)., Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups., Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions., Competing Interests: Disclosure LP-A is a board member of Genomica and has received honoraria from Roche/Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Merck Serono, Pharmamar, Novartis, Celgene, Sysmex, Amgen, and Incyte, and travel, accommodations or expenses from Roche, AstraZeneca, AstraZeneca Spain, Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, and Pfizer; AS has received advisory fees from Array BioPharma and Incyte, honoraria from CytomX Therapeutics, AstraZeneca/MedImmune and Merck, research funding from LAM Therapeutics, and institutional research support from Roche, AstraZeneca/MedImmune, Boehringer Ingelheim, Astellas Pharma, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, TrovaGene, Takeda, MacroGenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, and Arch Therapeutics; DR has received honoraria from Merck and Nanobiotix, consultant fees from AstraZeneca and Suvica, and advisory board fees from AstraZeneca, Merck, Genentech, and Nanobiotix; DP has received advisory or lecture fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, and Roche, honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, and Roche, institutional research funding from AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo, and travel, accommodations or expenses from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Roche, Merck, Novartis, prIME Oncology, and Pfizer; DD has received institutional research funding from E.R. Squibb and Sons, AstraZeneca, Boehringer Ingelheim, Genentech, Eli Lilly and Company, Novartis Pharmaceuticals, Pfizer, Celgene, and Roche; AV has received honoraria from AstraZeneca, Gilead, and Seattle Genetics; RH has received advisory fees and honoraria from AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, Bristol-Myers Squibb, and Eli Lilly; SS has received research grants from Varian Medical Systems and ViewRay Inc., and honoraria from AstraZeneca, Eli Lilly, Merck Sharp and Dohme, and Celgene; CJL has received honoraria from Roche/Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Novartis, Celgene, Takeda, and Gilead; and travel, accommodations or expenses from Roche, AstraZeneca, Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly and Pfizer; BAP has received advisory fees from AstraZeneca and Bristol-Myers Squibb; and institutional research support from Bristol-Myers Squibb. A-MB and PAD are full-time employees of AstraZeneca with stock ownership; HB is an independent contractor, funded by AstraZeneca; CW was a full-time employee of AstraZeneca when the work was completed; SJA has received advisory fees from Bristol-Myers Squibb, Novartis, Merck, Boehringer Ingelheim, AstraZeneca/MedImmune, Cellular Biomedicine Group, and Memgen; CF-F has received research funding and travel support from Merck, AstraZeneca, and Elekta, and travel support from Pfizer; the remaining authors declare no potential conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Interstitial lung disease (ILD) is a term used to describe a heterogeneous group of lung disorders with characteristic clinical and imaging features. Patients with ILD are at an increased risk of developing NSCLC, which is frequently medically comorbid, often precluding operative management. In this scenario, radiotherapy (RT) is generally recommended; however, ILD is known to increase the risk of RT-related toxicity. Recommendations for treatment with appropriately individualized risks and benefits are thus dependent on integration of patient-, ILD-, and cancer-specific factors. We aim to provide an overview of ILD for the thoracic oncologist, an assessment of risk of thoracic RT in patients with ILD, and evidence-based recommendations for treatment in a variety of clinical scenarios., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Magnetic resonance (MR)-guided SABR was performed for patients with lung tumors in whom treatment delivery was challenging owing to tumor location, motion, or pulmonary comorbidity. Because stereotactic MR-guided adaptive radiation therapy (SMART) is a novel approach, we studied clinical outcomes in these high-risk lung tumors., Methods and Materials: Fifty consecutive patients (54 lung tumors) underwent SMART between 2016 and 2018 for either a primary lung cancer (29 patients) or for lung metastases (21 patients). Eligible patients had risk factors that could predispose them to toxicity, including a central tumor location (n = 30), previous thoracic radiation therapy (n = 17), and interstitial lung disease (n = 7). A daily 17-second breath-hold MR scan was acquired in treatment position, and on-table plan adaptation was performed using the anatomy of the day. Gated SABR was delivered during repeated breath-holds under continuous MR guidance., Results: All but 1 patient completed the planned SMART schedule. With daily plan adaptation, a biologically effective dose ≥100 Gy to 95% of the planning target volume was delivered in 50 tumors (93%). Median follow-up was 21.7 months (95% confidence interval, 19.9-28.1). Local control and overall and disease-free survival rates at 12 months were 95.6%, 88.0%, and 63.6%, respectively. Local failures developed in 4 patients: in 2 after reirradiation for a recurrent lung cancer and in 2 patients with a colorectal metastasis. Overall rates of any grade ≥2 and ≥3 toxicity were 30% and 8%, respectively. Commonest toxicities were grade ≥2 radiation pneumonitis (12%) and chest wall pain (8%). No grade 4 or 5 toxicities were observed., Conclusions: Use of MR-guided SABR resulted in low rates of high-grade toxicity and encouraging early local control in a cohort of high-risk lung tumors. Additional studies are needed to identify patients who are most likely to benefit from the SMART approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: We studied the benefits of using stereotactic MR-guided adaptive radiation therapy (SMART) for delivery of SABR in peripherally located lung tumors., Methods and Materials: Twenty-three patients (25 peripheral lung tumors) underwent SMART in 3-8 fractions on an MR Linac or Cobalt-60 system. Before each fraction, a breath-hold MR scan was acquired, followed by on-table plan adaptation based on the anatomy-of-the-day. Breath-hold gated delivery was performed under continuous MR-guidance using an in-room monitor. Benefits of on-table adaptation were studied by comparing 112 «predicted» plans, which are the baseline plans recalculated on the anatomy-of-the-day, with the on-table reoptimized plans., Results: The full SMART procedure took a median of 48 and 62 minutes on the MR Linac and Cobalt-60 system, respectively. Median SMART-PTVs were 9.5 cm 3 (range, 3.1-55.6). In 14 patients who had undergone a free-breathing 4DCT, SMART-PTVs measured 53.7% (range, 31.9-75.0) of PTVs that would have been generated using a motion-encompassing internal target volume approach. On-table adaptation improved prescription dose coverage of the PTV from a median of 92.1% in predicted plans, to 95.0% in reoptimized ones, thereby increasing the proportion of fractions delivering ≥100 Gy (BED 10Gy ) to 95% of PTV, from 90.2% to 100.0%., Conclusion: Delivery of gated breath-hold SABR using MR-guidance resulted in significantly smaller target volumes than would have been the case with an ITV-based approach. Although on-table adaptation ensured delivery of ablative doses in all fractions, the dosimetric benefits were modest, suggesting that daily online plan adaptation may not benefit most patients with peripheral lung tumors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study (ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC., Materials and Methods: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses., Results: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations., Conclusion: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Although isolated local (LRs) and regional recurrences (RRs) constitute a minority of post-stereotactic ablative radiotherapy (SABR) relapses, their management is becoming increasingly important as the use of SABR continues to expand. However, few evidence-based strategies are available to guide treatment of these potentially curable recurrences. On behalf of the Advanced Radiation Technology Committee of the International Association for the Study of Lung Cancer, this article was written to address management of recurrent disease. Topics discussed include diagnosis and workup, including the roles of volumetric and functional imaging as well as histopathologic methods; clinical outcomes after salvage therapy; patterns of recurrence after salvage therapy; and management options. Our main conclusions are that survival for patients with adequately salvaged LRs is similar to that for patients after primary SABR without recurrence, and survival for those with salvaged RRs (regardless of nodal burden or location) is similar to that of patients with de novo stage III disease. Although more than half of patients who undergo salvage do not develop a second relapse, the predominant pattern of second failure is distant, especially for RRs. Management requires rigorous multidisciplinary coordination. Isolated LRs can be managed with resection and nodal dissection, repeat SABR, thermal ablation, or systemic therapies. RRs can be treated with combined chemoradiotherapy, radiation or chemotherapy alone, or supportive services. Finally, regular and structured follow-up is recommended after post-SABR salvage therapy., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries., (Copyright © 2019 European Society for Medical Oncology. All rights reserved.)

Background and Purpose: In 2017 the ACROP guideline on SBRT for peripherally located early stage NSCLC was published. Later that year ICRU-91 about prescribing, recording and reporting was published. The purpose of this study is to quantify the current variation in prescription practice in the institutions that contributed to the ACROP guideline and to establish the link between the ACROP and ICRU-91 recommendations., Material and Methods: From each of the eight participating centres, 15 SBRT plans for stage I NSCLC were analyzed. Plans were generated following the institutional protocol, centres prescribed 3 × 13.5 Gy, 3 × 15 Gy, 3 × 17 Gy or 3 × 18 Gy. Dose parameters of the target volumes were reported as recommended by ICRU-91 and also converted to BED 10Gy ., Results: The intra-institutional variance in D98%, Dmean and D2% of the PTV and GTV/ITV is substantially smaller than the inter-institutional spread, indicating well protocollised planning procedures are followed. The median values per centre ranged from 56.1 Gy to 73.1 Gy (D2%), 50.4 Gy to 63.3 Gy (Dmean) and 40.5 Gy to 53.6 Gy (D98%) for the PTV and from 57.1 Gy to 73.6 Gy (D2%), 53.7 Gy to 68.7 Gy (Dmean) and 48.5 Gy to 62.3 Gy (D98%) for the GTV/ITV. Comparing the variance in PTV D98% with the variance in GTV Dmean per centre, using an F-test, shows that four centres have a larger variance in GTV Dmean, while one centre has a larger variance in PTV D98% (p values <0.01). This shows some centres focus on achieving a constant PTV coverage while others aim at a constant GTV coverage., Conclusion: More detailed recommendations for dose planning and reporting of lung SBRT in line with ICRU-91 were formulated, including a minimum PTV D98% of 100 Gy BED 10Gy and minimum GTV/ITV mean dose of 150 Gy BED 10Gy and a D2% in the range of 60-70 Gy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process., Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting., Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits., Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze patient-reported swallowing difficulties, healthcare resource utilization and associated costs during the PROCLAIM study. Methods: Patients with stage III non-squamous non-small cell lung cancer received pemetrexed-cisplatin (PemCis) combined with concurrent thoracic radiotherapy followed by consolidation pemetrexed, or concurrent chemoradiotherapy with etoposide-cisplatin (EtoCis) followed by standard consolidation chemotherapy. Patient - reported swallowing function was measured using diaries. Resource utilization (hospitalizations, transfusions, concomitant medications) was compared between treatment arms using Fisher's exact test and independent t -test. Medical resource use costs were analyzed using nonparametric Wilcoxon rank sum test. Results: Patient-reported difficulty in swallowing function (diary score ≥4) was 33.8% in the PemCis arm and 29% in the EtoCis arm. Overall resource use, including hospitalizations, was similar between treatment arms; however, fewer patients in the PemCis arm received transfusions and selected concomitant medications. Concurrent phase analyses were consistent with the overall study. A significantly lower percentage of patients (31.1% vs. 40.8%) were hospitalized in the PemCis arm. Total costs were significantly higher in the PemCis arm. Other medical costs (excluding study treatment costs) during the concurrent phase were lower for patients in the PemCis arm, due to significantly lower hospitalization costs and lower use of concomitant medications. Subgroup analysis yielded similar results. Conclusions: Patient-reported difficulty in swallowing post-baseline and resource utilization were consistent with previously reported safety outcomes. In the overall study, higher total costs for PemCis were driven by study drug cost. When adjusting for treatment duration, other monthly medical costs were favorable to PemCis. Patients on pemetrexed remained longer on therapy, suggesting better tolerability. ClinicalTrials.gov identifier: NCT00686959.

Purpose: As patients with centrally located lung tumors are at increased risk of toxicity with stereotactic ablative radiation therapy (SABR), we performed stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for such patients. We retrospectively analyzed the benefits of daily on-table plan adaptation., Methods and Materials: Twenty-five patients with central lung tumors underwent a total of 182 fractions of video-assisted, respiration-gated SMART on the MRIdian (ViewRay, Inc). Risk-adapted fractionation was used to deliver 60 Gy in 8 fractions (n = 20) or 55 Gy in 5 fractions (n = 5). For each fraction, daily MR-guided setup and on-table plan reoptimization, based on planning target volume (PTV) coverage and organ-at-risk (OAR) constraints, was performed. Gated breath-hold delivery was performed under continuous MR guidance. Benefits of daily plan reoptimization were studied by comparing 168 "predicted" plans, which are the calculated baseline plans on the anatomy of the day, with the reoptimized treatment plans., Results: The reoptimized plan was chosen for treatment in 92% of fractions. On-table plan adaptation improved PTV coverage in 61% of fractions by achieving superior coverage by the prescription dose (V 100% ) and a higher median dose (D 50% ). Mean increase in PTV V 100% was 4.6% (P < .01) with a median of 91.2% and 95.0% in predicted and reoptimized plans, respectively. The benefits of on-table adaptation persisted in an analysis restricted to fractions in which the PTV change was ≤1 cm 3 compared with baseline. On-table plan adaptation reduced the number of OAR planning constraint violations (P < .05). Maximum OAR doses remained mostly stable, with on-table reoptimization avoiding excessive OAR doses in selected cases., Conclusions: On-table plan reoptimization during breath-hold MR-guided SABR for central lung tumors improves target coverage while avoiding excessive OAR doses. The SMART approach may widen the therapeutic window of SABR in high-risk patients with central lung tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)