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Introduction: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established., Methods: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI)., Results: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses., Conclusions: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification., Competing Interests: Disclosure Dr. Donington reports receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck & Co., Inc., and Genentech, Inc./F. Hoffmann-La Roche Ltd., outside the submitted work. Dr. Joubert reports grants from AstraZeneca, Roche, Merck and Biomark Signature Inc. and personal fees from AstraZeneca and Merck, outside the submitted work. Dr. Mino-Kenudson reports receiving personal fees from AstraZeneca, Pfizer, Repare, Sanofi, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, and Elsevier, outside the submitted work. Dr. Nishimura reports receiving grants from IASLC, outside the submitted work. Dr. Nicholson reports receiving personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol Myers Squibb, Roche, AbbVie, Oncologica, UpToDate, the European Society of Oncology, Liberum, Takeda UK, and Sanofi and grants and personal fees from Pfizer, outside the submitted work. Dr. Papotti reports receiving personal fees from Roche, Eli Lilly, AstraZeneca, and Pfizer, outside the submitted work. Dr. Ugalde Figueroa reports receiving personal fees from AstraZeneca, Bristol, Roche, Medtronic, and Johnson & Johnson, outside the submitted work. Dr. Van Schil reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Janssen, outside the submitted work; and serving as President of International Association for the Study of Lung Cancer and Treasurer of Belgian Association for Cardiothoracic Surgery. Dr. Yang reports being on advisory boards for AstraZeneca and Genentech. He has also received honorarium from AstraZeneca, outside the submitted work. Dr. Lievens reports financing from the EU ImmunoSABR project, personal fees from the UpLung project, Astra-Zeneca, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system., Methods: Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis., Results: Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region., Conclusions: The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b)., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: This study analyzed all metastatic categories of the current TNM classification of NSCLC to propose modifications of the M component in the next edition (ninth) of the classification., Methods: A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stages IVA to IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using multivariable-adjusted Cox proportional hazards regression., Results: The eighth edition M categories revealed good discrimination in the ninth edition data set. Assessments revealed that an increasing number of metastatic lesions were associated with decreasing prognosis; because this seems to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was found with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, revealed that M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems., Conclusions: These data validate the eighth edition M1a and M1b categories, which are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems)., Competing Interests: Disclosure Dr. Fong reports receiving grants and contracts from MRFF EPCDR, NHMRC Ideas Grant, MRFF Next Generation Clinical Researchers Program, NHMRC; receiving funds from UpToDate as reviewer and Cochrane Clinical Answers as reviewer; and receiving equipment support from Olympus and Mevis Veolity. Mr. Rosenthal reports receiving fees for service from IASLC to complete work associated with publication. Ms. Giroux reports receiving fees for service from IASLC to complete work associated with publication. Dr. Nishimura reports receiving fees for service from IASLC to complete work associated with publication. Dr. Erasmus reports receiving honoraria from Canadian Association of Radiologists. Dr. Lievens reports receiving grants and contracts for the ImmunoSABR EU Project, HERO-VBHC chair; consulting fees from AstraZeneca; and honoraria from Merck Sharp & Dohme. Dr. Marom reports receiving honoraria from Boehringer Ingelheim, Merck, and AstraZeneca. Dr. Putora reports receiving grants or contracts from Bayer, Takeda, and AstraZeneca. Dr. Suárez reports receiving consulting fees from AstraZeneca and Roche; honoraria from AstraZeneca. 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.)

Introduction: An international database was created by the International Association for the Study of Lung Cancer to inform on the ninth edition of the TNM classification of lung cancer. The present analyses concern its T component., Methods: Data on 124,581 patients diagnosed with lung cancer from January 1, 2011 to December 31, 2019 were submitted to the International Association for the Study of Lung Cancer database. Of these, 33,982 met the inclusion criteria for the clinical T analysis, and 30,715 met the inclusion criteria for the pathologic postsurgical analysis. Survival was measured from the date of diagnosis or operation for clinically and pathologically staged tumors, respectively. T descriptors were evaluated in univariate analysis and multivariable Cox regression analysis adjusted for age, sex, pathologic type, and geographic region., Results: Comprehensive survival analysis revealed that the existing eighth edition T component criteria performed adequately in the ninth edition data set. Although pathologic chest wall or parietal pleura involvement (PL 3) yielded a worse survival compared with the other T3 descriptors, with a similar survival as T4 tumors, this difference was not observed for clinical chest wall or PL 3 tumors. Because of these inconsistent findings, no reallocation of chest wall or PL 3 tumors is advised., Conclusions: The T subcommittee members proposed not to implement any changes and keep the current eighth-edition T descriptors for the ninth edition., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs., Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors., Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023., Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions)., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population., Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred., Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

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.)

The status of lymph node involvement is a major component of the TNM staging system. The N categories for lung cancer have remained unchanged since the fourth edition of the TNM staging system, partly because of differences in nodal mapping nomenclature, partly because of insufficient details to verify possible alternative approaches for staging. In preparation for the rigorous analysis of the International Association for the Study of Lung Cancer database necessary for the ninth edition TNM staging system, members of the N-Descriptors Subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee reviewed the evidence for alternative approaches to categorizing the extent of lymph node involvement with lung cancer, which is currently based solely on the anatomical location of lymph node metastasis. We reviewed the literature focusing on NSCLC to stimulate dialogue and mutual understanding among subcommittee members engaged in developing the ninth edition TNM staging system for lung cancer, which has been proposed for adoption by the American Joint Committee on Cancer and Union for International Cancer Control in 2024. The discussion of the range of possible revision options for the N categories, including the pros and cons of counting lymph nodes, lymph node stations, or lymph node zones, also provides transparency to the process, explaining why certain options may be discarded, others deferred for future consideration. Finally, we provide a preliminary discussion of the future directions that the N-Descriptors Subcommittee might consider for the 10th edition and beyond., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: There is increasing evidence for the integration of locally ablative therapy into multimodality treatment of oligometastatic disease (OMD). To support standardised data collection, analysis, and comparison, a consensus OMD classification based on fundamental disease and treatment characteristics has previously been established. This study investigated the completeness of reporting the proposed OMD characteristics in literature and evaluated whether the proposed OMD classification system can be applied to the historical data., Methods and Materials: A systematic literature review was performed in Medline, Embase, and Cochrane, searching for prospective and retrospective studies, where stereotactic body radiation therapy was a treatment component of OMD. Reporting of the OMD characteristics as described in the European Organisation for Research and Treatment of Cancer/European Society for Radiotherapy and Oncology classification was analyzed, feasibility to retrospectively classify the proposed OMD states was investigated, and the effect of the categorization on overall survival (OS) was evaluated., Results: Our study shows incomplete reporting of the proposed OMD characteristics. The most fully reported characteristic was type of involved organs (88/95 studies); history of cancer progression was the least reported (not mentioned in 50/95 studies). Retrospective OMD classification of existing literature was only possible for 7 of the 95 studies. With respect to categorization as de novo, repeat, or induced OMD, homogeneous patient cohorts were observed in 21 of the 95 studies, most frequently de novo OMD in 20 studies. Differences in OS at 2, 3, or 5 years were not statistically significant between the different states. OS was significantly influenced by primary tumor histology, with superior OS observed for prostate cancer and worst OS observed for non-small cell lung cancer., Conclusions: The largely incomplete reporting of the proposed OMD characteristics hampers a retrospective classification of existing literature. To facilitate future comparison of individual studies, as well as validation of the OMD classification, comprehensive reporting of OMD characteristics using standardised terminology is recommended, as proposed by the European Organisation for Research and Treatment of Cancer/European Society for Radiotherapy and Oncology classification system and following the European Society for Radiotherapy and Oncology/American Society for Radiation Oncology consensus., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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

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

Purpose: 2-[ 18 F]FDG PET/CT is of utmost importance for radiation treatment (RT) planning and response monitoring in lung cancer patients, in both non-small and small cell lung cancer (NSCLC and SCLC). This topic has been addressed in guidelines composed by experts within the field of radiation oncology. However, up to present, there is no procedural guideline on this subject, with involvement of the nuclear medicine societies., Methods: A literature review was performed, followed by a discussion between a multidisciplinary team of experts in the different fields involved in the RT planning of lung cancer, in order to guide clinical management. The project was led by experts of the two nuclear medicine societies (EANM and SNMMI) and radiation oncology (ESTRO)., Results and Conclusion: This guideline results from a joint and dynamic collaboration between the relevant disciplines for this topic. It provides a worldwide, state of the art, and multidisciplinary guide to 2-[ 18 F]FDG PET/CT RT planning in NSCLC and SCLC. These practical recommendations describe applicable updates for existing clinical practices, highlight potential flaws, and provide solutions to overcome these as well. Finally, the recent developments considered for future application are also reviewed., (© 2022. The Author(s).)

In "Joint EANM/SNMMI/ESTRO Practice Recommendations for the Use of 2-[18F]FDG-PET/CT External Beam Radiation Treatment Planning in Lung Cancer V1.0" clinical indications for PET-CT in (non-)small cell lung cancer are highlighted and selective nodal irradiation is discussed. Additionally, concepts about target definition, target delineation and treatment evaluation are reviewed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ken Herrmann reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, outside the submitted work. - Rodney J. Hicks is on the Scientific Advisory Board of Telix Pharmaceuticals with any honoraria donated to his institution, he is a stock holder in this company, he is also an honorary Trustee of the International Cancer Imaging Society and honorary Board Member of Neuroendocrine Cancer Australia. - All the remaining authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The Quality Assurance project for stage III non-small cell lung cancer radiotherapy ProCaLung performed a multicentric two-step exercise evaluating mediastinal nodal Target Volume Definition and Delineation (TVD) variability and the opportunity for standardization. The TVD variability before and after providing detailed guidelines and the value of qualitative contour reviewing before applying quantitative measures were investigated., Materials and Methods: The case of a patient with stage III NSCLC and involved mediastinal lymph nodes was used as a basis for this study. Twenty-two radiation oncologists from nineteen centers in Belgium and Luxembourg participated in at least one of two phases of the project (before and after introduction of ProCaLung contouring guidelines). The resulting thirty-three mediastinal nodal GTV and CTV contours were then evaluated using a qualitative-before-quantitative (QBQ) approach. First, a qualitative analysis was performed, evaluating adherence to most recent guidelines. From this, a list of observed deviations was created and these were used to evaluate contour conformity. The second analysis was quantitative, using overlap and surface distance measures to compare contours within qualitative groups and between phases. A 'most robust' reference volume for these analyses was created using the STAPLE-algorithm and an averaging method., Results: Five GTV and seven CTV qualitative groups were identified. Second step contours were more often in higher-conformity groups (p = 0.012 for GTV and p = 0.024 for CTV). Median Residual Mean Square Distances improved from 2.34 mm to 1.36 mm for GTV (p = 0.01) and from 4.53 mm to 1.58 mm for CTV (p < 0.0001). Median Dice coefficients increased from 0.81 to 0.84 for GTV (p = 0.07) and from 0.82 to 0.89 for CTV (p ≤ 0.001). Using HC-contours only to generate references translated in more robust quantitative evaluations., Conclusion: Variability of mediastinal nodal TVD was reduced after providing the ProCaLung consensus guidelines. A qualitative review was essential for providing meaningful quantitative measures., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.L.: Personal fees from AstraZeneca (advisory board) and RaySearch (speaker fee), not related to this project. F.C., T.D., L.M., V.R., X.G., M.L.: None., (Copyright © 2021. Published by Elsevier B.V.)

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

Introduction: To compare neurocognitive functioning in patients with SCLC who received prophylactic cranial irradiation (PCI) with or without hippocampus avoidance (HA)., Methods: In a multicenter, randomized phase 3 trial (NCT01780675), patients with SCLC were randomized to standard PCI or HA-PCI of 25 Gy in 10 fractions. Neuropsychological tests were performed at baseline and 4, 8, 12, 18, and 24 months after PCI. The primary end point was total recall on the Hopkins Verbal Learning Test-Revised at 4 months; a decline of at least five points from baseline was considered a failure. Secondary end points included other cognitive outcomes, evaluation of the incidence, location of brain metastases, and overall survival., Results: From April 2013 to March 2018, a total of 168 patients were randomized. The median follow-up time was 26.6 months. In both treatment arms, 70% of the patients had limited disease and baseline characteristics were well balanced. Decline on the Hopkins Verbal Learning Test-Revised total recall score at 4 months was not significantly different between the arms: 29% of patients on PCI and 28% of patients on HA-PCI dropped greater than or equal to five points (p = 1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function, and processing speed did not change significantly different over time between the groups. The overall survival was not significantly different (p = 0.43). The cumulative incidence of brain metastases at 2 years was 20% (95% confidence interval: 12%-29%) for the PCI arm and 16% (95% confidence interval: 7%-24%) for the HA-PCI arm., Conclusions: This randomized phase 3 trial did not find a lower probability of cognitive decline in patients with SCLC receiving HA-PCI compared with conventional PCI. No increase in brain metastases at 2 years was observed in the HA-PCI arm., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts., Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies., Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting., Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts., 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 © 2020 Elsevier B.V. All rights reserved.)

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Lung cancer is the leading cause of cancer mortality and has a wide variation in treatment and outcomes in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must only be carried out in lung cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship., (Copyright © 2020. Published by Elsevier B.V.)

Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered., (Copyright © 2020. Published by Elsevier B.V.)

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: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR)., Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed., Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023., Trial Registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Background: Accurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative., Methods: Concerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5×), across 51 advanced stage lung cancer patients., Results: Genomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations., Conclusions: Copy number profiling of cell-free DNA enables histological classification. Since shallow whole-genome sequencing is inexpensive and often fully operational at routine molecular laboratories, this finding has current diagnostic potential, especially for patients with lesions that are difficult to reach.

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.)

Introduction: Inter-observer variability (IOV) in target volume delineation is a well-documented source of geometric uncertainty in radiotherapy. Such variability has not yet been explored in the context of adaptive re-delineation based on imaging data acquired during treatment. We compared IOV in the pre- and mid-treatment setting using expert primary gross tumour volume (GTV) and clinical target volume (CTV) delineations in locoregionally advanced head-and-neck squamous cell carcinoma (HNSCC) and (non-)small cell lung cancer [(N)SCLC]. Material and methods: Five and six observers participated in the HNSCC and (N)SCLC arm, respectively, and provided delineations for five cases each. Imaging data consisted of CT studies partly complemented by FDG-PET and was provided in two separate phases for pre- and mid-treatment. Global delineation compatibility was assessed with a volume overlap metric (the Generalised Conformity Index), while local extremes of IOV were identified through the standard deviation of surface distances from observer delineations to a median consensus delineation. Details of delineation procedures, in particular, GTV to CTV expansion and adaptation strategies, were collected through a questionnaire. Results: Volume overlap analysis revealed a worsening of IOV in all but one case per disease site, which failed to reach significance in this small sample ( p -value range .063-.125). Changes in agreement were propagated from GTV to CTV delineations, but correlation could not be formally demonstrated. Surface distance based analysis identified longitudinal target extent as a pervasive source of disagreement for HNSCC. High variability in (N)SCLC was often associated with tumours abutting consolidated lung tissue or potentially invading the mediastinum. Adaptation practices were variable between observers with fewer than half stating that they consistently adapted pre-treatment delineations during treatment. Conclusion: IOV in target volume delineation increases during treatment, where a disparity in institutional adaptation practices adds to the conventional causes of IOV. Consensus guidelines are urgently needed.

Background and Purpose: The prognostic value of radiomics for non-small cell lung cancer (NSCLC) patients has been investigated for images acquired prior to treatment, but no prognostic model has been developed that includes the change of radiomic features during treatment. Therefore, the aim of this study was to investigate the potential added prognostic value of a longitudinal radiomics approach using cone-beam computed tomography (CBCT) for NSCLC patients., Materials and Methods: This retrospective study includes a training dataset of 141 stage I-IV NSCLC patients and three external validation datasets of 94, 61 and 41 patients, all treated with curative intended (chemo)radiotherapy. The change of radiomic features extracted from CBCT images was summarized as the slope of a linear regression. The CBCT slope-features and CT-extracted features were used as input for a Cox proportional hazards model. Moreover, prognostic performance of clinical parameters was investigated for overall survival and locoregional recurrence. Model performances were assessed using the Kaplan-Meier curves and c-index., Results: The radiomics model contained only CT-derived features and reached a c-index of 0.63 for overall survival and could be validated on the first validation dataset. No model for locoregional recurrence could be developed that validated on the validation datasets. The clinical parameters model could not be validated for either overall survival or locoregional recurrence., Conclusion: In this study we could not confirm our hypothesis that longitudinal CBCT-extracted radiomic features contribute to improved prognostic information. Moreover, performance of baseline radiomic features or clinical parameters was poor, probably affected by heterogeneity within and between datasets., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Combined modality treatment (CMT) for malignant pleural mesothelioma (MPM) remains a matter of debate regarding the choice of surgical procedure: extrapleural pneumonectomy (EPP) or pleurectomy/decortication., Methods: We performed a prospective interventional cohort study between 2003 and 2014. All consecutive patients with any histological MPM subtype, ≤70 years old, World Health Organization performance status ≤1, medically fit for pneumonectomy and stage cT1-2cN0-2cM0 (TNM7) or lower were included. Eligibility for CMT was discussed by the multidisciplinary tumour board. Our local CMT protocol consisted of induction chemotherapy, followed by EPP and hemithoracic radiotherapy. Induction chemotherapy consisted of 3 cycles of cisplatin (75 mg/m2 day 1) and pemetrexed (500 mg/m2 day 1), each administered once every 3 weeks. If non-progressive, EPP was performed followed by hemithoracic radiotherapy (most frequently, intensity-modulated radiotherapy; dose 54 Gy/1.8 Gy ± boost). Feasibility and long-term survival analyses were performed. Overall survival and disease-free survival (DFS) were calculated from histological confirmation of a diagnosis of MPM., Results: Out of 197 patients, 97 started with CMT (79 epithelioid, 15 mixed and 3 sarcomatoid tumours, based on histological analysis). Clinical TNM was IA (n = 9)/IB (n = 8)/II (n = 57)/III (n = 23). A total of 76 patients underwent surgery (EPP: n = 56; exploratory thoracotomy: n = 20). The in-hospital mortality rate was 3.6%. Out of 56 patients who underwent surgery, 47 completed the entire CMT protocol. The intent-to-treat median and 5-year OS were 22.4 [95% confidence interval (CI) = 15.5-27.9] months and 11.2% (95% CI = 6.9-23.4). In patients who completed the CMT protocol (n = 47), these values were 33.2 (95% CI = 23.0-45.0) months and 24.2% (95% CI = 13.4-43.8). The intent-to-treat median and 5-year DFS were 15.6 (95% CI = 14.0-17.3) months and 9.9% (95% CI = 5.1-19.2), 19.8 (95% CI = 16.8-27.7) months and 17.2% (95% CI = 8.6-34.1) in those who had the full CMT. The Cox proportional hazards model showed a significantly lower DFS in positive lymph nodes (HR 2.79, 95% CI=1.35-5.78; P=0.006). In 30 (64%) patients with epithelioid type MPM without positive lymph nodes (pN0) after EPP, the 5-year DFS was 27.0% (95% CI=14.1-51.7)., Conclusions: CMT with EPP for MPM is feasible, with an acceptable surgical mortality rate, and results in a 5-year survival rate of 24%. Careful patient selection (staging and physical performance) is extremely important., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Automated planning aims to speed up treatment planning and improve plan quality. We compared manual planning with automated planning for lung stereotactic body radiation therapy based on dose-volume histogram statistics and clinical preference., Methods and Materials: Manual and automated intensity modulated radiation therapy plans were generated for 56 patients by use of software developed in-house and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients, and the impact of the automated plan (AP) on the total treatment cost was estimated. For the remaining 46 patients, each plan was checked against our clinical objectives, and a pair-wise dose-volume histogram comparison was performed. Three experienced radiation oncologists evaluated each plan and indicated their preference., Results: APs reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. Three APs and 0 manual plans failed our clinical objectives, and 13 APs and 9 manual plans showed a minor deviation. APs significantly reduced D 2% (2% of the volume receives a dose of at least D2%) for the spinal cord, esophagus, heart, aorta, and main stem bronchus (P < .05) while preserving target coverage. The radiation oncologists found >75% of the APs clinically acceptable without any further fine-tuning., Conclusions: APs may help to create satisfactory treatment plans quickly and effectively. Because critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Chemoradiation therapy trials of different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation therapy quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM trial evaluating 2 different chemoradiation therapy regimens. The RTQA results were evaluated from the PROCLAIM study, and the impact of irradiation deviations on efficacy outcomes was investigated., Methods and Materials: The study was conducted from 2008 to 2014. Review of the irradiation plan was mandated for all patients. Real-time review was performed prior to irradiation start for the first enrolled patient at each site and randomly in 20% of additional patients, with non-real-time review in the remainder. The RTQA criteria evaluated included planning target volume coverage, dose homogeneity, volume of lung receiving ≥20 Gy, and maximum point dose to spinal cord., Results: Major RTQA violations occurred in 40 of 554 patients, treated at 28 sites. Seven sites treated ≥2 patients with major violations. Stage IIIB disease and larger planning target volume were observed more frequently in patients with major violations. Major violations were more prevalent in sites treating either <6 patients or >15 patients. Patients treated at sites enrolling ≥2 patients with major violations (n = 86) had lower median overall survival (21.1 months vs 29.8 months; hazard ratio, 1.442) and progression-free survival (7.3 months vs 11.3 months; hazard ratio, 1.345) than patients treated at sites without major violations. These findings remained significant for overall survival on multivariate analysis., Conclusions: Major violations in treatment plans were uncommon in the PROCLAIM study, possibly reflecting mandatory RTQA. The RTQA violations were more frequent in patients requiring more complex chemoradiation therapy plans. Poorer observed outcomes at centers with multiple major violations are hypothesis generating., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee. Hence, we provide advice for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself. Concerning target volumes, recommendations are given for GTV delineation of primary tumour and lymph nodes followed by issues related to the delineation of CTVs for definitive and adjuvant radiotherapy. In the context of PTV delineation, recommendations about the management of geometric uncertainties and target motion are given. We further provide our opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation. This guideline intends to contribute to the standardisation and optimisation of the process of RT treatment planning for clinical practice and prospective studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lung cancer and its treatment have an important impact on the patients' health-related quality-of-life (HRQoL). A systematic literature review of prospective clinical studies published since 2005 and measuring HRQoL in patients with locally-advanced non-small cell lung cancer (LA- NSCLC) was performed. Besides reviewing the HRQoL impact of LA-NSCLC treatment, it critically examined the frequency, methodology and quality of HRQoL data collection and analysis in LA-NSCLC clinical studies. Out of 814 potentially eligible publications, only 27 (representing 19 individual studies) met the inclusion criteria. Eight studies documented an impact on HRQoL. Large variability in use of HRQoL instruments, statistical analysis and methodological quality was observed. Reporting of HRQoL data lacks standardization, but recent initiatives establishing recommendations to standardize the analysis and reporting of HRQoL in cancer trials are expected to address these issues. Overall, more research is needed to evaluate the treatment impact on HRQoL in both clinical trials and daily care., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Despite the lack of randomized evidence, stereotactic body radiotherapy (SBRT) is being accepted as superior to conventional radiotherapy for patients with T1-2N0 non-small-cell lung cancer in the periphery of the lung and unfit or unwilling to undergo surgery. To introduce SBRT in a system of coverage with evidence development, a correct financing had to be determined., Methods: A time-driven activity-based costing model for radiotherapy was developed. Resource cost calculation of all radiotherapy treatments, standard and innovative, was conducted in 10 Belgian radiotherapy centers in the second half of 2012., Results: The average cost of lung SBRT across the 10 centers (6221&OV0556;) is in the range of the average costs of standard fractionated 3D-conformal radiotherapy (5919&OV0556;) and intensity-modulated radiotherapy (7379&OV0556;) for lung cancer. Hypofractionated 3D-conformal radiotherapy and intensity-modulated radiotherapy schemes are less costly (3993&OV0556; respectively 4730&OV0556;). The SBRT cost increases with the number of fractions and is highly dependent of personnel and equipment use. SBRT cost varies more by centre than conventional radiotherapy cost, reflecting different technologies, stages in the learning curve and a lack of clear guidance in this field., Conclusions: Time-driven activity-based costing of radiotherapy is feasible in a multicentre setup, resulting in real-life resource costs that can form the basis for correct reimbursement schemes, supporting an early yet controlled introduction of innovative radiotherapy techniques in clinical practice.

Background: Adaptive radiotherapy (ART) could be a tool to reduce toxicity and to facilitate dose escalation in stage III NSCLC. Our aim was to identify the most appropriate time and potential benefit of ART., Material and Methods: We analyzed volume reduction and dosimetric consequences of 41 patients who were treated with concurrent (cCRT) (n = 21) or sequential (sCRT) chemoradiotherapy to a median dose of 70 Gy, 2 Gy/F. At every treatment fraction a cone-beam CT (CBCT) was performed. The gross tumor volume (GTV-T) was adapted (exclusion of lymph nodes) to create the GTV-T-F1. Every fifth fraction (F5-F30), the GTV-T-F1 was adapted on the CBCT to create a GTV-T-Fx. Dose volume histograms were recalculated for every GTV-T-Fx, enabling to create lookup tables to predict the theoretical dosimetric advantage on common lung dose constraints., Results: The average GTV reduction was 42.1% (range 4.0-69.3%); 50.1% and 33.7% for the cCRT and sCRT patients, respectively. A linear relationship between GTV-T-F1 volume and absolute volume decrease was found for both groups. The mean V5, V20, V30 and mean lung dose increased by 0.8, 3.1, 5.2 and 3.4%, respectively. A larger increase (p < 0.05) was observed for peripheral tumors and cCRT. Lookup tables were generated., Conclusion: ART offers the most beneficial dosimetric effects when performed around fraction 15, especially for patients with a large initial GTV-T treated by cCRT.

Purpose: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients., Material and Methods: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ≥2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC)., Results: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set., Conclusion: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC)., Methods and Materials: For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity)., Results: IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD., Conclusion: In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Radiotherapy, combined with chemotherapy, is the treatment of choice for a large group of non-small-cell lung cancer (NSCLC) patients. Recent developments in the treatment of these patients have led to improved survival. However, the clinical TNM stage is highly inaccurate for the prediction of survival, and alternatives are lacking. The objective of this study was to develop and validate a prediction model for survival of NSCLC patients, treated with chemoradiotherapy., Patients and Methods: The clinical data from 377 consecutive inoperable NSCLC patients, Stage I-IIIB, treated radically with chemoradiotherapy were collected. A prognostic model for 2-year survival was developed, using 2-norm support vector machines. The performance of the model was expressed as the area under the curve of the receiver operating characteristic and assessed using leave-one-out cross-validation, as well as two external data sets., Results: The final multivariate model consisted of gender, World Health Organization performance status, forced expiratory volume in 1 s, number of positive lymph node stations, and gross tumor volume. The area under the curve, assessed by leave-one-out cross-validation, was 0.74, and application of the model to the external data sets yielded an area under the curve of 0.75 and 0.76. A high- and low-risk group could be clearly identified using a risk score based on the model., Conclusion: The multivariate model performed very well and was able to accurately predict the 2-year survival of NSCLC patients treated with chemoradiotherapy. The model could support clinicians in the treatment decision-making process.

Introduction: For sulcus superior tumors and central cT4 tumors, low resectability and poor long-term survival rates are obtained with single-modality treatment., Methods: Analysis of all consecutive patients in our prospective database, who had potentially resectable superior sulcus (cT3-T4) and central cT4 tumors and were treated with induction chemoradiotherapy (two courses of cisplatin-etoposide) and concomitant radiotherapy (45 Gy/1.8 Gy) after multidisciplinary discussion. Surgery with attempted complete resection was performed in patients showing response or stable disease on computed tomography., Results: Between April 2002 and February 2008, 32 consecutive patients were enrolled. Two patients did not complete the induction chemoradiotherapy. Thirty patients were reassessed after induction, 28 had response or stable disease by conventional imaging. Twenty-seven patients were surgically explored since one patient became medically inoperable during induction treatment. The overall complete resectability was 78% (25/32). Resection was microscopically incomplete (R1) in two patients. In 11 patients (41%), a pneumonectomy was performed, and in 14 patients (52%), a chest wall resection was necessary. In 74% of the resected patients, there was a complete pathologic response or minimal residual microscopic disease. The mean postoperative hospital stay was 9.2 days with no hospital mortality and no bronchopleural fistula. With a median follow-up of 26.5 months, 5-year survival rates are 74% in the intent-to-treat population (n = 32) and 77% in completely resected patients (n = 25), with no statistically significant difference between sulcus superior tumors and centrally located T4 tumors., Conclusion: In patients with sulcus superior tumors and in selected patients with centrally located T4 tumors, trimodality treatment is feasible with acceptable morbidity and mortality. The complete resectability is high, and long-term survival is promising.

Background and Purpose: To investigate the financial consequences and the impact on daily implementation of CHART in lung cancer., Patients and Methods: A cost-effectiveness and cost-utility analysis were performed using Markov models, comparing the early and delayed costs and effects of CHART for NSCLC over a 4-year time span from a societal viewpoint. The outcome estimates were based on the CHART literature, the cost estimates on the standard practice of the Leuven University Hospitals, the radiotherapy costs being derived from an activity-based costing (ABC) programme developed in the department., Results: The additional societal cost per life-year gained was 9164 Euro, the incremental cost per quality-adjusted life-year 11,576 Euro. Sensitivity analyses confirmed the robustness of these results, the incremental cost-utility ratio remaining well under 20,000 Euro/QALY in all tested circumstances. The threshold analyses found the results of the study to be sensitive to the cost of CHART and to the quality of life after treatment. More specifically, standard treatment would become the optimal treatment if CHART would have a higher cost or would result in more long-term side effects., Conclusion: CHART should not be denied to patients with NSCLC on the basis of clinical or economic arguments. Other factors such as socio-economical, institutional, practical departmental and physician-bound barriers most probably explain the lack of implementation into daily practice.

This study shows the feasibility of accelerated vindesine-ifosfamide-cisplatin chemotherapy, immediately followed by intensive radiotherapy to the residual tumour in responding patients, in 16 patients with pathologically proven stage IIIB non-small lung cancer. All toxicities were reversible, with only two of ten patients experiencing grade 3 oesophagitis, no treatment-related deaths and no serious late effects., (Copyright 2002 Elsevier Science Ireland Ltd.)

BackgroundThe 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.MethodsFor 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.ResultsIn 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.ConclusionThis 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.