N2 N2 Non-small Cell Lung Cancer Research Articles

Prognostic Value of Preoperative N Subcategories in Patients with Stage IIIA N2 Non-Small Cell Lung Cancer.

Purpose To evaluate the preoperative risk factors in patients with pathologic IIIA N2 non-small cell lung cancer (NSCLC) who underwent upfront surgery and to evaluate the prognostic value of new N subcategories. Materials and Methods Patients with pathologic stage IIIA N2 NSCLC who underwent upfront surgery in a single tertiary center from January 2015 to April 2021 were retrospectively reviewed. Each patient's clinical N (cN) was assigned to one of six subcategories (cN0, cN1a, cN1b, cN2a1, cN2a2, and cN2b) based on recently proposed N descriptors. Cox regression analysis was used to identify the significant prognostic factors for recurrence-free survival (RFS) and overall survival (OS). Results A total of 366 patients (mean age ± SD, 62.0 years ± 10.1; 202 male patients [55%]) were analyzed. The recurrence rate was 55% (203 of 366 patients) over a median follow-up of 37.3 months. Multivariable analysis demonstrated that cN (hazard ratios [HRs] for cN1 and cN2b compared with cN0, 1.66 [95% CI: 1.11, 2.48] and 2.11 [95% CI: 1.32, 3.38], respectively) and maximum lymph node (LN) size at N1 station (≥12 mm; HR, 1.62 [95% CI: 1.15, 2.29]), in addition to clinical T category (HR, 1.51 [95% CI: 1.14, 1.99]), were independent prognostic factors for RFS. For OS, clinical N subcategories (cN1, cN2a2, and cN2b vs cN0; HRs, 1.91 [95% CI: 1.11, 3.27], 1.89 [95% CI: 1.13, 2.18], and 2.02 [95% CI: 1.07, 3.80], respectively) and LN size at N1 station (HR, 1.75 [95% CI: 1.12, 2.71]) were independent prognostic factors. For clinical N1, OS was further stratified according to LN size (log-rank test, P < .001). Conclusion Assessing the proposed N subcategories by reporting single versus multistation involvement of N2 disease and maximum size of metastatic LN, reflecting metastatic burden, at preoperative CT may offer useful prognostic information for planning optimal treatment strategies. Keywords: CT, Lung, Staging, Non-Small Cell Lung Cancer Supplemental material is available for this article. ©RSNA, 2024.

Efficacy of Postoperative Radiotherapy for Patients with New N2 Descriptors of Subclassification in Completely Resected Non-Small Cell Lung Cancer: A Real-World Study

Patients with N2 non-small cell lung cancer (NSCLC) were heterogeneous groups and required further stratification. The International Society for the Study of Lung Cancer (IASLC) added new descriptors of three sub-stages for stage N2 NSCLC: N2 at a single station without N1 involvement (N2a1), N2 at a single station with N1 involvement (N2a2), and N2 at multiple stations (N2b). This study aimed to investigate the efficacy of postoperative radiotherapy (PORT) for patients with these N2 descriptors. Patients with histologically confirmed NSCLC after complete resection and divided into PORT group and non-PORT group. The primary endpoint was DFS. The second endpoints were overall survival (OS) and locoregional recurrence-free survival (LRFS). Propensity-score matching (PSM) of baseline characteristics between the PORT and non-PORT groups was used for validation. Totally 1832 patients were enrolled, including 308 N2a1 patients, 682 N2a2 patients, and 842 N2b patients. The median follow-up time was 50.1 months. The survival outcomes of the PORT and non-PORT groups before PSM were shown in Table 1. For patients with N2a1, PORT could not improve the DFS (median DFS of the PORT group and the non-PORT group: not reached vs. 46.8 months, P = 0.41), OS (P = 0.85), or LRFS (P = 0.32), which were consistent with the multivariate analysis and data after the PSM. For patients with N2a2, PORT significantly improved the DFS (median DFS 29.7 vs. 22.2 months, P = 0.02), OS (P = 0.03), and LRFS (P = 0.01). The multivariate analysis and data after the PSM confirmed the benefits in DFS and LRFS, but no benefit was observed in OS (multivariate analysis: HR 0.79, P = 0.18; median OS after PSM: 103.7 vs. 63.1 months, P = 0.34). For patients with N2b, PORT could not improve the DFS (median DFS 20.6 vs. 21.2 months, P = 0.39) but significantly improved the OS (P<0.001) and LRFS (P<0.001). However, the multivariate analysis showed that PORT significantly improved DFS (HR 0.81, P = 0.03), consistent with the data after the PSM (median DFS 20.6 and 17.6 months, P = 0.04). PORT significantly improved the DFS and LRFS in patients with N2a2 and significantly improved the DFS, LRFS, and OS in patients with N2b. Patients with N2a1 could not benefit from PORT.

Reaching multidisciplinary consensus on the management of non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer

IntroductionThe optimal management of patients with non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer (NSCLC) remains controversial. In this modified Delphi study from France, we aimed to generate agreement through multidisciplinary decision-making on the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC. MethodsAn expert panel of 30 physicians from different specialities completed two Delphi rounds of a 76-item questionnaire, pertaining to: pathological confirmation of N2 disease; initial treatment approach; treatment approach in case of disease progression/stability following neoadjuvant chemotherapy; treatment approach taking into account various patient and tumour characteristics. Each questionnaire item was scored using a 9-point Likert scale. Consensus in agreement was achieved if ≥ 80 % of responses to a questionnaire item were scored between 7 and 9 and if the median value of the score to the item was ≥ 7. ResultsRegarding the pathologic confirmation of N2 disease, agreement (up to 100 %) was reached on endobronchial ultrasound/endoscopic ultrasound as the preferred method of initial mediastinal staging for paratracheal lymph nodes. There was also panellist agreement (up to 93 %) on the adoption as first-line treatment of surgery and (neo)adjuvant chemotherapy in patients with single-station disease, and of concurrent chemoradiotherapy followed by adjuvant immunotherapy in those with multi-station N2 disease. Panellists further agreed on the use of a non-surgical strategy, i.e., concurrent chemoradiotherapy with adjuvant immunotherapy, in patients with single-station N2 disease in case of: involvement of ≥ 2 mediastinal lymph nodes; disease progression following neoadjuvant chemotherapy; compromised cardiopulmonary function if compatible with radiotherapy; anticipated right pneumonectomy. ConclusionsThis Delphi study reinforces the importance of multidisciplinary discussions leading to the best individual approach to the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC, a challenging heterogeneous population.

Effect of postoperative radiotherapy on survival in patients with completely resected and pathologically confirmed stage N2 non-small-cell lung cancer: a systematic review and meta-analysis.

The role of postoperative radiotherapy (PORT) for patients with completely resected stage N2 non-small-cell lung cancer (NSCLC) has been controversial. This study aimed to investigate the efficacy of PORT and prognosis in these patients. An updated meta-analysis was conducted in this study to investigate the efficacy of PORT and prognosis in patients with completely resected and pathologically confirmed stage N2 NSCLC. This study is a systematic review and meta-analysis. Databases were searched up to 2 March 2022. All trials on patients with completely resected and pathologically confirmed stage N2 NSCLC undergoing PORT were screened, and data indicators in the PORT and non-PORT groups were extracted, respectively. The effect of PORT on overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) was estimated. Subgroup and sensitivity analyses were performed. In all, 20 studies involving 6340 patients were finally included. The PORT significantly increased OS [hazard ratio (HR) = 0.77, 95% CI: 0.71-0.84, p < 0.001), LRFS (HR = 0.63, 95% CI: 0.52-0.76, p < 0.001), and DFS (HR = 0.72, 95% CI: 0.63-0.82, p < 0.001) while it showed no significant difference in improving DMFS (HR = 0.86, 95% CI: 0.71-1.05, p = 0.14). Our results suggest that in the postoperative treatment of patients with completely resected and pathologically confirmed stage N2 NSCLC, the addition of PORT provides better local recurrence control and survival benefit, but no benefit for distant metastases. The PORT may be incorporated into the postoperative treatment options for some patients with high-risk factors. However, it needs to be validated by more prospective studies in the future. CRD42022314095.

The association of postoperative radiotherapy with survival in resected N2 non-small cell lung cancer.

The current staging system for completely resected pathologic N2 non-small cell lung cancer (NSCLC) treated with chemotherapy is not suitable for distinguishing those patients most likely to benefit from postoperative radiotherapy (PORT). This study aimed to construct a survival prediction model that will enable individualized prediction of the net survival benefit of PORT in patients with completely resected N2 NSCLC treated with chemotherapy. A total of 3,094 cases from between 2002 and 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patient characteristics were included as covariates, and their association with overall survival (OS) with and without PORT was assessed. Data from 602 patients from China were included for external validation. Age, sex, the number of examined/positive lymph nodes, tumor size, the extent of surgery, and visceral pleural invasion (VPI) were significantly associated with OS (P<0.05). Two nomograms were developed based on clinical variables to estimate individuals' net survival difference attributable to PORT. The calibration curve showed excellent agreement between the OS predicted by the prediction model and that actually observed. In the training cohort, the C-index for OS was 0.619 [95% confidence interval (CI): 0.598-0.641] in the PORT group and 0.627 (95% CI: 0.605-0.648) in the non-PORT group. Results showed that PORT could improve OS [hazard ratio (HR): 0.861; P=0.044] for patients with a positive PORT net survival difference. Our practical survival prediction model can be used to make an individualized estimate of the net survival benefit of PORT for patients with completely resected N2 NSCLC who have been treated with chemotherapy.

Machine Learning to Refine Selection Criteria of Post-Operative Radiotherapy for Resectable Stage III-N2 Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The role of post-operative radiotherapy (PORT) for completely resected N2 non-small cell lung cancer (NSCLC) is controversial, given the recently published LungART and PORT-C trials. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on the extent of nodal involvement. <h3>Materials/Methods</h3> Patients with completely resected N2 NSCLC were identified in the National Cancer Database diagnosed between 2004 and 2017. The query was subsequently limited to patients with pN2 disease, known pathologic T stage, and no evidence of distant metastasis. Patients were excluded if they had unknown follow-up, did not undergo surgery (lobectomy, bilobectomy, or pneumonectomy), did not undergo lymph node dissection, had positive margins, had unknown number of positive lymph nodes or total lymph nodes examined, or received neoadjuvant radiation. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation values (SHAP) were used to identify prognostic and predictive thresholds for the number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Multivariable (MVA) Cox proportional-hazards regression was used for confirmatory analysis. <h3>Results</h3> A total of 16,789 patients with completely resected N2 NSCLC were identified. Of the patients that met inclusion criteria, 6181 (36.8%) received PORT. When radiation treatment technique could be determined, about half received 3D conformal radiation therapy (18.7% of all patients) and about half received IMRT (19.9% of all patients). Median follow-up for the entire cohort was 32.0 months (0-183.1 months). Median OS of the whole population was 41.7 months (95%CI: 40.7-43.1). For patients who received PORT, median OS was 47.6 months (95%CI: 45.2-49.7). For patients who did not receive PORT, median OS was 38.6 months (95%CI: 37.1-39.9). Using SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On MVA, PORT was not significantly associated with OS (HR: 0.96; 95%CI: 0.92-1.01); (p=0.111). However, a subset analysis of patients with 3+ positive LNs revealed that PORT improved OS (HR: 0.91; 95%CI: 0.86-0.97; p=0.002). Patients with 3+ positive LNs had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 31% (95%CI: 29-32%) without PORT. Patients with 1-2 positive LNs had a 5-year OS of 49% (95%CI: 47-51%) with PORT compared to 44% (95%CI: 43-46%) without PORT. On a separate subset analysis, in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95%CI: 0.85-0.96; p=0.001). Patient with positive LNR of 0.34+ had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 29% (95%CI: 28-31%) without PORT. Patients with a positive LNR of 0.00-0.33 had a 5-year OS of 47% (95%CI: 45-49%) with PORT compared to 43% (95%CI: 42-44%) without PORT. <h3>Conclusion</h3> This study suggests that patients with 3+ positive LNs or a LNR of 0.34+ may present a subpopulation of patients who could benefit from PORT. These findings warrant further investigation in a future prospective study.

EP05.03-004 Risk Prediction of Multiple-station N2 Metastasis in Patients with Clinical Single-station N2 Non-small Cell Lung Cancer

Although the standard treatment for patients with N2 non-small-cell lung cancer (NSCLC) is definitive chemoradiation, several studies have demonstrated that minimal N2 disease, such as single-station N2 disease (N2 disease limited to a single mediastinal station), is a favorable prognostic indicator of resected N2 NSCLC. The objective of this study is to investigate long-term survival outcomes and develop a risk model for multiple-station N2 metastasis in patients with clinical single-station N2 NSCLC.

A new N descriptor for non-small cell lung cancer: the classification based on anatomic location, number and ratio of metastatic lymph nodes.

BackgroundThe current N classification, which is determined by the anatomical location of positive lymph nodes, does not effectively stratify N1 and N2 non-small cell lung cancer (NSCLC) patients into prognostically significant subgroups.MethodsWe acquired the clinical data of 3,234 N1 and N2 NSCLC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2015). We eliminated patients undergoing chemotherapy or radiation because chemotherapy and radiotherapy might lower lymph node stage, and the SEER database does not distinguish between therapy administered before and after surgery. We developed the N-new classification based on the former N stage, the number and ratio of lymph nodes. Patients were finally classified into four categories (N1a, N1b, N2a, N2b). Then, the N-new classification was validated in subgroups based on a variety of clinical characteristics, such as tumor size. The multivariable Cox regression analysis, the decision curve analysis (DCA) and the time-dependent receiver operating characteristic (ROC) analysis were conducted to compare the performance of the N-new classification and the current N classification.ResultsThe cancer-specific survival (CSS) and overall survival were significantly different among each pair of N-new classification. And the same results were shown in the majority of the subgroups determined by various clinical characteristics. Compared with the current N classification (C-index, 0.639), the N-new classification (C-index, 0.652) performed better in classifying N1 and N2 NSCLC patients into subgroups with distinctive clinical outcomes. The 5-year CSS rates were 49.7%, 41.4%, 30.4% and 20.4% for N1a, N1b, N2a and N2b, respectively.ConclusionsWhen compared to the current N classification, the N-new classification could be a more reliable and accurate prognostic determinant, which is worth considering in the revision of the 9th edition of the tumor, node, metastasis (TNM) staging system.

Long-term clinical outcomes and prognostic factors of upfront surgery as a first-line therapy in biopsy-proven clinical N2 non-small cell lung cancer.

BackgroundMultimodality therapy offers the best opportunity to improve pathological N2 non-small cell lung cancer (NSCLC) prognosis. This paper aimed to evaluate the long-term clinical outcomes and the prognostic factors of upfront surgery as first-line therapy in biopsy-proven clinical N2.MethodsRetrospective review of biopsy-proven cN2 NSCLC patients operated between 2007 and 2017. Upfront surgery was considered if the primary tumour was deemed completely resectable, with mediastinal nodal involvement confined to a single station and no preoperative evidence of extranodal tumour invasion.ResultsTwo hundred eighty-five patients who underwent radical resections were included. One hundred fifty-nine patients (55.8%) received induction chemotherapy. At follow-up completion, 127 (44.6%) patients had died. For the induction chemotherapy group, the median overall survival (OS) was 49 months [95% confidence interval (CI): 38–70 months], and the 5-year OS was 44.4%. The median and 5-year OS for the up front surgery group was 66 months (95% CI: 40–119 months) and 66.3%, respectively. There were no statistically significant differences between treatment approaches (p = 0.48). One hundred thirty-four patients (47.0%) developed recurrence. The recurrence-free survival (RFS) at 5 years was 17% (95% CI: 11–25%) for induction chemotherapy and 22% (95% CI: 9–32%) for upfront surgery; there were no statistically significant differences between groups (p = 0.93). No significant differences were observed based on the clinical N status (OS, p = 0.36; RFS, p = 0.65).ConclusionsUpfront surgery as first-line therapy for biopsy-proven cN2 NSCLC showed favourable clinical outcomes, similar to those obtained after induction chemotherapy followed by surgery. Therefore, it should be considered one of the multimodality treatment options in resectable N2 NSCLC.

Machine learning to refine prognostic and predictive nodal burden thresholds for post-operative radiotherapy in completely resected stage III-N2 non-small cell lung cancer

BackgroundThe role of post-operative radiotherapy (PORT) for completely resected N2 non-small-cell lung cancer (NSCLC) is controversial in light of recent randomized data. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on extent of nodal involvement. Materials/MethodsPatients with completely resected N2 NSCLC were identified in the National Cancer Database. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation (SHAP) values were used to identify prognostic and predictive thresholds of number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Cox proportional hazards regression was used for confirmatory analysis. ResultsA total of 16,789 patients with completely resected N2 NSCLC were identified. Using the SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On multivariate analysis, PORT was not significantly associated with OS (p = 0.111). However, on subset analysis of patients with 3+ positive LNs, PORT improved OS (HR: 0.91; 95% CI: 0.86–0.97; p = 0.002). On a separate subset analysis in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95% CI: 0.85–0.96; p = 0.001). Patients with 3+ positive lymph nodes had a 5-year OS of 38% with PORT compared to 31% without PORT. Patient with positive lymph node ratio 0.34+ had a 5-year OS of 38% with PORT compared to 29% without PORT. ConclusionsPatients with a high lymph node burden or lymph node ratio may present a subpopulation of patients who could benefit from PORT. To our knowledge, this is the first study to use machine learning algorithms to address this question with a large national dataset. These findings address an important question in the field of thoracic oncology and warrant further investigation in prospective studies.

Therapeutic Strategies for Resectable Stage-IIIA N2 Non-Small Cell Lung Cancer Patients: A Network Meta-Analysis.

Background:The National Comprehensive Cancer Network (NCCN) guidelines did not give an explicit comparison of the efficacy between surgery and radiotherapy in treating Stage-III N2 non–small cell lung cancer (NSCLC) patients, leaving a paucity for clinical reference. Through this study, we try to locate the optimum treatment strategy including surgical type for these patients.Methods:A systematic literature search was performed from PubMed, Cochrane Library, Embase, and Google Scholars. The endpoints were overall survival (OS), mean OS, and progression-free survival (PFS). The treatments comprised radiotherapy, lobectomy, and pneumonectomy. Network meta-analysis was carried out for calculating the odds ratio (OR) for binary variants. All the analyses implemented Stata 17.0 MP.Results:Eight clinical trials reporting 1756 patients met the inclusion criteria. Radiotherapy and surgery were equivalent in improving patients’ OS (OR = 0.842, 95% confidence interval [CI]: [0.645, 1.099]). The mean OS of patients were similar in terms of radiotherapy, lobectomy, and pneumonectomy. Besides, radiotherapy and surgery had equivalent effects in improving PFS (OR = 0.896, 95% CI: [0.718, 1.117]).Conclusions:Since lobectomy and pneumonectomy following neoadjuvant treatments had equivalent efficacy in prolonging OS for patients with stage-IIIA N2 NSCLC compared with definitive radiotherapy, young patients with favorable performance status (0) should try surgery to pursue better prognosis while elderly patients with unfavorable PS or radiosensitive pathology types should accept definitive radiotherapy. More high-quality clinical trials are needed to support our findings.

Lymph Node Parameters Predict Adjuvant Chemoradiotherapy Efficacy and Disease-Free Survival in Pathologic N2 Non-Small Cell Lung Cancer.

Pathologic N2 non-small cell lung cancer (NSCLC) is prominently intrinsically heterogeneous. We aimed to identify homogeneous prognostic subgroups and evaluate the role of different adjuvant treatments. We retrospectively collected patients with resected pathologic T1-3N2M0 NSCLC from the Shanghai Chest Hospital as the primary cohort and randomly allocated them (3:1) to the training set and the validation set 1. We had patients from the Fudan University Shanghai Cancer Center as an external validation cohort (validation set 2) with the same inclusion and exclusion criteria. Variables significantly related to disease-free survival (DFS) were used to build an adaptive Elastic-Net Cox regression model. Nomogram was used to visualize the model. The discriminative and calibration abilities of the model were assessed by time-dependent area under the receiver operating characteristic curves (AUCs) and calibration curves. The primary cohort consisted of 1,312 patients. Tumor size, histology, grade, skip N2, involved N2 stations, lymph node ratio (LNR), and adjuvant treatment pattern were identified as significant variables associated with DFS and integrated into the adaptive Elastic-Net Cox regression model. A nomogram was developed to predict DFS. The model showed good discrimination (the median AUC in the validation set 1: 0.66, range 0.62 to 0.71; validation set 2: 0.66, range 0.61 to 0.73). We developed and validated a nomogram that contains multiple variables describing lymph node status (skip N2, involved N2 stations, and LNR) to predict the DFS of patients with resected pathologic N2 NSCLC. Through this model, we could identify a subtype of NSCLC with a more malignant clinical biological behavior and found that this subtype remained at high risk of disease recurrence after adjuvant chemoradiotherapy.

Comparison of Two Proposed Changes to the Current Nodal Classification for Non--small Cell Lung Cancer Based on the Number and Ratio of Metastatic Lymph Nodes

The current nodal classification is unsatisfactory in distinguishing the prognostically heterogeneous N1 or N2 non-small cell lung cancer (NSCLC). Is the combination of the current N category and the number of metastatic lymph nodes (N-#number) or the combination of the current N category and the ratio of the number of positive to resected lymph nodes (N-#ratio) better than the current N category alone? We identified 2,162 patients with N1 or N2 NSCLC from the Surveillance, Epidemiology, and End Results database (2004-2016). We classified these patients into three N-#number categories (N-#number-1, N-#number-2a, N-#number-2b) and three N-#ratio categories (N-#ratio-1, N-#ratio-2a, N-#ratio-2b). Lung cancer-specific survival (LCSS) were compared using the Kaplan-Meier method. The prognostic significance of the new nodal classifications was validated across each tumor size category (≤3cm, 3-5cm, 5-7cm, >7cm). Cox proportional hazards regression was used to evaluate the association between each nodal classification and LCSS. The survival curves showed clear differences between each pair of N-#number and N-#ratio categories. A significant tendency toward the deterioration of LCSS from N-#number-1 to N-#number-2b was observed in all tumor size categories. However, the differences between each pair of N-#ratio categories were significant only in tumors from 3 to 7cm. Although all three nodal classifications were independent prognostic indicators, the N-#number classification provided more accurate prognostic stratifications compared with the N-#ratio classification and the current nodal classification. The N-#number classification followed by the N-#ratio classification might be better prognostic determinants than the current nodal classification in prognostically heterogeneous N1 or N2 NSCLC.

Stage III N2 non-small cell lung cancer treatment: decision-making among surgeons and radiation oncologists.

BackgroundStage III N2 non-small cell lung cancer (NSCLC) is a very heterogeneous disease associated with a poor prognosis. A number of therapeutic options are available for patients with Stage III N2 NSCLC, including surgery [with neoadjuvant or adjuvant chemotherapy (CTx)/neoadjuvant chemoradiotherapy (CRT)] or CRT potentially followed by adjuvant immunotherapy. We have no clear evidence demonstrating a significant survival benefit for either of these approaches, the selection between treatments is not always straightforward and can come down to physician and patient preference. The very heterogeneous definition of resectability of N2 disease makes the decision-making process even more complex.MethodsWe evaluated the treatment strategies for preoperatively diagnosed stage III cN2 NSCLC among Swiss thoracic surgeons and radiation oncologists. Treatment strategies were converted into decision trees and analysed for consensus and discrepancies. We analysed factors relevant to decision-making within these recommendations.ResultsFor resectable “non-bulky” mediastinal lymph node involvement, there was a trend towards surgery. Numerous participants recommend a surgical approach outside existing guidelines as long as the disease was resectable, even in multilevel N2. With increasing extent of mediastinal nodal disease, multimodal treatment based on radiotherapy was more common.ConclusionsBoth, surgery- or radiotherapy-based treatment regimens are feasible options in the management of Stage III N2 NSCLC. The different opinions reflected in the results of this manuscript reinforce the importance of a multidisciplinary setting and the importance of shared decision-making with the patient.

Thoracoscopic Vs Open Surgery Following Neoadjuvant Chemoradiation for Clinical N2 Lung Cancer

We evaluated the feasibility of video-assisted thoracoscopic surgery (VATS) following neoadjuvant concurrent chemoradiotherapy (nCCRT) for N2 non-small-cell lung cancer (NSCLC). We retrospectively reviewed patients with clinical N2 NSCLC who underwent lobectomy and lymph node dissection after nCCRT. The patients were matched using a propensity score based on age, sex, pulmonary function test, histologic type, clinical T factor, and method of N-staging. A total of 385 patients were enrolled between June 2012 and July 2017 (35 VATS, 350 open). After propensity matching (31 VATS, 112 open), the VATS group showed a significantly lower major complication rate (≥ grade II Clavien-Dindo classification; 9.7% vs 30.4%, P = 0.036). No significant differences were found between 2 group of 5-year survival rates (77.1% for the VATS group, 59.9% for the open group; P = 0.276) and recurrence-free survival rates (66.3% for the VATS group, 54.6% for the open group; P = 0.354). In multivariable analysis, VATS did not affect overall survival and recurrence-free survival. VATS was comparable to open thoracotomy in patients with clinical N2 NSCLC after nCCRT without compromising oncologic efficacy.

Mediastinal radiotherapy after adjuvant chemotherapy for resected non–small cell lung cancer with N2 lymphadenopathy: A novel meta-analysis

IntroductionTreatment for stage IIIA N2 non–small cell lung cancer (NSCLC) typically involves a combination of chemotherapy, radiotherapy, and surgery, but the optimal sequencing is not determined. Local recurrence rates following surgery remain high, and the role of postoperative radiotherapy (PORT) in N2 disease is unclear. This meta-analysis aims to determine whether PORT provides additional survival advantage beyond observation for patients with stage IIIA N2 disease who have undergone complete surgical resection and received adjuvant chemotherapy. MethodsAll studies comparing adjuvant chemotherapy and PORT versus adjuvant chemotherapy alone after curative surgical resection for stage IIIA N2 NSCLC were included. Meta-analysis was performed using random effects modelling in accordance with MOOSE (Meta-Analyses and Systematic Reviews of Observational Studies) guidelines. Subgroup analysis, heterogeneity, and risk of bias were assessed, with meta-regression to determine the effects of patient and tumor characteristics on outcomes. ResultsTen studies with a pooled dataset of 18,077 patients (5453 PORT, 12,624 no PORT) were included. PORT significantly improved both overall survival (OS) and disease-free survival (DFS) at 1 year (OS: hazard ratio [HR], 0.768; DFS: HR, 0.733), 3 years (OS: HR, 0.914; DFS: HR, 0.732), and 5 years (OS: HR, 0.898; DFS: HR, 0.735, all P < .0001). These effects were independent of specific patient or tumor characteristics. ConclusionsThis study demonstrates a significant DFS and OS benefit from the addition of PORT following adjuvant chemotherapy. We advocate the consideration of PORT for such patients following specialist multidisciplinary assessment and comprehensive discussion of the benefits and risks of treatment.

Postoperative Radiotherapy (PORT) Improves the Survival of Patients With N2 Non-Small Cell Lung Cancer (NSCLC) with Regional Nodes Examined (RNE) ≤16 - A Real World Study Using Surveillance, Epidemiology, and End Results (SEER) Database

PORT is widely used in patients with N2 NSCLC, but which subgroup population can benefit from PORT is still controversial. Our study is to evaluate the relationship between the RNE and the effect of PORT on survival of patients with N2 NSCLC from SEER database. Data from the SEER database were filtrated by the inclusion criteria of patients with NSCLC diagnosed at 2010-2016, with N2 disease (AJCC 7th) and treated with lobectomy or pneumonectomy. We excluded patients with unclear basic information (such as sex, histology or cause of death), multiple primary malignant tumors and M1 disease. All data were analyzed using the R version 3.6.2 software. And propensity-score matched (PSM) analysis was used to match the baseline characteristics between PORT group and non-PORT group. Kaplan-Meier method was used to estimate overall survival (OS) and cancer specific survival (CSS). Univariable and multivariable Cox proportional hazards models were adopted to estimate hazard ratios (HR) of predictors of survival. The HR of PORT for patients with different RNE was calculated to determine the best cut-off value of RNE. 2904 patients were included. The baseline characteristics were as follows: age≤70 (62.9%), white (80.5%), female (51.2%), grade 1-2 (53.0%), adenocarcinoma (67.1%), T2 (51.1%), lobectomy (89.9%), chemotherapy (74.9%), median number of positive regional nodes (3), median number of RNE (12). There were 1188 patients (40.9%) with PORT. RNE≤16 was chosen as the cut-off value and divided the patients into two cohorts. PSM was then conducted between the PORT group and the non-PORT group of each cohort. In RNE≤16 cohort (1398 patients), the median OS of the PORT and non-PORT groups were 48 months vs 40 months and 5-year OS rates were 42.93% vs 39.09%, respectively (P = 0.013). The median CSS were 59 months vs 44 months and 5-year CSS rates were 48.82% vs 43.15%, respectively (P = 0.008). Univariable analysis showed that PORT significantly improved OS (HR = 0.815, P = 0.013) and CSS (HR = 0.794, P = 0.008). Multivariable analysis confirmed that PORT was the significant predictor of OS (HR = 0.816, P = 0.014) and CSS (HR = 0.799, P = 0.011). In RNE>16 cohort (550 patients), The median OS of the PORT and non-PORT groups was 44 months vs 64 months and 5-year OS rates were 42.75% vs 50.69%, respectively (P = 0.210). The median CSS of the two groups were 47 months and not reached, the 5-year CSS rates were 46.17% vs 54.10%, respectively (P = 0.207). Neither univariable nor multivariable analysis showed that PORT was an individual predictive factor. For N2 NSCLC patients with RNE≤16, PORT can significantly improve the OS and CSS. However, for those with RNE>16, PORT may not improve survival, but even have the tendency of damage. These results need to be clarified by prospective randomized clinical trials.

Association of postoperative radiotherapy with survival in patients with completely resected pathologic N2 non-small cell lung cancer treated with chemotherapy.

e21008 Background: The current staging system for completely resected pathological N2 non-small-cell lung cancer (NSCLC) treated with chemotherapy is not suitable for predicting those patients most likely to benefit or not from post-operative radiotherapy (PORT). This study aimed to construct a survival prediction model that will enable individualized predictions of the net survival of PORT. Methods: A total of 3094 cases between 2002 and 2014 were extracted from the Surveillance, Epidemiology, and End Results databases. Patient characteristics were included as covariates, and their association for overall survival (OS) with and witout PORT was assessed. Externally validate data of 602 patients were included from China. Results: A total of 3696 patients were included for analysis. Age, gender, examined lymph node, positive lymph node, tumor size, extent of surgery, and visceral pleural invasion were significantly associated with OS, with P &lt; .05. The calibration curve for OS showed great agreement between prediction by survival prediction model and actual observation.In the training cohort, the C-index for OS was 0.619 (95% CI, 0.598-0.641) in the PORT group and 0.627 (95% CI, 0.605-0.648) in the non-PORT group. In the externally validation cohort, the C-index for OS was 0.599 (95% CI, 0.485- 0.713) in the PORT group and 0.595 (95% CI, 0.544-0.646) in non-PORT group. The two survival prediction models were developed based on clinical variables to estimate an individual's net survival gain or not attributable to PORT. We found that PORT could improve OS (HR, 0.861; P = 0.044) for patients with a positive PORT net survival benefit. Conclusions: We established a practical survival prediction model that can be used to make individualized predictions about the expected survival of PORT or without PORT in patients with completely resected pathological N2 NSCLC, treated with chemotherapy.

International guidelines on stage III N2 nonsmall cell lung cancer: surgery or radiotherapy?

Stage III N2 nonsmall cell lung cancer (NSCLC) is a complex disease with poor treatment outcomes. For patients in whom the disease is considered technically resectable, the main treatment options include surgery (with neoadjuvant or adjuvant chemotherapy/neoadjuvant chemoradiotherapy (CRT)) or CRT followed by adjuvant immunotherapy (dependent on programmed death ligand 1 status). As there is no clear evidence demonstrating a survival benefit between these options, patient preference plays an important role. A lack of a consensus definition of resectability of N2 disease adds to the complexity of the decision-making process. We compared 10 international guidelines on the treatment of NSCLC to investigate the recommendations on preoperatively diagnosed stage III N2 NSCLC. This comparison simplified the treatment paths to multimodal therapy based on surgery or radiotherapy (RT). We analysed factors relevant to decision-making within these guidelines. Overall, for nonbulky mediastinal lymph node involvement there was no clear preference between surgery and CRT. With increasing extent of mediastinal nodal disease, a tendency towards multimodal treatment based on RT was identified. In multiple scenarios, surgery or RT-based treatments are feasible and patient involvement in decision-making is critical.

Clinical implications of uncertain resection in scenarios of metastasis of the highest or most distant mediastinal lymph node station following surgical treatment of non-small-cell lung cancer

ObjectivesThe positive highest nodal station after operation is one of the definitions of “uncertain resection” proposed by the International Association for the Study of Lung Cancer. This study was performed to determine the prognostic value of positive highest or the most distant nodal station in patients with N2 non-small-cell lung cancer (NSCLC). Materials and MethodsThree hundred thirty-nine patients who underwent complete anatomical resection and mediastinal lymph node (LN) dissection for N2 NSCLC between 2000 and 2015 were reviewed. Cases of operative mortality, extracapsular invasion of LN and incomplete resection were excluded from analysis. ResultsThe mean age was 61.58 ± 9.43 years, and 235(69.3%) patients were male. The numbers of total dissected LNs and positive LNs were 29.90 ± 11.92 and 5.49 ± 5.90, respectively. The subcategory of N stage was divided as follows: N2a1, 91(26.8%); N2a2, 132(38.9%); and N2b, 116(34.2%). One hundred forty-two (41.9%) patients showed highest LN metastasis, and 162(47.8%) patients showed most distant LN metastasis. Kaplan–Meier analysis revealed no differences between distant LN negative and positive patients regarding 5-year overall survival (43.1% vs. 39.2%; p = 0.428) and between highest LN negative and positive patients regarding 5-year overall survival (42.1% vs. 40.0%; p = 0.539). On multivariable analysis, metastasis to the most distant mediastinal LN (hazard ratio (HR): 1.050; p = 0.755) and metastasis to the highest mediastinal LN (HR: 1.015; p = 0.924) were not related to overall survival. ConclusionThe current definition of uncertain resection based on metastasis of the highest or most distant LNs did not show survival differences in completely resected N2 NSCLC.