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Purpose: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors., Methods and Materials: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated., Results: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs., Conclusions: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Irradiation of the heart in thoracic cancers raises toxicity concerns. For accurate dose estimation, automated heart and substructure segmentation is potentially useful. In this study, a hybrid automatic segmentation is developed. The accuracy of delineation and dose predictions were evaluated, testing the method's potential within heart toxicity studies., Materials and Methods: The hybrid segmentation method delineated the heart, four chambers, three large vessels, and the coronary arteries. The method consisted of a nnU-net heart segmentation and partly atlas- and model-based segmentation of the substructures. The nnU-net training and atlas segmentation was based on lung cancer patients and was validated against a national consensus dataset of 12 patients with breast cancer. The accuracy of dose predictions between manual and auto-segmented heart and substructures was evaluated by transferring the dose distribution of 240 previously treated lung cancer patients to the consensus data set., Results: The hybrid auto-segmentation method performed well with a heart dice similarity coefficient (DSC) of 0.95, with no statistically significant difference between the automatic and manual delineations. The DSC for the chambers varied from 0.78-0.86 for the automatic segmentation and was comparable with the inter-observer variability. Most importantly, the automatic segmentation was as precise as the clinical experts in predicting the dose distribution to the heart and all substructures., Conclusion: The hybrid segmentation method performed well in delineating the heart and substructures. The prediction of dose by the automatic segmentation was aligned with the manual delineations, enabling measurement of heart and substructure dose in large cohorts. The delineation algorithm will be available for download., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Background: Real-world clinical outcomes of anaplastic lymphoma kinase positive ( ALK +) non-small cell lung cancer (NSCLC) patients vary. This study aimed to investigate the treatment and clinical outcomes of all ALK + NSCLC patients in Denmark in the period 2011-2018, regardless of disease stage., Materials and Methods: A national pathology database with complete coverage was used to identify ALK + NSCLC patients diagnosed between 2011 and 2018. Clinical data were obtained through retrospective chart reviews. Overall survival (OS) and duration of treatment (DOT) were analyzed using Kaplan-Meier methodologies., Results: A total of 209 ALK + NSCLC patients were included. The cohort had a slight overrepresentation of female patients (56.5%) with a mean age of 61.6 years. Most patients were adenocarcinoma cases (97%) and presented with an ECOG performance status of 0-1 (79%). Stage IIIb-IVb patients comprised 70% of the cohort. The use of ALK-tyrosine kinase inhibitors (TKIs) as first-line treatment increased over time, with the 1st generation ALK-TKI crizotinib being the predominant treatment in the 1st line. In 1st line treatment, 2nd generation ALK-TKIs had a median DOT more than twice the median DOT of crizotinib (25.1 and 9.1 months, respectively). The median OS for the entire cohort was 44.0 months. Patients with stage I-IIIA disease had a median OS that had not been reached, while those with stage IIIb-IVb disease had a median OS of 31.8 months. Patients with stage IIIb-IVb disease receiving an ALK-TKI as 1st line treatment had a median OS of 42.5 months with immature follow-up. Brain metastases at diagnosis or choice of 1st line treatment did not statistically significantly impact OS., Conclusion: This study gives insights into the treatment and outcome of ALK + NSCLC patients in Denmark and provides a real-world confirmation of the superior disease control provided by 2nd generation ALK-TKIs as compared to the 1st generation ALK-TKI crizotinib.

Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects., Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses., Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively., Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi., (Copyright © 2023 Elsevier Inc. 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.)

Amplification of the mesenchymal epithelial transition ( MET ) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR -mutated ( EGFR m+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFR m+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR -mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.

Background: Convincing results from randomized controlled trials (RCTs) have led to increasing use of immune checkpoint inhibitors (ICI) as part of standard therapies in real-world (RW) scenarios. However, RW patients differ clinically from RCT populations and might have reduced long-term survival. Currently, only sparse data on 3-5-year survival rate for RW patients with advanced non-small cell lung cancer (NSCLC) treated with ICI exist., Materials and Methods: A multicenter study was performed including 729 patients with advanced NSCLC receiving monotherapy with ICI (retrospective data ( n  = 566) and prospective data ( n  = 163)). Detailed baseline clinical characteristics, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), and baseline haematological count were registered. Kaplan-Meier estimates and log-rank test were used for survival analyses, Cox regression for determination of prognostic factors., Results: Median time of follow-up (FU) was 48.7 months (IQR 37.2-54.3). Median overall survival (OS) in first line treatment was 20.4 months (IQR 8.5-45.0) compared to 11.4 months (IQR 4.6-27.1) in ≥2nd line (HR 1.48, 95% CI 1.25-1.75). Estimated probability of OS was 30% at 3 years, 23% at 4 years, and 13% at 5 years in first line compared to 17, 13, and 11% in ≥2nd line, respectively. For those with performance status (PS) 2, the 2-year OS rate was 32% (95% CI 0.22-0.43) compared to 5% (95% CI 0.01-0.15) in patients with PD-L1 ≥ 50% versus <50%, respectively., Conclusions: Compared to RCTs, long-term OS and PFS rates are lower in real-world patients treated with ICI in first line but much improved compared to historic rates on chemotherapy. A promising flattening of both the OS and progression free survival curves illustrates that also a subset of real-world patients obtain long-term remission. Patients with PS 2 and PD-L1 ≥ 50% may obtain clinically meaningful 2-year PFS and OS rates.

Background and Purpose: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy., Materials and Methods: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS)., Results: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy., Conclusion: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Large blood volumes are irradiated when the heart is exposed to radiation. The mean heart dose (MHD) may be a good surrogate for circulating lymphocytes exposure. We investigated the association between MHD and radiation-induced lymphopenia and explored the impact of the end-of-radiation-therapy (EoRT) lymphocyte count on clinical outcomes., Materials and Methods: In total, 915 patients were analysed: 303 patients with breast cancer and 612 with intrathoracic tumours: oesophageal cancer (291), non-small cell lung cancer (265) and small cell lung cancer (56). Heart contours were generated using an interactive deep learning delineation process and an individual dose volume histogram for each heart was obtained. A dose volume histogram for the body was extracted from the clinical systems. We compared different models analysing the effect of heart dosimetry on the EoRT lymphocyte count using multivariable linear regression and assessed goodness of fit. We published interactive nomograms for the best models. The association of the degree of EoRT lymphopenia with clinical outcomes (overall survival, cancer treatment failure and infection) was investigated., Results: An increasing low dose bath to the body and MHD were associated with a low EoRT lymphocyte count. The best models for intrathoracic tumours included dosimetric parameters, age, gender, number of fractions, concomitant chemotherapy and pre-treatment lymphocyte count. Models for patients with breast cancer showed no improvement when adding dosimetric variables to the clinical predictors. EoRT lymphopenia grade ≥3 was associated with decreased survival and increased risk of infections among patients with intrathoracic tumours., Conclusion: Among patients with intrathoracic tumours, radiation exposure to the heart contributes to lymphopenia and low levels of peripheral lymphocytes after radiotherapy are associated with worse clinical outcomes., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In patients with cancer, sarcopenia is associated with treatment related complications, treatment cessation, poor quality of life and reduced overall survival. Despite this, there is limited knowledge about changes in skeletal muscle mass during chemotherapy. The aim of this systematic review and meta-analysis was to investigate the change of skeletal muscle mass and sarcopenia during chemotherapy treatment among patients with lung cancer., Methods: A systematic literature search was conducted in three databases, PubMed, EMBASE and Web of Science. Observational studies with patients with lung cancer were eligible for inclusion if skeletal muscle mass was measured before and after receiving chemotherapy treatment., Results: Ten cohort studies with a total of 867 participants met the inclusion criteria. During 5.2 ± 2.9 months of chemotherapy treatment, patients with lung cancer experienced a significant loss of skeletal muscle mass with a standardized mean difference (SMD) of: -0.25 (95% CI -0.47 to -0.03). The pretreatment prevalence of sarcopenia varied across studies from 35% to 74%. Only one study reported prevalence of sarcopenia both before and after chemotherapy treatment with an increase from 35% to 59%., Conclusion: The present data demonstrate a marked loss of skeletal muscle mass in patients with lung cancer undergoing chemotherapy treatment, as well as a high prevalence of sarcopenia. As sarcopenia is associated with poor clinical outcomes, it seems important to include and use assessments of skeletal muscle mass in clinical practice to identify patients in need for interventions. Moreover, interventional studies to hinder development of sarcopenia are needed.

Introduction: The immune system has proven to be a key player in the progression as well as containment of cancer with new treatment strategies based on immunotherapy targeting this interaction. Assessing immune function could reveal critical information about the immune response to therapeutic interventions, revealing predictive biomarkers for tailored care and precision medicine., Methods: We investigated immune function in 37 patients with inoperable non-small cell lung cancer (NSCLC) undergoing treatment with PD-L1 immune checkpoint inhibitor (ICI), chemotherapy (CT) or chemo-radiotherapy (CT/RT). Blood samples before (day 0) and during therapy (day 7, 21 and 80) were investigated by a standardized immunoassay, TruCulture®., Results: Outcomes revealed a developing innate immune response induced by both immunotherapy and chemotherapy. NSCLC-patients displayed evidence of chronic innate immune activation and exhaustion prior to treatment. This pattern was particularly pronounced during treatment in patients dying within 12-months follow-up. Compared to treatment with CT, ICI demonstrated a higher ex vivo-stimulated release of proinflammatory cytokines., Discussion: These preliminary findings may pave the way for tailored treatment and immune-monitoring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ryssel, Egebjerg, Nielsen, Lundgren, Pøhl, Langer, Kjaer, Ostrowski and Fischer.)

Background: This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP)., Materials and Methods: In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522)., Results: The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS -mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1., Conclusion: Performing extensive genomic analysis in patients with known KRAS -mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer with dismal prognosis. Long-term outcomes after primarily video-assisted thoracoscopic surgery (VATS) have not yet been described in LCNEC. This study aims to determine overall survival and recurrence-free survival after VATS as well as to identify prognostic factors for survival and recurrence., Methods: Data were obtained from a prospective institutional database. Kaplan-Meier estimates of overall survival and recurrence-free survival were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model., Results: Data from 82 consecutive patients undergoing surgical resection from 2009 to 2020 were included. All patients underwent surgical resection with curative intent, of whom 96.3% were by a VATS approach. Morbidity was low without any conversions or 30-day mortality. Lobectomy was performed in 87.8% of patients, followed by wedge resection in 4.9% and segmentectomy in 3.7%. No pneumonectomies were performed. Radical resection (R0) was achieved in 97.6%. Thirty-four patients (41.5%) had adjuvant platinum-based chemotherapy and high proportion completed at least four series (76.7%). The mean follow-up was 5.1 years. The 1-year, 3-year, and 5-year overall survival rates were 86%, 54%, and 45%, while the corresponding recurrence-free survival rates were 67%, 45%, and 35%. Advanced age was an independent predictor of poor overall survival (HR 2.08; 95% CI 1.04-4.17; p = 0.038)., Conclusion: A 96.3% VATS rate was feasible in LCNEC and associated with a low morbidity rate and a high compliance with adjuvant chemotherapy. Overall survival and recurrence-free survival was comparable to previous series using thoracotomy., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim of this study was to assess the test-retest repeatability and interobserver variation in healthy tissue (HT) metabolism using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/computed tomography (PET/CT) of the thorax in lung cancer patients., Methods: A retrospective analysis was conducted in 22 patients with non-small cell lung cancer who had two PET/CT scans of the thorax performed 3 days apart with no interval treatment. The maximum, mean and peak standardized uptake values (SUVs) in different HTs were measured by a single observer for the test-retest analysis and two observers for interobserver variation. Bland-Altman plots were used to assess the repeatability and interobserver variation. Intrasubject variability was evaluated using within-subject coefficients of variation (wCV)., Results: The wCV of test-retest SUVmean measurements in mediastinal blood pool, bone marrow, skeletal muscles and lungs was less than 20%. The left ventricle (LV) showed higher wCV (>60%) in all SUV parameters with wide limits of repeatability. High interobserver agreement was found with wCV of less than 10% in SUVmean of all HT, but up to 22% was noted in the LV., Conclusion: HT metabolism is stable in a test-retest scenario and has high interobserver agreement. SUVmean was the most stable metric in organs with low FDG uptake and SUVpeak in HTs with moderate uptake. Test-retest measurements in LV were highly variable irrespective of the SUV parameters used for measurements., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Respiratory motion is one of the major challenges in radiotherapy. In this work, a comprehensive and clinically plausible set of 4D numerical phantoms, together with their corresponding "ground truths," have been developed and validated for 4D radiotherapy applications., Methods: The phantoms are based on CTs providing density information and motion from multi-breathing-cycle 4D Magnetic Resonance imagings (MRIs). Deformable image registration (DIR) has been utilized to extract motion fields from 4DMRIs and to establish inter-subject correspondence by registering binary lung masks between Computer Tomography (CT) and MRI. The established correspondence is then used to warp the CT according to the 4DMRI motion. The resulting synthetic 4DCTs are called 4DCT(MRI)s. Validation of the 4DCT(MRI) workflow was conducted by directly comparing conventional 4DCTs to derived synthetic 4D images using the motion of the 4DCTs themselves (referred to as 4DCT(CT)s). Digitally reconstructed radiographs (DRRs) as well as 4D pencil beam scanned (PBS) proton dose calculations were used for validation., Results: Based on the CT image appearance of 13 lung cancer patients and deformable motion of five volunteer 4DMRIs, synthetic 4DCT(MRI)s with a total of 871 different breathing cycles have been generated. The 4DCT(MRI)s exhibit an average superior-inferior tumor motion amplitude of 7 ± 5 mm (min: 0.5 mm, max: 22.7 mm). The relative change of the DRR image intensities of the conventional 4DCTs and the corresponding synthetic 4DCT(CT)s inside the body is smaller than 5% for at least 81% of the pixels for all studied cases. Comparison of 4D dose distributions calculated on 4DCTs and the synthetic 4DCT(CT)s using the same motion achieved similar dose distributions with an average 2%/2 mm gamma pass rate of 90.8% (min: 77.8%, max: 97.2%)., Conclusion: We developed a series of numerical 4D lung phantoms based on real imaging and motion data, which give realistic representations of both anatomy and motion scenarios and the accessible "ground truth" deformation vector fields of each 4DCT(MRI). The open-source code and motion data allow foreseen users to generate further 4D data by themselves. These numeric 4D phantoms can be used for the development of new 4D treatment strategies, 4D dose calculations, DIR algorithm validations, as well as simulations of motion mitigation and different online image guidance techniques for both proton and photon radiation therapy., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objectives: In a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 fractions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years., Materials and Methods: 170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of ≥10 was defined as clinically significant., Results: Maximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales., Conclusion: TRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC. Trial reg Clinicaltrials.gov NCT0204184., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers., Materials and Methods: Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR)., Results: By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2., Conclusion: Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer., Competing Interests: Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerViewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Daniel S. W. TanHonoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, PfizerConsulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, PfizerResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche Ulrik N. LassenHonoraria: Bayer, Pfizer, NovartisConsulting or Advisory Role: Bayer, PfizerResearch Funding: BMS (Inst), Roche (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Lilly (Inst) Serge LeyvrazConsulting or Advisory Role: Bayer, ImmunocoreTravel, Accommodations, Expenses: Bayer, Immunocore Jyoti D. PatelConsulting or Advisory Role: AbbVie, AstraZeneca, Takeda Science FoundationResearch Funding: Bristol Myers Squibb (Inst) Lee RosenResearch Funding: Pfizer (Inst), Bayer (Inst), PsiOxus Therapeutics (Inst), Rgenix (Inst) Benjamin SolomonConsulting or Advisory Role: BayerResearch Funding: AstraZeneca/Merck (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/358846 Ricarda NorenbergEmployment: Bayer HealthConsulting or Advisory Role: Bayer Health (Inst) Laura DimaEmployment: Bayer Nicoletta BregaEmployment: BayerLeadership: BayerStock and Other Ownership Interests: BayerTravel, Accommodations, Expenses: BayerOther Relationship: Bayer Lin ShenConsulting or Advisory Role: MSD, Bristol Myers Squib, AstraZeneca, Daiichi Sankyo, Roche, Mingji biopharmaceutical, Harbour BioMed, MerckSpeakers' Bureau: Hutchison Whampoa, MSDResearch Funding: Yaojie Ankang (Nanjing) Technology Co, Ltd (Inst), Baiji Shenzhou (Beijing) Biotechnology Co, Ltd (Inst), Beijing Xiantong Biomedical Technology Co, Ltd (Inst), QiLu Pharmaceutical (Inst), Zaiding Pharmaceutical (Inst) Victor MorenoEmployment: STARTConsulting or Advisory Role: Merck, Bristol Myers Squibb, Bayer, Janssen Oncology, Roche, BasileaSpeakers' Bureau: BayerResearch Funding: AbbVie (Inst), ACEA Biosciences (Inst), Adaptimmune (Inst), Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), BeiGene (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Celgene (Inst), Eisai (Inst), E-therapeutics (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Menarini (Inst), Merck (Inst), Nanobiotix (Inst), Novartis (Inst), Pfizer (Inst), PharmaMar (Inst), PsiOxus Therapeutics (Inst), Puma Biotechnology (Inst), Regeneron (Inst), RigonTEC (Inst), Roche (Inst), Sanofi (Inst), Sierra Oncology (Inst), Synthon (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Tesaro (Inst), Transgene (Inst)Expert Testimony: Medscape/Bayer, NanobiotixTravel, Accommodations, Expenses: Sanofi/RegeneronOther Relationship: Bristol Myers Squibb Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon TherapeuticsConsulting or Advisory Role: Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GmbH, Harbor BioMed, SpringWorks Therapeutics, Gilead Sciences, Mirati Therapeutics, EcoR1 Capital, Cadila PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Dynavax Technologies (Inst), Pfizer (Inst), Loxo (Inst), Corvus Pharmaceuticals (Inst), Plexxikon (Inst), Jounce Therapeutics (Inst), ADC Therapeutics (Inst), Advenchen Laboratories (Inst), Incyte (Inst), Taiho Pharmaceutical (Inst), Bayer (Inst), Astex Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Genome & Company (Inst), Moderna Therapeutics (Inst), ADC Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Elevation Oncology (Inst), Vincerx Pharma (Inst), Day One Therapeutics (Inst)Travel, Accommodations, Expenses: Bayer Jessica J. LinHonoraria: Pfizer, OncLiveConsulting or Advisory Role: C4 Therapeutics, Genentech, Nuvalent, Inc, Blueprint Medicines, Turning Point Therapeutics, Turning Point TherapeuticsResearch Funding: Hengrui Therapeutics (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Neon Therapeutics (Inst), Relay Therapeutics (Inst), Elevation Oncology (Inst), Bayer (Inst), Roche (Inst)Travel, Accommodations, Expenses: PfizerNo other potential conflicts of interest were reported.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Competing Interests: We declare no competing interests.

Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity., Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea., Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage., Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine overall survival and recurrence-free survival after resection of bronchopulmonary carcinoids by means of predominantly minimally invasive surgery and lung-sparing resections. In addition, we aimed to identify prognostic factors for overall survival., Materials and Methods: Retrospective review of consecutive patients operated for bronchopulmonary carcinoids between January 2009 and October 2020 identified from a prospectively collected database., Results: A total of 236 patients representing 240 cases of bronchopulmonary carcinoids were included. Of these, 212 (88.3 %) were typical carcinoids, while 28 (11.7 %) were atypical carcinoids. A Video-Assisted Thoracoscopic Surgery (VATS) approach was used in 75 % of cases. There was no 30-day mortality. The median follow-up was 5.6 years for overall survival and 4.7 years for recurrence-free survival. 5- and 10-year overall survival rates were 89 % and 71 %, while 5- and 10-year recurrence-free survival rates were 84 % and 71 %. Patients with atypical carcinoids had significantly reduced overall survival and recurrence-free survival rates (HR 3.4; 95 % CI 1.5-7.6; p = 0.003 and HR 5.4; 95 % CI 2.6-11.4; p < 0.001). Independent predictors of overall survival included atypical carcinoid (HR 2.7; 95 % CI 1.2-6.0; p = 0.018) and age > 60 years (HR 2.9; 95 % CI 1.2-7.3; p = 0.021)., Conclusion: Surgery for bronchopulmonary carcinoids by means of predominantly VATS and lung-sparing resections provides favorable long-term survival. Atypical carcinoids and age > 60 years are independent predictors of poor overall survival., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: A major burden of introducing an online daily adaptive proton therapy (DAPT) workflow is the time and resources needed to correct the daily propagated contours. In this study, we evaluated the dosimetric impact of neglecting the online correction of the propagated contours in a DAPT workflow., Material and Methods: For five NSCLC patients with nine repeated deep-inspiration breath-hold CTs, proton therapy plans were optimised on the planning CT to deliver 60 Gy-RBE in 30 fractions. All repeated CTs were registered with six different clinically used deformable image registration (DIR) algorithms to the corresponding planning CT. Structures were propagated rigidly and with each DIR algorithm and reference structures were contoured on each repeated CT. DAPT plans were optimised with the uncorrected, propagated structures (propagated DAPT doses) and on the reference structures (ideal DAPT doses), non-adapted doses were recalculated on all repeated CTs., Results: Due to anatomical changes occurring during the therapy, the clinical target volume (CTV) coverage of the non-adapted doses reduces on average by 9.7% (V95) compared to an ideal DAPT doses. For the propagated DAPT doses, the CTV coverage was always restored (average differences in the CTV V95 < 1% compared to the ideal DAPT doses). Hotspots were always reduced with any DAPT approach., Conclusion: For the patients presented here, a benefit of online DAPT was shown, even if the daily optimisation is based on propagated structures with some residual uncertainties. However, a careful (offline) structure review is necessary and corrections can be included in an offline adaption., 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 © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We previously proposed an immune cell score (tumour node metastasis (TNM)-Immune cell score) classifier as an add-on to the existing TNM staging system for non-small cell lung cancer (NSCLC). Herein, we examined how to reliably assess a tertiary lymphoid structure (TLS) score to refine the TNM staging system., Methods: Using immunohistochemistry (CD8/cytokeratin), we quantified TLS in resected NSCLC whole-tumour tissue sections with three different scoring models on two independent collections (total of 553 patients). In a pilot setting, NanoString gene expression signatures were analysed for associations with TLS., Results: The number of TLSs significantly decreased in stage III patients as compared to stage II. The TLS score was an independent positive prognostic factor, regardless of the type of (semi)-quantification strategy used (four-scale semi-quantitative; absolute count of total TLS; subpopulation of mature TLS) or the endpoint (disease-specific survival; overall survival; time to recurrence). Subgroup analyses revealed a significant prognostic impact of TLS score within each pathological stage, patient cohort and main histological subtype. Targeted gene expression analysis showed that high TLS levels were associated with the expression of B cell and adaptive immunity genes/metagenes including tumour inflammation signature., Conclusions: The TLS score increases the prognostic power in each pathological stage and hence has the potential to refine TNM staging in resected NSCLC.

Background: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival., Methods: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m 2 or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m 2 on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845., Findings: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group)., Interpretation: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules., Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Exercise can improve treatment-related side effects, quality of life, and function in patients with various types of cancer; however, more evidence is needed for patients with advanced inoperable lung cancer., Material and Methods: We randomized 218 patients with advanced inoperable lung cancer to a 12-week supervised, structured exercise training program (aerobic, strength, and relaxation training) twice weekly versus usual care. Primary outcome was change in maximal oxygen uptake (VO 2 peak). Secondary outcomes were muscle strength, functional capacity, forced expiratory volume in 1 s, health-related quality of life, anxiety, and depression., Results: There was no significant difference between the intervention and control groups in VO 2 peak. There was a significant improvement in muscle strength. There was also a significant difference between the two for social well-being (Functional Assessment of Cancer Therapy-Lung, FACT-L), anxiety, and depression., Conclusion: There was a significant reduction in the level of anxiety and depression and a significant increase in all muscle strength outcomes in the intervention group compared to patients randomized to usual care. There was a significant difference between the groups for social well-being. The primary outcome did not show a significant improvement in VO 2 peak. Based on our results, future patients with advanced inoperable lung cancer should be considered for supervised exercise during the course of their disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC). Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables. Results : Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p <.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively. Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Background and Purpose: Non-small cell lung cancer (NSCLC) patients show typically large anatomical changes during treatment, making recalculation or adaption necessary. For report and review, the applied treatment dose can be accumulated on the reference planning CT using deformable image registration (DIR). We investigated the dosimetric impact of using six different clinically available DIR algorithms for dose accumulation in presence of inter-fractional anatomy variations., Materials and Methods: For seven NSCLC patients, proton treatment plans with 66 Gy-RBE to the planning target volume (PTV) were optimised. Nine repeated CTs were registered to the planning CT using six DIR algorithms each. All CTs were acquired in visually guided deep-inspiration breath-hold. The plans were recalculated on the repeated CTs and warped back to the planning CT using the corresponding DIRs. Fraction doses warped with the same DIR were summed up to six different accumulated dose distributions per patient, and compared to the initial dose., Results: The PTV-V95 of accumulated doses decreased by 16% on average over all patients, with variations due to DIR selection of 8.7%. A separation of the dose effects caused by anatomical changes and DIR uncertainty showed a good agreement between the dose degradation caused by anatomical changes and the dose predicted from the average of all DIRs (differences of only 1.6%)., Conclusion: The dose degradation caused by anatomical changes was more pronounced than the uncertainty of employing different DIRs for dose accumulation, with averaged results from several DIRs providing a good representation of dose degradation caused by anatomy. However, accumulated dose variations between DIRs can be substantial, leading to an additional dose uncertainty., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection., Methods: Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection., Results: cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA., Conclusion: Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection., Competing Interests: The authors have declared that no competing interests exist.

Aim: The aim was to validate promising radiomic features (RFs) 1 on 18 F-flourodeoxyglucose positron emission tomography/computed tomography-scans ( 18 F-FDG PET/CT) of non-small cell lung cancer (NSCLC) patients undergoing definitive chemo-radiotherapy., Methods: 18 F-FDG PET/CT scans performed for radiotherapy (RT) planning were retrieved. Auto-segmentation with visual adaption was used to define the primary tumour on PET images. Six pre-selected prognostic and reproducible PET texture -and shape-features were calculated using texture respectively shape analysis. The correlation between these RFs and metabolic active tumour volume (MTV) 3 , gross tumour volume (GTV) 4 and maximum and mean of standardized uptake value (SUV) 5 was tested with a Spearman's Rank test. The prognostic value of RFs was tested in a univariate cox regression analysis and a multivariate cox regression analysis with GTV, clinical stage and histology. P-value ≤ 0.05 were considered significant., Results: Image analysis was performed for 233 patients: 145 males and 88 females, mean age of 65.7 and clinical stage II-IV. Mean GTV was 129.87 cm 3 (SD 130.30 cm 3 ). Texture and shape-features correlated more strongly to MTV and GTV compared to SUV-measurements. Four RFs predicted PFS in the univariate analysis. No RFs predicted PFS in the multivariate analysis, whereas GTV and clinical stage predicted PFS (p = 0.001 and p = 0.008 respectively)., Conclusion: The pre-selected RFs were insignificant in predicting PFS in combination with GTV, clinical stage and histology. These results might be due to variations in technical parameters. However, it is relevant to question whether RFs are stable enough to provide clinically useful information., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Regorafenib prolonged overall survival (OS) versus placebo in patients with treatment-refractory metastatic colorectal cancer (mCRC) in phase III trials. We conducted an observational study of regorafenib for patients with mCRC in real-world clinical practice., Methods: The international, prospective, CORRELATE study recruited patients with mCRC previously treated with approved therapies, for whom the decision to treat with regorafenib was made by the treating physician according to the local health authority approved label. The primary objective was safety, assessed by treatment-emergent adverse events (TEAEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03)., Results: A total of 1037 patients were treated. The median age was 65 years (range: 24-93); 87% of patients had Eastern Cooperative Oncology Group performance status 0-1, 56% of patients had KRAS, 7% had NRAS and 4% had BRAF mutations. The initial regorafenib dose was 160 mg/day in 57% of patients. The most common grade III or IV drug-related TEAEs were fatigue (9%), hand-foot skin reaction (7%) and hypertension (6%). Drug-related grade V (fatal) TEAEs occurred in 1% of patients. Dose reductions for drug-related TEAEs occurred in 24% of patients. Median OS was 7.7 months (95% confidence interval [CI]: 7.2-8.3), and median progression-free survival (PFS) was 2.9 months (95% CI: 2.8-3.0)., Conclusions: In this real-world, observational study of patients with mCRC, the regorafenib toxicity profile was similar to that reported in phase III trials. The starting dose for almost half of patients was less than the approved 160-mg dose, and the median OS and PFS were in the range observed in phase III trials., Trial Registration: NCT02042144., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We hypothesized that gross tumor volume (GTV) of primary tumor (GTV T ) and nodal volumes (GTV N ) were predictors of first failure site in non-small cell lung cancer (NSCLC). We aimed at also comparing the prognostic model's complexity to its ability to generate absolute risk predictions with emphasis on variables available at the time of diagnosis. Materials and methods: Three hundred and forty-two patients treated with definitive chemoradiotherapy (CRT) for adenocarcinoma (AC) or squamous cell carcinoma (SCC) in 2009-2017 were analyzed. Clinical data, standardized uptake values on FDG-PET/CT, GTV T and GTV N were analyzed using multivariate competing risk models. Results: One hundred and thirty-seven patients had SCC. As first site of failure 49 had locoregional failure (LRF), 40 had distant metastasis (DM) and 24 died with no evidence of disease (NED). In 205 patients with AC, 34 had LRF, 118 had DM as first failure site and 17 died with NED. Performance status predicted LRF ( p  = .02) and UICC stage risk of DM ( p  = .05 for stage 3, p  < .001 for stage 4). Adding histopathology changed predictions with much reduced risk of LRF in AC compared to SCC (HR = 0.5, 95% CI: (0.3-0.75), p  = .001). Conversely, AC had a higher rate of DM than SCC (HR = 2.1, 95% CI: (1.5-3.0], p  < .001). Addition of FDG metrics and tumor/nodal volume data predicted DM risk ( p  = .001), but with smaller impact on absolute risk compared to histopathology. Separation of GTV in nodal and tumor lesions did not improve risk predictions. Conclusions: We quantified the effect of adding volumetric and quantitative imaging to competing risk models of first failure site, but did not find tumor volume components to be important. Histopathology remains the simplest and most important factor in prognosticating failure patterns in NSCLC.

Objectives: GSK3052230 (FP-1039) is a soluble fusion protein that acts as ligand trap sequestering fibroblast growth factors (FGFs) involved in tumor growth and angiogenesis, while sparing the hormonal FGFs. Because of this selectivity, the molecule is predicted to avoid toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Herein we report the results of a phase 1b study where GSK3052330 was administered with standard of care chemotherapy in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) patients., Methods and Methods: Eligible patients with stage IV or recurrent metastatic sqNSCLC harboring FGFR1 gene amplification received escalating doses of GSK3052230 in combination with paclitaxel and carboplatin at the starting doses 200 mg/m 2 and AUC of 6, respectively, in the first line setting (Arm A) or docetaxel 75 mg/m 2 in second line (Arm B). The primary endpoints of the study were safety and tolerability, to identify a maximum tolerated dose (MTD), and to assess overall response rate (ORR) based on investigator assessment., Results: Twenty-nine patients were enrolled into the study, including 20 patients on Arm A and 9 patients on Arm B. There were no dose limiting toxicities in either Arm and the MTD was not reached. The most common adverse events (AEs) were compatible with the chemotherapy backbone used in each Arm, including neutropenia, alopecia, nausea, arthralgia, asthenia, diarrhea and peripheral neuropathy. The overall response rate and median progression-free survival were 47% and 5.5 months, respectively, for Arm A and 0% and 4.6 months, respectively, for Arm B., Conclusion: GSK3052230 is a novel FGFR pathway inhibitor, which is well tolerated in combination with chemotherapy. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC)., Aim: To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded)., Material and Methods: Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS., Results: 162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19-89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p < 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p < 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p < 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC., Conclusion: In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: Motion management in the treatment of lung cancer is necessary to assure highest quality of the delivered radiation therapy. In this study, the breath-hold technique is experimentally investigated for pencil beam scanned (PBS) proton therapy, with respect to the dosimetric effect of residual breath-hold motion., Material and Methods: Three-dimensional (3D)-printed tumours extracted from CT scans of three patients were inserted into a dynamic anthropomorphic breathing phantom. The target was set up to move with the individual patient's tumour motion during breath-hold as previously assessed on fluoroscopy. Target dose was measured with radio-chromic film, and both single field uniform dose (SFUD) and intensity-modulated proton therapy (IMPT) plans were delivered. Experiments were repeated for each patient without any motion, to compute the relative dose deviation between static and breath-hold cases., Results: SFUD plans showed small dose deviations between static and breath-hold cases, as evidenced by the gamma pass rate (3%, 3 mm) of 85% or higher. Dose deviation was more evident for IMPT plans, with gamma pass rate reduced to 50-70%., Conclusions: The breath-hold technique is robust to residual intra-breath-hold motion for SFUD treatment plans, based on our experimental study. IMPT was less robust with larger detected dose deviations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: The PET-boost randomized phase II trial (NCT01024829) investigated dose-escalation to the entire primary tumour or redistributed to regions of high pre-treatment FDG-uptake in inoperable non-small cell lung cancer (NSCLC) patients. We present a toxicity analysis of the 107 patients randomized in the study., Materials and Methods: Patients with stage II-III NSCLC were treated with an isotoxic integrated boost of ≥72 Gy in 24 fractions, with/without chemotherapy and strict dose limits. Toxicity was scored until death according to the CTCAEv3.0., Results: 77 (72%) patients were treated with concurrent chemoradiotherapy. Acute and late ≥G3 occurred in 41% and 25%. For concurrent (C) and sequential or radiotherapy alone (S), the most common acute ≥G3 toxicities were: dysphagia in 14.3% (C) and 3.3% (S), dyspnoea in 2.6% (C) and 6.7% (S), pneumonitis in 0% (C) and 6.7% (S), cardiac toxicity in 6.5% (C) and 3.3% (S). Seventeen patients died of which in 13 patients a possible relation to treatment could not be excluded. In 10 of these 13 patients progressive disease was scored. Fatal pulmonary haemorrhages and oesophageal fistulae were observed in 9 patients., Conclusion: Personalized dose-escalation in inoperable NSCLC patients results in higher acute and late toxicity compared to conventional chemoradiotherapy. The toxicity, however, was within the boundaries of the pre-defined stopping rules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Quantitative PET/MRI is dependent on reliable and reproducible MR-based attenuation correction (MR-AC). In this study, we evaluated the quality of current vendor-provided thoracic MR-AC maps and further investigated the reproducibility of their impact on 18 F-FDG PET quantification in patients with non-small cell lung cancer. Methods: Eleven patients with inoperable non-small cell lung cancer underwent 2-5 thoracic PET/MRI scan-rescan examinations within 22 d. 18 F-FDG PET data were acquired along with 2 Dixon MR-AC maps for each examination. Two PET images (PET A and PET B ) were reconstructed using identical PET emission data but with MR-AC from these intrasubject repeated attenuation maps. In total, 90 MR-AC maps were evaluated visually for quality and the occurrence of categorized artifacts by 2 PET/MRI-experienced physicians. Each tumor was outlined by a volume of interest (40% isocontour of maximum) on PET A , which was then projected onto the corresponding PET B SUV mean and SUV max were assessed from the PET images. Within-examination coefficients of variation and Bland-Altman analyses were conducted for the assessment of SUV variations between PET A and PET B Image artifacts were observed in 86% of the MR-AC maps, and 30% of the MR-AC maps were subjectively expected to affect the tumor SUV. SUV Results: Image artifacts were observed in 86% of the MR-AC maps, and 30% of the MR-AC maps were subjectively expected to affect the tumor SUV. SUV mean resulted in coefficients of variation of 5.6% and 6.6%, respectively, and scan-rescan SUV variations were within ±20% in 95% of the cases. Substantial SUV variations were seen mainly for scan-rescan examinations affected by respiratory motion. max Artifacts occur frequently in standard thoracic MR-AC maps, affecting the reproducibility of PET/MRI. These, in combination with other well-known sources of error associated with PET/MRI examinations, lead to inconsistent SUV measurements in serial studies, which may affect the reliability of therapy response assessment. A thorough visual inspection of the thoracic MR-AC map and Dixon images from which it is derived remains crucial for the detection of MR-AC artifacts that may influence the reliability of SUV.Conclusion: Artifacts occur frequently in standard thoracic MR-AC maps, affecting the reproducibility of PET/MRI. These, in combination with other well-known sources of error associated with PET/MRI examinations, lead to inconsistent SUV measurements in serial studies, which may affect the reliability of therapy response assessment. A thorough visual inspection of the thoracic MR-AC map and Dixon images from which it is derived remains crucial for the detection of MR-AC artifacts that may influence the reliability of SUV., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: The aim of the study was to build a model of first failure site- and lesion-specific failure probability after definitive chemoradiotherapy for inoperable NSCLC., Methods: We retrospectively analyzed 251 patients receiving definitive chemoradiotherapy for NSCLC at a single institution between 2009 and 2015. All patients were scanned by fludeoxyglucose positron emission tomography/computed tomography for radiotherapy planning. Clinical patient data and fludeoxyglucose positron emission tomography standardized uptake values from primary tumor and nodal lesions were analyzed by using multivariate cause-specific Cox regression. In patients experiencing locoregional failure, multivariable logistic regression was applied to assess risk of each lesion being the first site of failure. The two models were used in combination to predict probability of lesion failure accounting for competing events., Results: Adenocarcinoma had a lower hazard ratio (HR) of locoregional failure than squamous cell carcinoma (HR = 0.45, 95% confidence interval [CI]: 0.26-0.76, p = 0.003). Distant failures were more common in the adenocarcinoma group (HR = 2.21, 95% CI: 1.41-3.48, p < 0.001). Multivariable logistic regression of individual lesions at the time of first failure showed that primary tumors were more likely to fail than lymph nodes (OR = 12.8, 95% CI: 5.10-32.17, p < 0.001). Increasing peak standardized uptake value was significantly associated with lesion failure (OR = 1.26 per unit increase, 95% CI: 1.12-1.40, p < 0.001). The electronic model is available at http://bit.ly/LungModelFDG., Conclusions: We developed a failure site-specific competing risk model based on patient- and lesion-level characteristics. Failure patterns differed between adenocarcinoma and squamous cell carcinoma, illustrating the limitation of aggregating them into NSCLC. Failure site-specific models add complementary information to conventional prognostic models., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: advanced-stage non-small cell lung cancer (NSCLC) is characterized by having limited treatment options and thus a poor prognosis. However, new treatment options, in the form of targeted agents (TA), have emerged during recent years. This systematic review aims to provide an overview of the accessible literature in PubMed evaluating TA used on NSCLC patients, and the resulting survival outcomes., Method: this systematic literature review was conducted by reviewing all relevant literature in PubMed. Six separate searches were performed: Three searches where controlled entry terms were used and three free text searches. Furthermore, other relevant publications were included manually. A total of seventy-two studies met the search criteria and were thus further analyzed and evaluated., Results: In the included studies, various TAs and their effect on different molecular targets have been evaluated. Clinical responses vary considerably among the different genetic aberrations. The majority of studies evaluated TA for epidermal growth factor receptor (EGFR) mutations and TA for echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements. Studies regarding the use of TA for Rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), ROS proto-oncogene 1 (ROS1) rearrangement, Receptor tyrosine-protein kinase erbB-2 (ERBB2), Phosphatidylinositol 3-kinase (PIK3CA)/v-akt murine thymoma viral oncogene homolog; protein kinase B(AKT)/Phosphatase and tensin homolog deleted on chromosome 10(PTEN), The mammalian target of rapamycin (mTOR), and Mesenchymal-epithelial transition factor (MET) were included as well. In general, studies comparing treatment outcomes in EGFR-mutated patients and EML4-ALK (ALK) rearranged patients after use of either TA or standard chemotherapy, present significant better results after TA., Conclusions: This systematic review provides an overview of available literature in PubMed regarding NSCLC and TA. Included studies point toward that TA appears to be a promising therapeutic tool in treating NSCLC patients and use of TA is expected to result in improved treatment outcomes.

Purpose: We evaluated the feasibility of treating patients with locally advanced non-small cell lung cancer (NSCLC) with pencil beam scanned intensity modulated proton therapy (IMPT) in breath-hold., Methods and Materials: Fifteen NSCLC patients who had previously received 66 Gy in 33 fractions with image guided photon radiation therapy were included in the present simulation study. In addition to a planning breath-hold computed tomography (CT) scan before the treatment start, a median of 6 (range 3-9) breath-hold CT scans per patient were acquired prospectively throughout the radiation therapy course. Three-field IMPT plans were constructed using the planning breath-hold CT scan, and the four-dimensional dose distributions were simulated, with consideration of both patient intra- and interfraction motion, in addition to dynamic treatment delivery., Results: The median clinical target volume receiving 95% of the prescribed dose was 99.8% and 99.7% for the planned and simulated dose distributions, respectively. For 3 patients (20%), the dose degradation was >5%, and plan adjustment was needed. Dose degradation correlated significantly with the change in water-equivalent path lengths (P<.01) in terms of the percentage of voxels with 3-mm or more undershoot on repeat CT scans. The dose to the organs at risk was similar for the planned and simulated dose distributions. Three or fewer breath-holds per field would be required for 12 of the 15 patients, which was clinically feasible., Conclusions: For 9 of 15 NSCLC patients, IMPT in breath-hold was both dosimetrically robust and feasible to deliver regarding the treatment time. Three patients would have required plan adaption to meet the dosimetric criteria. The change in water-equivalent path length is an indicator of plan robustness and should be considered for the selection of patients for whom the plan would require adaptation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p.E746&#95;A750delELREA) and a previously unreported 2bp frame-shift microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. Interestingly, FGFR3-mutations have previously been described in other cancer types of Caucasian patients and may represent an alternative pathway to EGFR-signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen for SCLC combined with erlotinib continuation was implemented obtaining significant objective response. However, after completing 6 cycles of this combination, new pulmonary and hepatic metastases appeared and showed persistence of the original EGFR- and FGFR3-mutated ADC phenotype together with acquisition of the erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, this advanced EGFR-mutated NSCLC displayed very rapid onset and heterogeneous genetic and phenotypic mechanisms of TKI-resistance occurring at different times and locations of metastatic disease: concomitant FGFR3-mutation before and during TKI-treatment as potential intrinsic mechanism for the rapid progression; transformation to SCLC at first progression during TKI-therapy; acquired T790M EGFR-mutation at second progression. Our case also underlines that, when achievable, rebiopsies of progressive sites during TKI-treatment are important for identifying heterogeneous histopathological and molecular resistance mechanisms and better defining possible treatment modifications., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans., Material and Methods: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue., Results: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation., Conclusions: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: The incidence of and survival from lung cancer are associated with socioeconomic position, and disparities have been observed in both curative and palliative treatment for lung cancer. 'Patient navigation' is valuable in addressing health disparity, with timely treatment and transition to care. We conducted a pilot study to test the feasibility of a patient navigator program (PAtient COach) for newly diagnosed lung cancer. We present the trial, the findings from the pilot study and discuss factors that might have affected recruitment rates., Material and Methods: We invited 24 lung cancer patients referred for chemotherapy to the Oncology Department at Herlev University Hospital, Denmark, to participate in the pilot study. To be eligible, patients had to live alone, have no formal education beyond secondary school, have one or more comorbid conditions, have a performance status of 1 or 2 or be over 65 years of age. The patient navigators targeted four phases of treatment: planning, initiation, compliance and end of treatment., Results: Six months after the start of the study, we had recruited only six patients, due mainly to inherent patient resistance and because only 50% of eligible patients were invited. Of the 18 patients who did not wish to participate, 13 agreed to fill in a baseline questionnaire. The most frequent reason given for not wanting to participate was a belief that a patient navigator would be of no benefit., Conclusions: The pilot study met a number of internal and external obstacles to patients' recruitment. The study provides insight into the barriers to recruitment of socially disadvantaged cancer patients to clinical trials and will inform future trial designs.

Objective: We investigated the impact of deep inspiration breath-hold (DIBH) and tumour baseline shifts on image quality and registration uncertainty in image-guided DIBH radiotherapy (RT) for locally advanced lung cancer., Methods: Patients treated with daily cone beam CT (CBCT)-guided free-breathing (FB) RT had an additional CBCT in DIBH at three fractions. These CBCT scans were offline rigidly registered (on tumour) to FB and DIBH CT scans acquired at planning. All registrations were repeated to evaluate the intraobserver uncertainty. CBCT scans were scored on degree of streak artefacts and visualization of tumour and anatomical structures. We examined the impact of tumour baseline shift between consecutive DIBHs on CBCT image quality., Results: CBCT scans from 15 patients were analysed. Intraobserver image registration uncertainty was approximately 2 mm in both FB and DIBH, except for the craniocaudal direction in FB, where it was >3 mm. On the 31st fraction, the intraobserver uncertainty increased compared with the second fraction. This increase was more pronounced in FB. Image quality scores improved in DIBH compared with FB for all parameters in all patients. Simulated tumour baseline shifts ≤2 mm did not affect the CBCT image quality considerably., Conclusion: DIBH CBCT improved image quality and reduced registration uncertainty in the craniocaudal direction in image-guided RT of locally advanced lung cancer. Baseline shifts ≤2 mm in DIBH during CBCT acquisition did not affect image quality. Advances in knowledge: DIBH RT has dosimetric advantages over FB; this work demonstrates an additional benefit of DIBH in terms of registration accuracy because of improved image quality.