Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

Objectives: Patients with locally advanced non-small cell lung cancer (NSCLC) were included in a prospective trial for radiotherapy in deep inspiration breath hold (DIBH). We evaluated DIBH compliance and target position reproducibility. Methods: Voluntary, visually guided DIBHs were performed with optical tracking. Patients underwent three consecutive DIBH CT scans for radiotherapy planning. We evaluated the intrafractional uncertainties in the position of the peripheral tumour, lymph nodes and differential motion between them, enabling PTV margins calculation. Patients who underwent all DIBH imaging and had tumour position reproducibility <8 mm were up-front DIBH compliant. Patients who performed DIBHs throughout the treatment course were overall DIBH compliant. Clinical parameters and DIBH-related uncertainties were validated against our earlier pilot study. Results: 69 of 88 included patients received definitive radiotherapy. 60/69 patients (87%) were up-front DIBH compliant. DIBH plan was not superior in seven patients and three lost DIBH ability during the treatment, leaving 50/69 patients (72%) overall DIBH compliant. The systematic and random errors between consecutive DIBHs were small but differed from the pilot study findings. This led to slightly different PTV margins between the two studies. Conclusions: DIBH compliance and reproducibility was high. Still, this validation study highlighted the necessity of designing PTV margins in larger, representative patient cohorts. Advances in knowledge: We demonstrated high DIBH compliance in locally advanced NSCLC patients. DIBH does not eliminate but mitigates the target position uncertainty, which needs to be accounted for in treatment margins. Margin design should be based on data from larger representative patient groups.

Circulating tumor DNA (ctDNA) has the potential to become a reliable biomarker for identifying minimal residual disease (MRD) and predicting recurrence in patients with non-small cell lung cancer (NSCLC) following curative treatment. However, there is a lack of studies that investigate the clinical validity of ctDNA using a tumor-agnostic approach, which can provide significant clinical benefits. We analyzed samples from 45 NSCLC patients recruited in a prospective national multicenter study, all of whom had undergone curative treatment. A total of 38 pre-treatment plasma samples and 76 post-treatment plasma samples were examined using a commercially available cancer personalized profiling by deep sequencing (CAPP-seq) strategy, and a tumor-agnostic approach. Post-treatment samples were collected at two distinct landmark time points: Follow-up 1 (0.5-4.5 months post-treatment) and Follow-up 2 (4.5-7.5 months post-treatment). Detectable ctDNA post-treatment was significantly associated with increased risk of tumor recurrence and shorter recurrence-free survival (RFS). Using only a single blood sample taken from Follow-up 2, we correctly identified MRD in 50% of the patients who later experienced recurrence. However, subgroup analysis further revealed that in patients treated with radiotherapy or chemoradiotherapy (CRT), ctDNA detection was significantly linked to shorter RFS in the MRD analysis from Follow-up 2, but not in the MRD analysis from Follow-up 1. These findings suggest that post-treatment ctDNA, detected using a tumor-agnostic approach, is a reliable biomarker for predicting recurrence in NSCLC patients following curative treatment. However, the optimal timing for blood sampling to detect MRD appears to depend on the type of curative treatment received.

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. 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. 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. 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.

Background. Carcinomas and their metastases often retain the keratin patterns of their epithelial origin, and are therefore useful as lineage-specific markers in diagnostic pathology. Recently, it has become clear that intermediate filaments composed by keratins play a role in modulation of cell proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non-small cell lung cancer (NSCLC). Material and methods. Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7) and keratin 34βE12 expression by immunohistochemistry and validated in a comparable independent Norwegian cohort of 276 stage I-IIIA NSCLC patients. Results. Based on keratin 34βE12/K7 expression, three subgroups with significantly different median cancer-specific survival rates were identified (34βE12+/K7+, 168 months vs. 34βE12+/K7+, 73 months vs. 34βE12-/K7+, 30 months; p = 0.0004). In multivariate analysis, stage II-IIIA (HR 2.9), 34βE12+/K7+ (HR 1.90) and 34βE12-/K7+ (HR 3.7), were prognostic factors of poor cancer-specific survival (CSS) (p < 0.001). Validation in the Norwegian cohort confirmed that stage II-IIIA (HR 2.3), 34βE12+/K7+ (HR 1.6), and 34βE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p < 0.05). Multivariate Cox proportional-hazard analysis demonstrated that 34βE12+/K7 + and 34βE12+/K7 + status was significantly associated with poor overall survival (p < 0.05). Conclusion. Keratin 34βE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival.

PURPOSE: Radiation dose escalation for locally advanced non–small cell lung cancer (LA-NSCLC) has been challenged by toxicity concerns. The Scandinavian phase III multicenter dose-escalation trial NARLAL2 (ClinicalTrials.gov identifier: NCT02354274 ) used a novel approach to dose escalation: heterogeneous escalation driven by the fluorodeoxyglucose positron emission tomography–avid region, with strict normal tissue dose constraints. We report early toxicity within 6 months of random assignment. MATERIALS AND METHODS: Patients were recruited from seven institutions in Scandinavia. Eligibility criteria included performance status 0-1, NSCLC stage IIB-IIIB, and feasibility of delivering 66 Gy/33 fraction treatment plan. Patients were randomly assigned between standard (66 Gy) and heterogeneously dose-escalated radiotherapy. Two treatment plans were made for each patient before random assignment with matched mean lung dose and V _20Gy , and strict dose constraints for all normal tissues. Toxicity was evaluated weekly during radiotherapy, and every 3 months after random assignment. Concurrent chemotherapy was cisplatin/carboplatin and vinorelbine. RESULTS: Between January 2015 and March 2023, 350 patients were randomly assigned. The as-treated analysis included 178 patients in the standard and 172 in dose-escalated (mean tumor dose 88 Gy) arms. Median gross tumor and planning target volumes were, respectively, 54 cm ³ and 321 cm ³ (standard arm) and 61 cm ³ and 339 cm ³ (escalated arm). No difference in early toxicity between the two arms was observed. Grade 2 esophagitis during radiotherapy was 28.1% and 25.6%, grade 3 esophagitis 7.3% and 4.1%, grade 2 pneumonitis 15.7% and 20.3%, and grade 3 pneumonitis 3.9% and 5.8% in standard and escalated arms, respectively. For both arms, the maximum grade of early toxicity aggregated over all toxicities was 35% and 1% for grades ≥3 and 5, respectively. Four patients died from potential treatment-related toxicity. CONCLUSION: Heterogeneous dose escalation did not increase early toxicity despite delivery of 88 Gy mean dose to the primary tumor, demonstrating this as an attractive strategy for LA-NSCLC radiotherapy dose escalation.