N2 Non-small Cell Lung Cancer Research Articles

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.

Investigations of the distant metastatic non-small cell lung cancer without local lymph node involvement: Real world data from a large database.

This study aimed to investigate the presentations and survival outcomes of the distant metastatic non-small cell lung cancer (NSCLC) without lymph node involvement to obtain a clearer picture of this special subgroup of metastatic NSCLC. A least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis was used to select the prognostic variables. A nomogram and corresponding risk-classifying systems were constructed. The C-index and calibration curves were used to evaluate the performance of the model. Overall survival (OS) curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare OS differences between groups. Propensity score matching (PSM) was performed to reduce bias. A total of 12 610 NSCLC patients with M1 category (N0 group: 3045 cases; N1-3 group: 9565 cases) were included. Regarding the N0 group, multivariate analysis demonstrated that age, sex, race, surgery, grade, tumor size, and M category were independent prognostic factors. A nomogram and corresponding risk-classifying systems were formulated. Favorable validation results were obtained from the C-index, calibration curves, and survival comparisons. Survival curves demonstrated that N0 NSCLC patients had better survival than N1-3 NSCLC patients both before and after PSM. Furthermore, the survival of resected N0M1 patients was superior to that of those without surgery. In this study, a prognostic nomogram and risk-classifying systems designed for the T1-4N0M1 NSCLC patients showed acceptable performance. Primary lung tumor resection might be a feasible treatment for this population subset. Additionally, we proposed that lymph node stage might have a place in the forthcoming tumor-node-metastasis (TNM)staging proposal for NSCLC patients with M1 category.

Multimodal Therapy for T4 N2 Non–Small Cell Lung Cancer With Additional Ipsilateral Pulmonary Nodules

BackgroundThe optimal treatment strategy for T4 non–small cell lung cancer (NSCLC) with additional intrapulmonary nodules in a different ipsilateral lobe (T4-Add) is not well characterized across clinical N stages. This study evaluated long-term survival of patients with T4-Add N2 NSCLC who received multimodal therapy including surgical resection and chemotherapy vs concurrent chemoradiation. MethodsPatients with T4-Add N2 M0 NSCLC in the National Cancer Database from 2010 to 2015 were included. Long-term survival was evaluated and compared between patients who underwent primary site surgical resection with chemotherapy and those who received concurrent chemoradiation by Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching on 9 common prognostic variables including comorbidities. ResultsOf the 499 patients diagnosed with T4-Add N2 M0 NSCLC who satisfied study eligibility criteria, 220 (44.1%) received primary site surgical resection with chemotherapy and 279 (55.9%) received chemoradiation. After multivariable adjusted Cox proportional hazards modeling, surgical resection with chemotherapy was associated with better long-term survival than chemoradiation. In a propensity score–matched analysis of 100 patients who received surgical resection with chemotherapy and 100 patients who received chemoradiation, patients who received surgical resection with chemotherapy had better 5-year overall survival. ConclusionsThe results of this national analysis of patients with T4 N2 NSCLC with additional nodules in a different ipsilateral lobe suggest that multimodal therapy including surgery may confer a survival benefit compared with chemoradiation alone. These findings support further evaluation of surgical resection as part of multimodal therapy for carefully selected patients with T4-Add N2 disease.

Development and validation of a nomogram for predicting overall survival of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy.

Currently, the prognosis of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy is poor. The goal of this research was to develop and validate a novel nomogram for exactly predicting the overall survival (OS) of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. The data applied in our research were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. We divided selected data into a training cohort and a validation cohort using R software, with a ratio of 7:3. Univariate Cox regression and multivariate Cox regression were utilized to select significant variables to build the nomogram. To validate our nomogram, calibration curves, receiver operating characteristic curves (ROC), decision curve analysis (DCA), and Kaplan-Meier survival curves were employed. The nomogram model was also compared with the tumor-node-metastasis (TNM) staging system by utilizing net reclassification index (NRI) and integrated discrimination improvement (IDI). Eight variables-age, sex, operative type, LN removed number, chemotherapy, AJCC stage, M stage, histology-were statistically significant in the multivariate Cox regression analysis and were selected to develop our nomogram. Based on ROC curves, calibration curves, and DCA analysis, our novel nomogram demonstrated good predictive accuracy and clinical utility. Using Kaplan-Meier (KM) survival curves and log-rank tests, the risk stratification system was able to stratify patients based on their estimated mortality risk. The nomogram performed better than the TNM staging system based on the NRI and IDI indexes. We developed and validated a nomogram to predict prognosis of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. Using this nomogram, clinicians may find this nomogram useful in predicting OS of targeted patients and making more appropriate treatment decisions.

A Comparison of Total Thoracoscopic and Robotic Surgery for Lung Cancer Lymphadenectomy

Background: Robotic-assisted thoracic surgery (RATS) is used increasingly frequently in major lung resection for early stage non-small-cell lung cancer (NSCLC) but has not yet been fully evaluated. The aim of this study was to compare the surgical outcomes of lymph node dissection (LND) performed via RATS with those from totally thoracoscopic (TT) four-port videothoracoscopy. Methods: Clinical and pathological data were collected retrospectively from patients with clinical stage N0 NSCLC who underwent pulmonary resection in the form of lobectomy or segmental resection between June 2010 and November 2022. The assessment criteria were number of mediastinal lymph nodes and number of mediastinal stations dissected via the RATS approach compared with the four-port TT approach. Results: A total of 246 pulmonary resections with LND for clinical stages I–II NSCLC were performed: 85 via TT and 161 via RATS. The clinical characteristics of the patients were similar in both groups. The number of mediastinal nodes dissected and mediastinal stations dissected was significantly higher in the RATS group (TT: mean ± SD, 10.72 ± 3.7; RATS, 14.74 ± 6.3 [p &lt; 0.001]), except in the inferior mediastinal stations. There was no difference in terms of postoperative complications. Conclusions: In patients with early stage NSCLC undergoing major lung resection, the quality of hilomediastinal LND performed using RATS was superior to that performed using TT.

Prognostic significance of uncertain resection for metastasis in the highest mediastinal lymph node after surgery for clinical N0 non-small cell lung cancer.

The International Association for the Study of Lung Cancer defined types of surgical resection and considered the positivity of the highest mediastinal lymph node resected a parameter of "uncertain resection" (R-u). We investigated the metastases in the highest mediastinal lymph node, defined as the lowest numerically numbered station among those resected. We aimed to evaluate the prognostic value of R-u compared with R0. We selected 550 patients with non-small cell lung cancer at clinical Stage I, IIA, IIB (T3N0M0), or IIIA (T4N0M0) undergoing lobectomy and systematic lymphadenectomy between 2015 and 2020. The R-u group included patients with positive highest mediastinal resected lymph node. In the groups of patients with mediastinal lymph node metastasis, we defined 31 as R-u (45.6%, 31/68). The incidence of metastases in the highest lymph node was related to the pN2 subgroups (p < 0.001) and the type of lymphadenectomy performed (p < 0.001). The survival analysis compared R0 and R-u: 3-year disease-free survival was 69.0% and 20.0%, respectively, and 3-year overall survival was 78.0% and 40.0%, respectively. The recurrence rate was 29.7% in R0 and 71.0% in R-u (p-value < 0.001), and the mortality rate was 18.9% and 51.6%, respectively (p-value < 0.001). R-u variable showed a tendency to be a significant prognostic factor for disease-free survival and overall survival (hazard ratio: 4.6 and 4.5, respectively, p-value < 0.001). The presence of metastasis in the highest mediastinal lymph node removed seems to be an independent prognostic factor for mortality and recurrence. The finding of these metastases represents the margin of cancer dissemination at the time of surgery, so it could imply metastasis into the N3 node or distant metastasis.

Complete thoracoscopic lobectomy versus hybrid video-assisted thoracoscopic lobectomy for non-small cell lung cancer.

Video-assisted thoracoscopic surgery (VATS) is the standard approach to lobectomy for early-stage non-small cell lung cancer (NSCLC). However, there are many different types. One of its approaches is complete thoracoscopic surgery (CTS), which may be less invasive because of low chest wall stress. This study compared the treatment outcomes of CTS and hybrid VATS lobectomy for NSCLC. In total, 442 eligible patients with clinical N0 NSCLC underwent lobectomy between 2007 and 2016. Patients were classified into a group of patients who underwent CTS and a group of those who underwent hybrid VATS. Propensity score matching was performed between the two groups. There were 175 patients after matching. The median follow-up period in the CTS and hybrid VATS groups was 60 and 63months, respectively. The CTS group showed less blood loss (CTS, 50mL vs. 100mL, p = 0.005), fewer complications (CTS, 25.7% vs. 36.6%, p = 0.037), and shorter postoperative hospital stays (CTS, 8days vs. 12days, p < 0.001). There was no significant difference in the postoperative 30-day mortality rates. Between the patients who underwent CTS and hybrid VATS groups, the 5-year overall survival rates were 85.4% and 86.0% (p = 0.701), the relapse-free survival rates were 76.5% and 74.9% (p = 0.435), and the lung cancer-specific survival rates were 91.5% and 91.7% (p = 0.90), respectively. CTS is less invasive and has superior short-term outcomes as an approach to lobectomy for early-stage NSCLC.

Treatment outcomes of lobectomy with and without mediastinal lymph node dissection in older patients with clinical N0 non-small cell lung cancer.

To reduce surgical stress, we omit mediastinal lymph node dissection (MLND) in patients with non-small cell lung cancer aged ≥80 years without N1 metastasis, as confirmed via surgery. This study examined the effect of MLND omission on prognosis. Altogether, 212 eligible patients with clinical N0 non-small cell lung cancer underwent video-assisted thoracoscopic lobectomy between 2007 and 2017. Patients were classified into two groups as follows: patients aged 75-79 years who underwent MLND group, and patients aged ≥80 years in whom MLND was omitted (non-MLND group). Propensity score matching was performed between the two groups. There were 86 patients after matching. The non-MLND group showed shorter operative time (237.5 min vs. 207.5 min, p = 0.018). No differences in postoperative complications were noted between the two groups. Between the MLND group and non-MLND group, the 5-year overall survival rates were 84.0% and 84.7% (p = 0.989), relapse-free survival rates were 69.8% and 74.7% (p = 0.855), and cancer-specific survival rates were 91.4% and 91.6% (p = 0.700), respectively. These results did not differ significantly. This study demonstrated that MLND does not affect the prognosis of patients with non-small cell lung cancer aged ≥80 years. Lobectomy without MLND is one of the surgical treatment options in older patients with clinical N0 non-small cell lung cancer. Naturally, the clinical stage of patients must be carefully evaluated before surgery.

Prognostic significance of extranodal extension in patients with pathologic N1 non-small cell lung cancer undergoing complete resection.

The prognostic significance of extranodal extension (ENE) remains unclear in patients with pathologic N1 (pN1) non-small-cell lung cancer (NSCLC) undergoing surgery. We evaluated the prognostic impact of ENE in patients with pN1 NSCLC. From 2004 to 2018, we retrospectively analyzed the data of 862 patients with pN1 NSCLC who underwent lobectomy and more (lobectomy, bilobectomy, pneumonectomy, sleeve lobectomy). According to their resection status and the presence of ENE, patients were classified into R0 without ENE (pure R0) (n=645), R0 with ENE (R0-ENE) (n=130), and incomplete resection (R1/R2) groups (n=87). The primary and secondary endpoints were 5-year overall survival (OS) and recurrence-free survival (RFS), respectively. The prognosis of the R0-ENE group was significantly worse than the pure R0 group for both OS (5-year rate: 51.6% vs. 65.4%, P=0.008) and RFS (44.4% vs. 53.0%, P=0.04). According to the recurrence pattern, a difference of RFS was found only for distant metastasis (55.2% vs. 65.0%, P=0.02). The multivariable Cox analysis revealed that the presence of ENE was a negative prognostic factor in patients who did not undergo adjuvant chemotherapy [hazard ratio (HR) =1.58; 95% confidence interval (CI): 1.06-2.36; P=0.03], but it was not in those with adjuvant chemotherapy (HR =1.20; 95% CI: 0.80-1.81; P=0.38). For patients with pN1 NSCLC, the presence of ENE was a negative prognostic factor for both OS and RFS, regardless of resection status. The negative prognostic effect of ENE was significantly associated with an increase in distant metastasis and was not observed in patients who underwent adjuvant chemotherapy.

Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .

Programmed death ligand-1 expression and occult lymph node metastasis in non-small cell lung cancer.

Identifying the preoperative risk factors for lymph node upstaging could contribute to the development of individualized perioperative treatment for patients with non-small cell lung cancer (NSCLC). The current study aimed to evaluate the risk factors for lymph node upstaging, including gene mutation and programmed death ligand-1 expression in patients with resectable NSCLC. Data on the clinicopathological characteristics of patients who underwent lobectomy for clinical N0 NSCLC at our institution were collected. The clinicopathological findings of the pathological N0 and lymph node upstaging groups were then analyzed. Univariate and multivariate analyses were performed to examine the predictive factors for nodal upstaging. Of 291 patients, 40 had postoperative nodal upstaging (n = 25, N1; n = 15, N2). Large tumor size and high maximum standardized uptake value were significantly associated with nodal upstaging. The nodal upstaging group had a higher proportion of patients with solid adenocarcinoma and lymphatic, vascular, and pleural invasion than the pathological N0 group. Further, the nodal upstaging group had a higher proportion of patients with positive programmed death ligand-1 expression than the pathological N0 group. Univariate and multivariate analyses showed that tumor size and positive programmed death ligand-1 expression were associated with nodal upstaging. The appropriate therapeutic strategy including preoperative treatment and resection should be cautiously considered preoperatively in patients with clinical N0 NSCLC who have large tumors and positive programmed death ligand-1 expression.

99mTc-MAA accumulation within tumor in preoperative lung perfusion SPECT/CT associated with occult lymph node metastasis in patients with clinically N0 non-small cell lung cancer

Background99mTc-MAA accumulation within the tumor representing pulmonary arterial perfusion, which is variable and may have a clinical significance. We evaluated the prognostic significance of 99mTc-MAA distribution within the tumor in non-small cell lung cancer (NSCLC) patients in terms of detecting occult nodal metastasis and lymphovascular invasion, as well as predicting the recurrence-free survival (RFS).MethodsTwo hundred thirty-nine NSCLC patients with clinical N0 status who underwent preoperative lung perfusion SPECT/CT were retrospectively evaluated and classified according to the visual grading of 99mTc-MAA accumulation in the tumor. Visual grade was compared with the quantitative parameter, standardized tumor to lung ratio (TLR). The predictive value of 99mTc-MAA accumulation with occult nodal metastasis, lymphovascular invasion, and RFS was assessed.ResultsEighty-nine (37.2%) patients showed 99mTc-MAA accumulation and 150 (62.8%) patients showed the defect on 99mTc-MAA SPECT/CT. Among the accumulation group, 45 (50.5%) were classified as grade 1, 40 (44.9%) were grade 2, and 4 (4.5%) were grade 3. TLR gradually and significantly increased from grade 0 (0.009 ± 0.005) to grade 1 (0.021 ± 0.005, P < 0.05) and to grade 2–3 (0.033 ± 0.013, P < 0.05). The following factors were significant predictors for occult nodal metastasis in univariate analysis: central location, histology different from adenocarcinoma, tumor size greater than 3 cm representing clinical T2 or higher, and the absence of 99mTc-MAA accumulation within the tumor. Defect in the lung perfusion SPECT/CT remained significant at the multivariate analysis (Odd ratio 3.25, 95%CI [1.24 to 8.48], p = 0.016). With a median follow-up of 31.5 months, the RFS was significantly shorter in the defect group (p = 0.008). Univariate analysis revealed that cell type of non-adenocarcinoma, clinical stage II-III, pathologic stage II-III, age greater than 65 years, and the 99mTc-MAA defect within tumor as significant predictors for shorter RFS. However, only the pathologic stage remained statistically significant, in multivariate analysis.ConclusionThe absence of 99mTc-MAA accumulation within the tumor in preoperative lung perfusion SPECT/CT represents an independent risk factor for occult nodal metastasis and is relevant as a poor prognostic factor in clinically N0 NSCLC patients. 99mTc-MAA tumor distribution may serve as a new imaging biomarker reflecting tumor vasculatures and perfusion which can be associated with tumor biology and prognosis.

Abstract 3387: ctDNA dynamics in early stage node negative lung cancers

Abstract Introduction: Patients with early-stage lung cancers have a high risk of relapse and death even after curative surgery. Detection of circulating tumour DNA (ctDNA) in plasma perioperatively is associated with shorter recurrence free survival (RFS). ctDNA-Lung-Detect is an investigator-initiated prospective study of ctDNA detection and association with RFS in patients with early stage non-small cell lung cancer (NSCLC). Methods: Patients with clinically staged T&amp;lt;4cm N0 NSCLC planned for surgical resection at the Princess Margaret/University Health Network underwent ctDNA assessment before and after surgery (~1 month and 1 year). ctDNA minimal residual disease (MRD) was detected using the highly sensitive and specific tumor-informed Residual Disease and Recurrence (RaDaR®, Inivata, Cambridge, UK) assay, which can track up to 48 tumor-specific variants in plasma. Results: Since August 2021, 64 eligible patients were enrolled (Table 1). One had isolated metastasis from a remote non-lung primary and subsequently excluded; another had their preoperative sample missed but was included. Preoperative ctDNA was detected in 15/62 (23.8%) patients and 1/63 (1.6%) post-operatively at the 1-month landmark timepoint (occult N2 disease found at surgery). All but one (93.3%) had ctDNA clearance with surgical resection. Two patients have recurred radiographically and in plasma at 1 year post-operatively, 1/15 with preoperative ctDNA detected (6.7%) and 1/47 without preoperative ctDNA detected (2.1%). Patients with higher T stage, tumor size, squamous histology, and without actionable driver alterations were more likely to have ctDNA detected at any timepoint. Conclusions: In patients with early stage NSCLC (small node negative tumors), 24% have detectable ctDNA pre-operatively. Surgical resection led to ctDNA clearance in 93% of cases. Our results support ongoing testing beyond the initial MRD landmark. Assessment of the impact on RFS post resection is ongoing. Citation Format: Jamie Feng, Tom Waddell, Kazuhiro Yasufuku, Andrew Pierre, Shaf Keshavjee, Jonathan Yeung, Marcelo Cypel, Laura Donahoe, Elliot Wakeam, Marc de Perrot, Jennifer Law, Alexandra Salvarrey, Lisa W. Le, Jennifer Lister, Michael Cabanero, Ming Tsao, Christodoulos Pipinikas, Karen Howarth, Natasha Leighl. ctDNA dynamics in early stage node negative lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3387.

Diagnostic Performance of Endosonography to Detect Mediastinal Lymph Node Metastasis in Patients with Radiological N1 Non-Small Cell Lung Cancer.

Guidelines recommend that non-small cell lung cancer (NSCLC) patients with suspected hilar lymph node (LN) metastases should undergo invasive mediastinal LN staging prior to surgical treatment via endosonography. We evaluated the diagnostic performance of endosonography for detecting occult mediastinal metastases (OMM) and determined the factors associated with OMM in NSCLC patients with radiological N1. Patients with confirmed primary NSCLC with radiological N1 who underwent endosonography for nodal staging assessment from January 2013 to December 2019 were retrospectively analyzed. The prevalence of OMM was found to be 83/279 (29.7%) and only 38.6% (32/83) were diagnosed via endosonography. However, five of them were confirmed as N3 by endosonography. The overall diagnostic sensitivity, negative predictive value, accuracy, and area under the curve of endosonography were 38.6%, 79.4%, 81.7%, and 0.69, respectively. In multivariable analysis, central tumor (adjusted odds ratio [aOR], 2.05; 95% confidence interval [CI], 1.15-3.68; p=0.016), solid tumor (aOR, 10.24; 95% CI, 1.32-79.49; p=0.026), and adenocarcinoma (aOR, 3.01; 95% CI, 1.63-5.55; p<0.001) were related to OMM in radiological N1 NSCLC patients. Although the sensitivity of endosonography for detecting OMM was only 40%, the prevalence of OMM was not low (30%) and some cases even turned out to be N3 diseases. Clinicians should be aware that OMM may be more likely in patients with central, solid, and adenocarcinomatous tumor when performing nodal staging in radiological N1 NSCLC via endosonography.

Survival outcome of upfront surgery for clinical single-station N2 non-small cell lung cancer.

Pathological N2 (pN2) non-small cell lung cancer (NSCLC) is diverse; its treatment depends on the clinical N (cN) status. We aimed to determine the efficacy of upfront surgery for cN2pN2 NSCLC. The study included 43 cN2pN2 NSCLC patients who underwent upfront surgery at the Shizuoka Cancer Center between 2002 and 2017. Survival outcome, focusing on cN2 status, was retrospectively investigated. Mediastinal lymph nodes were pre-operatively evaluated using computed tomography and positron emission tomography. Surgical eligibility criteria included single-station cN2. N2 with N1 and skip N2 were defined as N2 with and without ipsilateral hilar lymph node metastasis, respectively. A platinum-doublet regimen was used for adjuvant chemotherapy. Survival curves were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model. Clinical-skip N2 and cN2 with N1 cases included 22 and 21 patients, respectively. Twenty-three patients received adjuvant chemotherapy. The median follow-up duration was 73months. Clinical-skip N2 had a significantly better 5-year recurrence-free survival (RFS) than cN2 with N1 (58.3 vs 28.6%, P = 0.038) and was an independent favorable RFS predictor. Recurrence within 18 months occurred in 71% of cN2 with N1 cases. Five-year overall survival and RFS rates in patients receiving adjuvant chemotherapy vs those without adjuvant chemotherapy were 82.2 vs 41.9% (P = 0.019) and 56.5 vs 28.0% (P = 0.049), respectively. Clinical-skip N2 had an excellent prognosis, and upfront surgery was acceptable. Conversely, upfront surgery followed by chemotherapy is not recommended for cN2 with N1 patients because of early recurrence.

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.

Importance of Lymph Node Evaluation in ≤2-cm Pure-Solid Non-Small Cell Lung Cancer

BackgroundThe prevalence of lymph node (LN) metastasis in small-sized lung cancer varies depending on the tumor size and proportion of ground-glass opacity. We investigated occult LN metastasis and prognosis in patients with small-sized non-small cell lung cancer (NSCLC), mainly focusing on the pure-solid tumor. MethodsWe retrospectively reviewed patients with ≤2-cm clinical N0 NSCLC who underwent lung resection with curative intent from 2003 to 2017. Among them we analyzed patients who also underwent adequate complete systematic LN dissection. Pathologic results and disease-free survival of the radiologically mixed ground-glass nodule (mGGN) and pure-solid nodule (PSN) groups were analyzed. ResultsOf 1329 patients analyzed, 591 had mGGNs and PSNs. As tumor size increased, patients in the mGGN group showed no difference in LN metastasis: ≤1 cm, 2.27%; 1.0 to 1.5 cm, 2.19%; and 1.5 to 2.0 cm, 2.18% (P = .999). However the PSN group showed a significant difference in LN metastasis as the tumor size increased: ≤1 cm, 2.67%; 1.0 to 1.5 cm, 12.46%; and 1.5 to 2.0 cm, 21.31% (P < .001). In the multivariate analysis tumor size was a significant predictor of nodal metastasis in the PSN group but not in the mGGN group. In terms of 5-year disease-free survival, the mGGN group showed a better prognosis than the PSN group (94.4% vs 71.2%, P < .001). ConclusionsWe need to conduct a thorough LN dissection during surgery for small-sized NSCLC, especially for pure-solid tumors ≥ 1 cm.

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.

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.

Review for N2 Sub-staging in Non-small Cell Lung Cancer

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) divided N2 into three sub-stages: N2 at a single station without N1 involvement (N2a1), N2 at a single station with N1 involvement (N2a2), and N2 at multiple stations (N2b). These new descriptors significantly distinguished the overall survival (OS), disease-free survival (DFS), and recurrence pattern of patients with different N2 sub-stages. The OS and DFS of N2a1 were not sufficiently distinguished from N1 at multiple stations (N1b). The OS and DFS of N2a2 were intermediate between those of N2a1 and N2b. Current evidence did not support the further subdivision of the N2b. The main recurrence pattern of N2a1, N2a2 and N2b were distant metastasis, and the risks of distant metastasis increased successively. N2a1 patients were at low risk of locoregional recurrence, which could not be reduced by postoperative radiotherapy (PORT). N2a2 and N2b patients had a similar higher risk of locoregional recurrence, which could be reduced to a similar level of N2a1 patients by PORT. .