Erratum: BR.31 Trial: Adjuvant Durvalumab as the Third Contender in Resected Non-Small Cell Lung Cancer.

Radical lobectomy, proposed as a curative treatment for lung cancer in 1960, has long been regarded as the standard surgical approach. The findings of two phase III randomized controlled trials comparing limited resection versus lobectomy for non-small cell lung cancer (NSCLC) ≤2 cm have challenged the long-standing evidence supporting lobectomy as the universal surgical option for all patients with lung cancer. The Japanese clinical oncology group (JCOG) and West Japan Oncology Group (WJOG) (JCOG0802/WJOG4607L) demonstrated both the non-inferiority and superiority of segmentectomy, while the Cancer and Leukemia Group B trial (CALGB140503) conducted by the Alliance for Clinical Trials in Oncology in North America, confirmed the non-inferiority of limited resection, including wedge resection for NSCLC measuring ≤2 cm. As both trials demonstrated non-inferiority of limited resection in NSCLC ≤2 cm, their results are often summarized together. However, patient background, radiological findings, prognosis, and extent of resection differ significantly between the two trials and should be interpreted with caution. Previous trials have demonstrated that preserving lung parenchyma helps maintain pulmonary function and improves patient prognosis by enabling appropriate management of subsequent malignancy or other diseases. Limited resection, including segmentectomy, is currently the standard of care for early-stage NSCLC. The JCOG and WJOG are conducting trials to determine whether the indications for limited resection can be expanded to include patients with NSCLC >2 cm or those with stage I NSCLC. This review article outlines the results of previous trials, provides an overview of ongoing trials, and discusses prospects for limited resection.

The Evolving Role of Adjuvant TKI in Lung Cancer: From Historical Trials to Future Strategies National Cancer Center Hospital East, Japan.

Pulmonary macrophage-targeted RNAi and mRNA co-delivery via SORT lipid nanoparticles enhances immunotherapy in lung cancer.

Atezolizumab combined with cisplatin plus vinorelbine as adjuvant therapy for completely resected non-small cell lung cancer with epidermal growth factor receptor mutation (West Japan Oncology Group 11719L: ADJUST study)

Surgical Challenges After Neoadjuvant Therapy.

Neoadjuvant Chemoimmunotherapy.

Pathologic stage II non-small cell lung cancer (NSCLC) exhibits heterogeneous outcomes despite curative resection. Although adjuvant EGFR-TKI and immunotherapy have improved survival in resected NSCLC, subgroup analyses from major trials show only modest benefit in stage II disease. Given these limited gains and the variable cost-effectiveness of adjuvant therapy across regions, identifying prognostic factors is essential to guide treatment decisions and support value-based precision care. We retrospectively analyzed 115 patients with pathologic stage II NSCLC (27 IIA, 88 IIB) who underwent complete resection at a tertiary hospital in Taiwan (2016-2023). Clinicopathologic variables-including histologic subtype, spread through air spaces (STAS), and lymphovascular invasion (LVI) - were reviewed. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier and Cox proportional hazards analyses. The 5-year RFS and OS rates were 50.9% and 67.9%, respectively. Independent predictors of recurrence included tumor size >4 cm [hazard ratio (HR)=2.88, p=0.008], N1 nodal status (HR=3.20, p=0.016), and high-risk adenocarcinoma subtype (micropapillary/solid; HR=2.80, p=0.014). Adjuvant chemotherapy significantly improved OS (76.4% vs. 37.2%, p=0.002). Tumor size, nodal involvement, and histologic subtype are key prognostic determinants in stage II NSCLC. Identifying high-risk patients is crucial to optimize selection for adjuvant immunotherapy or targeted therapy and to ensure clinical and economic benefit.

Advances in Systemic Therapy for Lung Cancer: Update on Biomarkers and Novel Drugs for Patients with Stage IV Non-Small Cell Lung Cancer (NSCLC).

The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a new scoring system that evaluates both inflammatory and nutritional status. We aimed to investigate the clinical significance of the CALLY index as a prognostic biomarker in resected non-small-cell lung cancer (NSCLC). We classified 581 and 634 patients with NSCLC clinical stages I-IIIA who underwent surgery between 2013 and 2018 as the discovery and validation cohorts, respectively. The CALLY index was calculated using the following formula: (serum albumin × lymphocytes) / (CRP × 104). The cutoff value of the CALLY index in the discovery cohort was determined using a time-dependent receiver operating characteristic curve analysis. Patients were classified into CALLY-high and CALLY-low groups, and associations between the CALLY index and clinicopathological factors and prognosis was evaluated. In the discovery cohort, 329 (56.6%) and 252 (43.3%) patients were classified as CALLY-high and CALLY-low, respectively; in the validation cohort, 353 (55.7%) and 281 (44.3%) patients were classified as CALLY-high and CALLY-low, respectively. In both cohorts, the CALLY-low group was associated with older age, male sex, smoking, and advanced cancer stage. Multivariable analysis in both cohorts showed that CALLY-low was an independent poor prognostic factor for recurrence-free survival: hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.02-2.02 and HR 1.4; 95% CI 1.02-1.87, respectively. It was also an independent poor prognostic factor for overall survival: HR 2.1; 95% CI 1.31-3.25 and HR 1.6; 95% CI 1.11-2.29, respectively. The CALLY index is a useful prognostic predictor in resected NSCLC.

ObjectivesWaiting for postoperative pathologic confirmation of visceral pleural invasion (VPI) may delay treatment decisions. This study aimed to develop a contrast-enhanced CT-based radiomics model for preoperative prediction of VPI in early-stage non-small cell lung cancer (NSCLC).Materials and methodsWe retrospectively enrolled 523 surgically resected NSCLC patients (195 with VPI, 328 without VPI) with clinically staged IA based on preoperative imaging between December 2019 and June 2022. Patients were randomly divided into training, validation, and testing sets at a ratio of 5:2:3. For each patient, 13 CT features were recorded, including the types I–V tumor relationships to the pleura. Regions of interest (ROIs) were segmented semi-automatically using deep learning. Least absolute shrinkage and selection operator (LASSO) regression was applied to select key radiomics features. Three models were developed: a CT-feature model, a radiomics model, and a combined model. The performance and clinical utility of these models were evaluated using the area under the curve (AUC) and decision curve analysis.ResultsThe tumor relationship to the pleura, density, maximum diameter, and spiculation were selected to construct the CT-feature model. A total of 10 optimal features formed the radiomics model. The radiomics model achieved an AUC of 0.812 in the testing set, outperforming the CT-feature model (0.714). Furthermore, the combined model showed a slightly higher AUC (0.825) compared to the radiomics model.ConclusionsThe radiomics model demonstrated satisfactory performance for predicting VPI in early-stage NSCLC, outperforming the CT-feature model. The integration of radiomics and CT features may provide enhanced predictive value.Critical relevance statementThis study constructed a contrast-enhanced CT-based radiomics model with promising performance for the preoperative prediction of VPI, which aims to guide treatment planning for early-stage NSCLC.Key PointsVPI affects the tumor-node-metastasis (TNM) staging of tumors and subsequent treatment strategies.The radiomics model outperformed the CT-feature model in predicting VPI.The contrast-enhanced CT-based radiomics model may be valuable for optimizing clinical decision-making.Graphical

Long-term outcomes of preoperative nivolumab with or without relatlimab in patients with resectable non-small-cell lung cancer (NEOpredict-Lung).

Spread through air spaces (STAS) has been identified as an invasion pattern in non-small cell lung cancer (NSCLC). This study evaluated the association between tumor STAS and various clinicopathological parameters of NSCLC, with emphasis on the prognostic role of STAS. We evaluated 96 cases of NSCLC for STAS. STAS-positive cases were graded according to the distance between the edge of the primary tumor and the furthest STAS, in millimeters, or the number of alveoli separating STAS from the tumor. STAS was observed in 33 patients (34.4%). In 28 cases, STAS was located in airspaces >3 alveoli away from the primary tumor. In 18 cases, STAS was found in airspaces > 2.5 mm away from the edge of the primary tumor. Morphologically, 18 cases of STAS demonstrated a solid nest pattern, eight showed a micropapillary cluster pattern, and seven exhibited a single-cell pattern. In multivariate analysis, only high tumor grade (p = .001) was independently associated with STAS in NSCLC. The presence of STAS (p = .047), lymphovascular invasion (p = .001), positive surgical margin (p = .021), adenocarcinoma histology (p = .020), and postoperative therapy (p = .049) showed a statistically significant lower overall survival (OS). However, multivariate analyses showed that STAS is not an independent predictor of OS in NSCLC. In addition, STAS-positive cases with an extension of >2.5 mm had significantly lower disease-free survival (DFS) (p = .018). The findings demonstrated that STAS is independently associated with a higher tumor grade and appears to have an adverse impact on OS and DFS in the examined subpopulation.

Perioperative chemoimmunotherapy is the standard of care for resectable, locally advanced non-small cell lung cancer (NSCLC). While pathological complete response (pCR) correlates with excellent survival outcomes, some patients without pCR still exhibit long-term survival. Here we evaluate the added value of minimal residual disease (MRD). MRD was assessed in 60 patients from the NADIM II trial (NCT03838159) using Guardant Reveal assay. In NADIM II, NSCLC patients without EGFR or ALK alterations were randomized to receive neoadjuvant nivolumab plus chemotherapy (experimental arm) or chemotherapy alone, followed by surgery. Patients in the experimental arm with R0 resection received adjuvant nivolumab. MRD detection rate was 9.6%. MRD after surgery or during adjuvant treatment was associated with inferior EFS and OS (HR: 10.2; 95%CI: 3.7-28.3 and HR: 10.0; 95%CI: 2.0-49.9, respectively). All patients with MRD-negative plasma samples in at least two time points were alive (HR: not estimable [NE], p < 0.001), with only one relapse (HR: 41.6; 95%CI: 5.0-348.8), corresponding to a patient relapsing with a single brain metastasis. MRD enhanced the prognostic value of pCR for both EFS (p<0.001) and OS (p=0.015). Among non-pCR patients, MRD remained a significant prognostic marker (HR: 6.2; 95%CI: 2.2-17.1 and HR: 6.5; 95%CI: 1.3-32.5, for EFS and OS respectively). All non-pCR patients with MRD-negative results in at least two time points were alive (HR: NE, p=0.025), with one relapse (HR: 19.9; 95%CI: 2.4-165.6), corresponding to the aforementioned case. MRD may refine prognostic evaluation beyond pCR in resectable NSCLC undergoing perioperative chemoimmunotherapy.

This study aimed to develop and validate a temporal radiomics model based on pre- and post-treatment CT scans for the preoperative prediction of pathologic complete response (pCR) in patients with resectable non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemoimmunotherapy (NCI). Data from 263 patients with resectable NSCLC who underwent NCI followed by curative surgery and had both pre- and post-treatment CT scans were retrospectively collected. Patients from one hospital were randomly divided into training and internal test sets at a 7:3 ratio, while patients from two other hospitals served as the external test set. Radiomics features were extracted from the CT scans at both timepoints and delta features capturing the temporal changes were calculated. Radiomics models based on different features were developed using the least absolute shrinkage and selection operator for feature selection, followed by logistic regression. Model performance was evaluated using the area under the curve (AUC). The radiomics model based on delta features yielded AUCs of 0.85, 0.76, and 0.72 in the training, internal test, and external test sets, respectively, which were superior to the radiomics models based on pre-treatment features (0.74, 0.66, and 0.62, respectively) and post-treatment features (0.80, 0.76, and 0.65, respectively). By integrating the optimal features from all three feature sources, the combined model achieved further improvements in performance, with AUCs of 0.89, 0.85, and 0.78, respectively, across the three sets. A CT-based radiomics model incorporating temporal features from pre- and post-treatment scans shows favorable performance for the non-invasive preoperative estimation of pCR to NCI in patients with NSCLC.

Adjuvant immunotherapy improved patient outcomes in two trials in completely resected non-small cell lung cancer (NSCLC), but with conflicting primary end point results. The Canadian Cancer Trials Group BR.31 trial evaluated adjuvant durvalumab in completely resected early-stage NSCLC. Following resection of stage IB (≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer 7th Edition) and optional adjuvant chemotherapy, patients were randomly assigned 2:1 to durvalumab 20 mg/kg or placebo 20 mg/kg once every 4 weeks for 12 cycles. Random assignment was stratified by stage, extent of nodal dissection, tumor cell (TC) PD-L1 expression, adjuvant chemotherapy use, and center. The primary end point was investigator-assessed disease-free survival (DFS). Secondary outcomes included overall survival (OS), adverse events, and quality of life. The primary analysis was in the subgroup with cancers that had a PD-L1 TC expression ≥25%, no common activating EGFR mutations (EGFR-), and no ALK gene rearrangements (ALK-). Secondary analyses in hierarchical order included DFS in the subgroup whose tumors were EGFR-/ALK- with PD-L1 TC ≥1%, followed by all patients whose tumors were EGFR-/ALK-, followed by OS in the same primary and secondary subgroups in the same hierarchical order. Of 1,415 patients randomly assigned, 1,219 (86%) had EGFR-/ALK- tumors: 815 randomly assigned to durvalumab and 404 to placebo. With a median follow-up of 60 months, there were no differences in DFS between patients assigned durvalumab (316) versus placebo (161) in the primary population (stratified hazard ratio [HR], 0.93 [95% CI, 0.71 to 1.25]; P = .64) or in the secondary populations. Grade 3 to 4 adverse events were higher in durvalumab-treated patients (D = 26% v P = 20%). Adjuvant durvalumab following complete resection was not associated with improvement in DFS compared with placebo in EGFR-/ALK- NSCLC, regardless of PD-L1 status.

The intrapulmonary location of a tumor is important for evaluating recurrence risk. This study assessed the prognostic impact of the tumor-pleura distance (TPd) in patients with clinical stage IA solid-predominant or pure-solid non-small cell lung cancer (NSCLC), as well as associations with pleural invasion, recurrence, and tumor subtype defined by the consolidation-to-tumor ratio (CTR). A total of 358 patients who underwent anatomical lung resection for clinical stage IA NSCLC between 2014 and 2023 were retrospectively analyzed. TPd and CTR were measured on preoperative computed tomography. Receiver-operating characteristic analysis for pleural invasion identified an optimal TPd cutoff of 2.0mm. A 2-mm cutoff classified tumors as pleura-adjacent (< 2mm) or non-pleura-adjacent (≥ 2mm), with pleural invasion observed in 23.5% of pleura-adjacent and 4.5% of non-pleura-adjacent tumors (P < 0.001). The 5-year recurrence-free survival (RFS) rate was significantly lower in the pleura-adjacent group (68.9% vs. 80.2%, P = 0.021). Multivariate analysis identified pleura-adjacent as an independent predictor of RFS (HR, 1.755; 95% confidence interval (CI) 1.097-2.805; P = 0.019). In the pure-solid subgroup, pleura-adjacent tumors were an independent predictor of RFS (HR, 2.168; 95% CI 1.283-3.663; P = 0.004); no association was found in the solid-predominant subgroup. In the pure-solid subgroup, competing-risk analysis identified pleura-adjacent as an independent risk factor for locoregional recurrence (HR, 2.558; 95% CI 1.250-5.234; P = 0.010). TPd < 2mm is a radiological marker strongly associated with pleural invasion. Its adverse prognostic impact was the most evident in pure-solid tumors, in which pleura-adjacent lesions were linked to poorer RFS and higher locoregional recurrence.

Osteopenia is an independent risk factor for a poor prognosis in several malignant tumors. However, its significance in lung cancer is unclear. In this retrospective cohort study, we aimed to evaluate the prognostic impact of preoperative osteopenia in patients with surgically resected non-small cell lung cancer. We included 546 patients who underwent curative resection for clinical stage I-IIIA non-small cell lung cancer at our institute during 2013-2018. Bone mineral density was evaluated with computed tomographic measurement of pixel density in the core at the bottom of the 11th thoracic vertebra. The cutoff value was 148 and 111 Hounsfield units for men and women, respectively, based on the time-dependent receiver operating characteristic curve for overall survival. Patients were divided into osteopenia and non-osteopenia groups, and the associations of osteopenia with clinicopathological features and prognosis were analyzed. Two hundred fifty-one patients (46.0%) were classified into the osteopenia group. The rates of patients ≥70 years old and ever-smokers in the osteopenia group were higher than those in the non-osteopenia group. The 5-year overall survival (77.1% vs 91.5%) and recurrence-free survival (63.7% vs 80.0%) rates of the osteopenia group were worse than those of the non-osteopenia group. Multivariable analysis revealed that osteopenia was an independent poor prognostic factor for overall survival (hazard ratio: 2.2, 95% confidence interval: 1.38-3.51, P < 0.001) and recurrence-free survival (hazard ratio: 1.5, 95% confidence interval: 1.05- 2.11, P = 0.024). Preoperative osteopenia is an independent poor prognostic factor for patients with resected clinical stage I-IIIA non-small cell lung cancer.

IntroductionIn early stage non-small cell lung cancer (NSCLC), recurrence is frequent despite surgery and systemic treatments. Observational studies suggest that physical exercise and nutrition could improve outcomes, such as survival and treatment tolerance; however, solid evidence is lacking. The STARLighT trial aims to assess the effects of a telehealth-delivered combined exercise and nutrition intervention on clinical, biological and patient-reported outcomes in early stage NSCLC.Methods and analysisSTARLighT is a multicentre master protocol study conducted in Italy, comprising two cohorts of patients affected by early stage NSCLC (stages IB–IIIA) epidermal growth factor receptor and anaplastic lymphoma kinase wild type. Cohort A will include 46 patients with resectable NSCLC receiving neoadjuvant treatment and will exploit a single-arm phase II design. Cohort B will enrol 268 patients undergoing adjuvant treatment (including as a part of a perioperative strategy) and proposes a randomised controlled phase III design. Patients in Cohort A and those allocated to the interventional arm in Cohort B will receive a tailored telehealth-delivered exercise and nutritional intervention. The control group will receive the usual care plus educational material. For cohort A, two coprimary endpoints are set: pathological complete response and quality of life, whereas the primary endpoint for cohort B is 2-year disease-free survival. Secondary and exploratory endpoints include a series of clinical (eg, overall survival and safety), biological (immune–inflammatory markers, gut microbiota and transcriptomics) and patient-reported outcomes (eg, sleep habits, physical activity, anxiety and depression and distress) evaluations.Ethics and disseminationThe study is approved by the Ethics Committee of the University of Verona (Prot. No. 33979) and registered on ClinicalTrials.gov (NCT07042724). Findings will be disseminated through peer-reviewed journals, scientific meetings, public forums and guideline updates.Trial registration numberClinicaltrial.gov: NCT07042724.

Real-world outcomes of stage III NSCLCs managed by surgery or definitive radiation therapy in the era of immunotherapy.