pN2 Non-small Cell Lung Cancer Research Articles

EP.08E.02 Long Term Impact of IASLC Uncertain Resection (Run) Definition in Surgically Resected pN2 Non-Small Cell Lung Cancer

EP.08E.02 Long Term Impact of IASLC Uncertain Resection (Run) Definition in Surgically Resected pN2 Non-Small Cell Lung Cancer

Risk prediction of multiple-station N2 metastasis in patients with upfront surgery for clinical single-station N2 non-small cell lung cancer

To investigate long-term outcomes and develop a risk model for pathological multi–station N2 (pN2b) in patients who underwent upfront surgery for clinical single–station N2 (cN2a) non–small cell lung cancer (NSCLC). From 2006 to 2018, 547 patients who had upfront surgery for suspected cN2a NSCLC underwent analysis. A risk model for predicting pN2b metastasis was developed using preoperative clinical variables via multivariable logistic analysis. Among 547 clinical cN2a NSCLC patients, 118 (21.6%), 58 (10.6%), and 371 (67.8%) had pN0, pN1, and pN2. Among 371 pN2 NSCLC patients, 77 (20.8%), 165 (44.5%), and 129 (34.7%) had pN2a1, pN2a2, and pN2b. The 5-year overall survival rates for pN2a1 and pN2a2 were significantly higher than for pN2b (p = 0.041). Histologic type (p < 0.001), age ≤ 50 years (p < 0.001), preoperatively confirmed N2 metastasis (p < 0.001), and clinical stage IIIB (vs. IIIA) (p = 0.003) were independent risk factors for pN2b metastasis. The risk scoring system based on this model demonstrated good discriminant ability for pN2b disease (area under receiver operating characteristic: 0.779). In cN2a NSCLC patients, those with multiple N2 metastases indicate worse prognosis than those with a single N2 metastasis. Our risk scoring system effectively predicts pN2b in these patients.

Recurrence Dynamics of Pathological N2 Non-small Cell Lung Cancer Based on IASLC Residual Tumor Descriptor.

This study investigated the recurrence patterns and timing in patients with pathologic N2 (pN2) non-small cell lung cancer (NSCLC) according to the residual tumor (R) descriptor proposed by the International Association for the Study of Lung Cancer (IASLC). From 2004 to 2021, patients with pN2 NSCLC who underwent anatomical resection were analyzed according to the IASLC R criteria using medical records from a single center. Survival analysis was performed using Cox proportional hazards models. Recurrence patterns between complete (R0) and uncertain resections (R[un]) were compared. In total, 1,373 patients were enrolled in this study: 576 (42.0%) in R0, 286 (20.8%) in R(un), and 511 (37.2%) in R1/R2 according to the IASLC R criteria. The most common reason for R(un) classification was positivity for the highest lymph node (88.8%). In multivariable analysis, the hazard ratios for recurrence in R(un) and R1/R2 compared to R0 were 1.18 (95% confidence interval [CI], 0.96-1.46) and 1.58 (1.31-1.90), respectively. The hazard rate curves displayed similar patterns among groups, peaking at approximately 12 months after surgery. There was a significant difference in distant recurrence patterns between R0 and R(un). Further analysis after stratification with the IASLC N2 descriptor showed significant differences in distant recurrence patterns between R0 and R(un) in patients pN2a1 and pN2a2 disease, but not in those with pN2b disease. The IASLC R criteria has prognostic relevance in patients with pN2 NSCLC. R(un) is a highly heterogeneous group, and the involvement of the highest mediastinal lymph node can affect distant recurrence patterns.

Differences in the Prognostic Impact between Single-zone and Multi-zone N2 Node Metastasis in Patients with Station-based Multiple N2 Non-Small Cell Lung Cancer.

The International Association for the Study of Lung Cancer suggest further subdivision of pathologic N (pN) stage in non-small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups. This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal. Among 996 eligible patients, 211 (21.2%), 394 (39.6%) and 391 (39.4) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT stage, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio 0.67, 95% confidence interval 0.49-0.90, p<0.009) and was comparable to that of N2a2 disease (1.12, 0.83-1.49, p=0.46). Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Prognostic biomarker tumor-infiltrating lymphocytes failed to serve as a predictive biomarker for postoperative radiotherapy in completely resected pN2 non-small cell lung cancer: a retrospective analysis

BackgroundEvidence suggests that radiotherapy is a potent immunomodulator in non-small cell lung cancer (NSCLC). Conversely, it has rarely been demonstrated if immune infiltration can influence radiotherapy efficacy. Herein, we explored the effect of tumor-infiltrating lymphocytes (TILs) on the response to postoperative radiotherapy (PORT) in completely resected stage III-pN2 NSCLC.MethodsThis retrospective study included 244 patients with pathologically confirmed stage III-N2 NSCLC who underwent complete resection at our institution between 2014 and 2020. TILs were assessed with permanent full-face hematoxylin and eosin (H&E) sections and the evaluation of TILs was based on a published guideline. Patients were stratified into the TILlow or TILhigh group with a cutoff value of 50%. Kaplan-Meier method and Log‐rank test were utilized to assess disease-free survival (DFS) and overall survival (OS). Univariate and multivariate Cox regression analysis were conducted to determine prognostic indicators.ResultsAmong 244 patients, a total of 121 patients received PORT whereas 123 did not. TILs level in patients with PORT was significantly higher than that in patients without PORT (p < 0.001). High TILs level was significantly associated with an improved DFS and OS in all the entire chort (DFS, p < 0.001; OS, p = 0.001), PORT chort (DFS, p = 0.003; OS, p = 0.011) and non-PORT chort (DFS, p < 0.001; OS, p = 0.034). There were no significant survival differences between different treatment modalities in the low TILs infiltration (DFS, p = 0.244; OS, p = 0.404) and high TILs infiltration (DFS, p = 0.167; OS, p = 0.958) groups.ConclusionsTILs evaluated with H&E sections could represent a prognostic biomarker in patients with completely resected pN2 NSCLC, and high TILs infiltration was associated with favorable survival outcomes.The predictive value of TILs for PORT still need to be further explored in the future.

NUF2 Expression in Cancer Tissues and Lymph Nodes Suggests Post-Surgery Recurrence of Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection.

Frequency and predictive factors of nodal micro-metastasis (NMM) in resectable non-small cell lung cancer.

The frequency of lymph nodal micrometastasis (NMM) in resectable non-small cell lung cancer (NSCLC) is frequently underestimated when relying solely on standard hematoxylin and eosin staining during pathological examination. This is a retrospective cross-sectional diagnostic research. Medical records of resectable pN0 NSCLC patients who underwent curative resection in Maharaj Nakorn Chiang Mai Hospital between January 2006 to December 2017 were retrospectively reviewed. Immunohistochemistry (IHC) staining using cytokeratin AE1/AE3, p53 and BerEP4 markers was employed to detect NMM. Primary objective of this study was to determine frequency of NMM in pN0 resectable NSCLC. This study included 98 patients with pN0 NSCLC, of which 47 were male and 51 were female. NMM was detected in 21 of 98 patients (21.43%). Lymph node station 10 and 7 were the most common site of micrometastasis among patients with N1 and N2 micrometastasis, respectively. Cytokeratin AE1/AE3 was the most sensitive antibody in detecting micrometastasis in lymph nodes, identifying 25 out of 27 positive lymph nodes. Tumor size greater than 4 cm was a statistically significant predictive factor for NMM with risk ratio 6.69 [95% confidence interval (CI): 2.38-18.85, P<0.001]. NMM was identified in 21.43% of pN0 resectable NSCLC patients and tumor size greater than 4 cm is predictive factor for NMM.

Prognostic factors for recurrence-free survival in resected pathologic N2-stage III non-small cell lung cancer treated with upfront surgery.

The standard treatment for pathological N2 (pN2) non-small-cell lung cancer (NSCLC) patients is definitive chemoradiation. Surgery might be beneficial for resectable pN2 disease, so we investigated the recurrence-free interval of upfront surgery for selected patients with resectable pN2 disease. The clinicopathologic characteristics of patients with pN2 NSCLC who underwent upfront anatomical resection at Taipei Veterans General Hospital from 2011 January to 2019 December were retrospectively reviewed. A Cox regression model was used to identify prognostic factors of recurrence-free survival (RFS). In total, 84 patients after curative lung anatomic resection were analyzed, with a 44-month median survival. The 1-, 3-, and 5-year RFS rates were 63.1%, 31.3%, and 19.9%, respectively, with a median RFS of 18.9 months. Multivariable cox regression analysis identified that the significant predictor for RFS was a tumor size of more than 3 cm (hazard ratio [HR] = 1.74, 95% CI, 1.07-2.83, p = 0.027). Visceral pleural invasion, LN harvest number, tumor stage, and N2 status including single zone (N2a) or multiple zones (N2b) were not prognostic factors in this study. Upfront surgery for resectable N2 disease achieved favorable outcomes in selected patients, especially better recurrence control with limited tumor size. Therapeutic advances might encourage surgeons to aggressive intervention.

Adjuvant chemotherapy in pathological node-negative non-small cell lung cancer

Non–small cell lung cancer (NSCLC) is associated with a poor survival rate, even for patients with early-stage cancer. Identifying patients with pathological N0 NSCLC who may benefit from adjuvant chemotherapy treatment after surgery is essential. We conducted a retrospective cohort study used data from the Surveillance, Epidemiology, and End Results database and included 26,380 patients with pathological N0 NSCLC after surgery between January 2018, and December 2019. Among 26,380 patients, 24,273 patients received surgery alone and the other 2107 patients received surgery plus adjuvant chemotherapy. After 1:1 propensity score matching, both groups contained 2107 patients. Adjuvant chemotherapy did not show significantly better 24-month survival in T2aN0 NSCLC patients (83.41% vs. 82.91%, p = 0.067), although it did for T2bN0 patients (86.36% vs. 81.70%, p = 0.028). Poorly-differentiated NSCLC remained a high-risk factor for pT2N0, and adjuvant chemotherapy provided better 24-month survival after matching (86.36% vs. 81.70%, p = 0.029). In conclusion, when treating pN0 NSCLC, adjuvant chemotherapy had a beneficial effect when the tumor size was larger than 4 cm. The effect when the tumor size was between 3 and 4 cm was not remarkable. Poorly-differentiated NSCLC was a high-risk factor in the pT2N0 stage.

The additional radiotherapy to adjuvant chemotherapy improves the prognosis of stage III-N2 with highest mediastinal lymph node metastasis in non-small cell lung cancer.

The benefits of adjuvant chemoradiation therapy (CRT) for heterogeneous pathological N2 (pN2) diseases remain unclear in non-small cell lung cancer (NSCLC). This study aimed to investigate suitable pN2 patients for adjuvant CRT. This study retrospectively reviewed the data of patients with pN2 NSCLC in Shanghai Pulmonary Hospital from January 2012 to December 2016. Included cases were subdivided as highest mediastinal lymph node (HM) (n = 732) metastasis and non-HM metastasis (n = 677) groups according to the International Association for the Study of Lung Cancer (IASLC). Furthermore, the Kaplan-Meier and Cox models were used to evaluate the prognostic benefits of adjuvant CRT in heterogeneous pN2 subgroups. A total of 1409 patients were enrolled in this study, with a median follow-up time of 63.8months. Patients with HM involvement had worse prognoses (p < 0.001 for recurrence-free survival (RFS) and overall survival (OS)). Furthermore, the survival improvement of adjuvant CRT was significant for these patients (p < 0.001 for RFS and p = 0.032 for OS), regardless of whether it was single (p < 0.001 for RFS and p = 0.029 for OS) or multiple pN2 (p < 0.001 for RFS and p = 0.026 for OS) diseases. According to multivariable cox analysis, the long-term RFS and OS in the cancerous HM group were independently predicted by pathological N stage (p = 0.002 for RFS and p < 0.001 for OS) and adjuvant CRT (p < 0.001 for RFS and p = 0.011 for OS). Metastatic HM was associated with a worse prognosis in pN2 disease. Our analysis supported that adjuvant CRT significantly improved both RFS and OS for these patients.

Prognostic Impact of the Immune-Cell Infiltrate in N1-Positive Non–Small-Cell Lung Cancer

IntroductionThe tumoral immune milieu plays a crucial role for the development of non–small-cell lung cancer (NSCLC) and may influence individual prognosis. We analyzed the predictive role of immune cell infiltrates after curative lung cancer surgery. Materials and MethodsThe tumoral immune-cell infiltrate from 174 patients with pN1 NSCLC and adjuvant chemotherapy was characterized using immunofluorescence staining. The density and distribution of specific immune cells in tumor center (TU), invasive front (IF) and normal tissue (NORM) were correlated with clinical parameters and survival data. ResultsTumor specific survival (TSS) of all patients was 69.9% at 5 years. The density of tumor infiltrating lymphocytes (TIL) was higher in TU and IF than in NORM. High TIL density in TU (low vs. high: 62.0% vs. 86.7%; p = .011) and the presence of cytotoxic T-Lymphocytes (CTLs) in TU and IF were associated with improved TSS (positive vs. negative: 90.6% vs. 64.7% p = .024). High TIL-density correlated with programmed death-ligand 1 expression levels ≥50% (p < .001). Multivariate analysis identified accumulation of TIL (p = .016) and low Treg density (p = .003) in TU as negative prognostic predictors in squamous cell carcinoma (p = .025), whereas M1-like tumor- associated macrophages (p = .019) and high programmed death-ligand 1 status (p = .038) were associated with better survival in adenocarcinoma. ConclusionThe assessment of specific intratumoral immune cells may serve as a prognostic predictor in pN1 NSCLC. However differences were observed related to adenocarcinoma or squamous cell carcinoma histology. Prospective assessment of the immune-cell infiltrate and further clarification of its prognostic relevance could assist patient selection for upcoming perioperative immunotherapies.

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.

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.

Uncertain resection of highest mediastinal lymph node positive among pN2 non-small cell lung cancer patients: survival analysis of postoperative radiotherapy and driver gene mutations.

The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients. 140 selected patients were grouped according to whether they received PORT and their DGMS. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of each group were evaluated by Kaplan-Meier analyses. COX regression was used to evaluate the effects of various factors on DFS and OS. Of 140 patients, thirty-four patients (24.3%) received PORT, and forty (28.6%) had positive driver gene mutation status (DGp). PORT significantly prolonged LRFS (p = 0.002), DFS (p = 0.019) and OS (p = 0.02), but not DMFS (p = 0.062). By subgroup analysis, in patients with negative driver gene mutation status (DGn), those receiving PORT had notably longer LRFS (p = 0.022) and DFS (p = 0.033), but not DMFS (p = 0.060) or OS (p = 0.215), compared to those not receiving PORT. Cox analysis showed that the number of positive lymph nodes (PLNs) and administration of PORT were independent prognostic factors of DFS, and pathology, PLNs, and DGMS may be prognostic factors of OS (all p < 0.05). Postoperative radiotherapy may improve locoregional recurrence-free and disease-free survival in patients with pN2 NSCLC with positive highest mediastinal lymph nodes, while driver gene mutation status impacted OS significantly. Only patients with positive driver gene mutations experienced significant overall survival benefits from postoperative radiotherapy.

Postoperative Radiotherapy can Improve the Disease-Free Survival of EGFR Wild Type Patients with pN2 NSCLC after Complete Resection and Adjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> Recently published phase III trials showed that postoperative radiotherapy (PORT) did not improve the survival of patients with pN2 non-small-cell lung cancer (NSCLC) after complete resection. However, the effect of PORT for pN2 NSCLC with different EGFR status remains unclear. <h3>Materials/Methods</h3> From 2010 to 2019, consecutive patients with pN2 NSCLC after complete resection and adjuvant chemotherapy who had detection of EGFR status were retrospectively analyzed. PORT was administered using IMRT at 2 Gy per fraction up to 50 Gy over 5 weeks. Patients were categorized into 4 groups according to EGFR status and treatment: Group 1 (EGFR wild type with PORT), Group 2 (EGFR wild type without PORT), Group3 (EGFR-mutated with PORT), Group 4 (EGFR-mutated without PORT). The Kaplan-Meier method and log-rank test were used to evaluate the disease-free survival (DFS), overall survival (OS), locoregional relapse free survival (LRFS), and distant metastasis free survival (DMFS). <h3>Results</h3> Totally 575 patients were enrolled. 264 patients (45.9%) were EGFR wild type, including 96 with PORT and 168 without PORT. 311 patients (54.1%) were EGFR-mutated, including 109 with PORT and 202 without PORT. The median DFS was 28.4 months in Group 1 and 17.3 months in Group 2 (HR 0.70, 95% CI 0.52-0.96, p=0.032). The median OS was not reached in Group 1 and Group 2 (HR 0.75, 95%CI 0.46-1.21, p=0.263). LRFS was statistically higher in Group 1 than Group 2 (HR 0.64, 95%CI 0.43-0.96, p=0.041). However, no significant difference was shown in DMFS (HR 0.75, 95%CI 0.54-1.04, P=0.097). Group 3 and Group 4 showed median DFS of 20.2 months and 25.7 months (HR 1.113, 95% CI 0.84-1.53, p=0.402), respectively. The median OS was not reached in either Group 3 or Group 4 (HR 0.64, 95% CI 0.33-1.21, p=0.201). LRFS was not significantly different (HR 0.83, 95% CI 0.53-1.31, p=0.45) in Group3 vs Group4, neither was DMFS (HR 1.15, 95%CI 0.85-1.57, p=0.73). <h3>Conclusion</h3> For completely resected pN2 NSCLC, PORT can improve DFS and LRFS in EGFR wild type patients. However, PORT may not prolong survival in EGFR-mutated patients. Prospective randomized clinical trials are needed for validation.

Validation of the Role of Postoperative Radiotherapy in Improving Disease-Free Survival of Patients with Stage III ypN2 Non-Small Cell Lung Cancer after Neoadjuvant Therapy Followed by Complete Resection – A Propensity-Score Matching Study

<h3>Purpose/Objective(s)</h3> Although the Lung ART study, a phase III trial, showed that postoperative radiotherapy (PORT) could not significantly improve the disease-free survival (DFS) of patients with pN2 non-small cell lung cancer (NSCLC) after complete resection. However, its subgroup analysis showed that PORT did significantly improve the DFS of those with ypN2 NSCLC after neoadjuvant therapy and surgery. Our study aimed to validate the effect of PORT on the survival of patients with ypN2 NSCLC. <h3>Materials/Methods</h3> Patients was filtrated from our center from 2004 to 2021. The inclusion criteria of patients were as follows: 1) diagnosed with NSCLC; 2) accepted neoadjuvant systematic treatments including chemotherapy, tyrosine kinase inhibitors (EGFR, ALK), or immune checkpoint inhibitors; 3) received complete resection (R0 resection); 4) with stage III ypN2 disease (AJCC 8^th). We excluded patients with multiple primary malignant tumors and those who died within four months after surgery. The primary endpoint was DFS. The second endpoints were overall survival (OS) and locoregional recurrence-free survival (LRFS). Propensity-score matching (PSM) was used to match the baseline characteristics between the PORT group and the non-PORT group. Kaplan-Meier method was used to estimate the endpoints. All data were analyzed using R 4.1.2. <h3>Results</h3> Totally 185 patients were included in the final analysis. There were 49 patients (26.5%) with PORT. After 1:1 PSM between the PORT group and the non-PORT group, 82 patients remained with 41 in each group. The baseline characteristics of majority in the matched cohort were as follows: male (75.6%), smoking history (79.3%), performances scores 0-1 (100%), adenocarcinoma (47.6%), grade 3-4 (58.5%), receiving neoadjuvant chemotherapy (91.5%), lobectomy (82.9%), ypT1-2 (78.9%), and ypN2b (51.2%). The median age of patients was 58. The median numbers of examined and positive lymph nodes were 20.5 and 6. The median follow-up time was 49.5 months. The median DFS of the PORT group and the non-PORT group were 25.5 months vs. 18.6 months, with the 5-year DFS rates of 43.4% vs. 24.8%, respectively (P=0.044). The median LRFS of the two groups were not reached vs. 56.8 months, with the 5-year LRFS rates of 89.1% vs. 39.8% (P<0.001). The median OS of the two groups were not reached vs. 67.7 months, with the 5-year OS rates of 76.7% vs. 34.8% (P=0.092). <h3>Conclusion</h3> For patients with stage III ypN2 NSCLC after neoadjuvant systematic therapy followed by complete resection, PORT can significantly improve the DFS and LRFS, but failed to improve OS. However, the results need to be clarified by prospective randomized clinical trials.

EP05.01-027 Uncertain Resection of pN2 NSCLC Patients-survival Analysis of Postoperative Radiotherapy and Driver Gene Mutations

The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients.

A decision support framework for postoperative radiotherapy in patients with pathological N2 non-small cell lung cancer

IntroductionPostoperative radiotherapy (PORT) plays a highly controversial role in pathological N2 (pN2) non-small cell lung cancer (NSCLC) disease. Recent studies reveal that not all patients can benefit from PORT. Further research is needed to identify predictors of PORT. MethodsA total of 1044 pathologic stage T1-3N2M0 NSCLC patients were analyzed. Risk factors of distant metastasis were identified by the log-rank tests and the multivariable Cox models. We integrated risk factors of distant metastasis and our previously published loco-regional recurrence (LRR) related prognostic index into a decision support framework (DSF) to predict the outcomes of PORT. An independent cohort was used to validate the DSF. ResultsWe defined patients with more than two of three identified LRR-related features (heavy cigarette smoking history, clinical N2 status, and more than four positive lymph nodes) as a high LRR risk group. We found the high-intermediate-risk histological type (with micropapillary and/or solid components) was associated with a higher risk of distant metastasis (HR = 1.207, 95 % CI 1.062 to 1.371, P = 0.0038), but not LRR. We built the DSF by combining these two types of features. Patients were stratified into four groups by using the DSF. PORT significantly improved OS only in the subgroup without high-risk histological features (without micropapillary or solid components) and with a high risk for LRR (three-year OS: 66.7 % in the PORT group vs 50.2 % in the non-PORT group; P = 0.023). ConclusionsA particular pN2 subgroup with a high risk of LRR and without micropapillary or solid components could benefit from PORT.

Role of Adjuvant Radiotherapy in Non-Small Cell Lung Cancer-A Review.

Simple SummaryThe role of postoperative radiotherapy (PORT) in completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2) is controversial. The aim of our review was to study the literature relating to PORT for completely resected NSCLC patients with pN2 involvement. The Lung ART and PORT-C trials indicate better locoregional control with PORT, but this has not yet translated into survival benefits. Given the conflicting results, guidelines do not recommend the use of PORT routinely. Future research should focus on identifying subgroups of patients who might benefit from PORT.Background: For patients with completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2), the administration of adjuvant chemotherapy is the standard of care. The role of postoperative radiation therapy (PORT) is controversial. Methods: We describe the current literature focusing on the role of PORT in completely resected NSCLC patients with pN2 involvement and reflect on its role in current guidelines. Results: Based on the results of the recent Lung ART and PORT-C trials, the authors conclude that PORT cannot be generally recommended for all resected pN2 NSCLC patients. A substantial decrease in the locoregional relapse rate without translating into a survival benefit suggests that some patients with risk factors might benefit from PORT. This must be balanced against the risk of cardiopulmonary toxicity with potentially associated mortality. Lung ART has already changed the decision making for the use of PORT in daily practice for many European lung cancer experts, with lower rates of recommendations for PORT overall. Conclusions: PORT is still used, albeit decreasingly, for completely resected NSCLC with pN2 involvement. High-level evidence for its routine use is lacking. Further analyses are required to identify patients who would potentially benefit from PORT.

Optimal positive lymph node ratio showing the benefit of postoperative radiotherapy in pathologic N2 non-small cell lung cancer: an exploratory study using the Surveillance, Epidemiology, and End Results data.

PurposeThis study aimed to identify the clinical parameters having the beneficial effect of postoperative radiotherapy (PORT) in pathologic N2 (pN2) non-small cell lung cancer (NSCLC) using the Surveillance, Epidemiology, and End Results (SEER) data.Materials and methodsAmong non-metastatic NSCLC patients in the SEER data, we included patients who diagnosed after 2002, who confirmed as pN2 after lobectomy or pneumonectomy, and who coded as underwent PORT or observation. Patients who survived less than 4 months of diagnosis were excluded in consideration of the perioperative mortality. After performing propensity score matching (PSM) on the selected patients, we compared PORT group with surgery alone group. We also performed exploratory subgroup analysis to find patients who could benefit from PORT.ResultsAmong the selected 4,456 patients, 1,729 patients received PORT, and 2,727 patients did not. There was no survival benefit of PORT in all patients with pN2 disease (hazard ratio [HR] = 1.03, p = 0.5). In subgroup analyses, the patients with a positive lymph node (LN) ratio of 60%–80% showed the significant benefit of PORT (HR = 0.71, p = 0.002).ConclusionPORT did not show the significant survival benefit in patients with pN2 disease after correcting the confoundedness in the SEER data. However, a specific range of LN ratios can be a potential indicator maximizing the survival benefit of PORT.