ER predicts poor prognosis in male lung squamous cell cancer of stage IIIA-N2 disease after sequential adjuvant chemoradiotherapy.

Introduction: The efficacy of postoperative radiotherapy (PORT) is still unclear in non-small cell lung cancer (NSCLC) patients with pIIIA-N2 disease. Estrogen receptor (ER) was proven significantly associated with poor clinical outcome of male lung squamous cell cancer (LUSC) after R0 resection in our previous study. Methods: A total of 124 male pIIIA-N2 LUSC patients who completed four cycles of adjuvant chemotherapy and PORT after complete resection were eligible for enrollment in this study from October 2016 to December 2021. ER expression was evaluated using immunohistochemistry assay. Results: The median follow-up was 29.7 months. Among 124 patients, 46 (37.1%) were ER positive (stained tumor cells≥1%), and the rest 78 (62.9%) were ER negative. Eleven clinical factors considered in this study were well balanced between ER+ and ER- groups. ER expression significantly predicted a poor prognosis in disease-free survival (DFS, HR=2.507; 95% CI: 1.629-3.857; log-rank p=1.60×10-5). The 3-year DFS rates were 37.8% with ER- vs. 5.7% with ER+, with median DFS 25.9 vs. 12.6 months, respectively. The significant prognostic advantage in ER- patients was also observed in overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The 3-year OS rates were 59.7% with ER- vs. 48.2% with ER+ (HR, 1.859; 95% CI: 1.132-3.053; log-rank p=0.013), the 3-year LRFS rates were 44.1% vs. 15.3% (HR=2.616; 95% CI: 1.685-4.061; log-rank p=8.80×10-6), and the 3-year DMFS rates were 45.3% vs. 31.8% (HR=1.628; 95% CI: 1.019-2.601; log-rank p=0.039). Cox regression analyses indicated that ER status was the only significant factor for DFS (p=2.940×10-5), OS (p=0.014), LRFS (p=1.825×10-5) and DMFS (p=0.041) among other 11 clinical factors. Conclusions: PORT might be more beneficial for ER negative LUSCs in male, and the examination of ER status might be helpful in identifying patients suitable for PORT.

Beneficial effects of postoperative radiotherapy for IIIA­N2 non­small cell lung cancer after radical resection analysed using the propensity score­matching method.

The objective of the present study was to investigate the role of postoperative radiotherapy (PORT) after radical resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). Subgroups of patients who benefited from PORT were evaluated. A retrospective review of 288 consecutive patients with resected pIIIA-N2 NSCLC at Beijing Chest Hospital (Beijing, China) was performed. Of these patients, 61 received PORT. The 288 patients were divided into PORT and non-PORT groups according to the treatment received. The baseline characteristics of the two patient groups were balanced using propensity score-matching (PSM; 1:1 matching). In total, 60 patients in the PORT group and 60 patients in the non-PORT group were matched. After PSM, the median survival time of the matched patients was 53 months. The 1-, 3- and 5-year overall survival (OS) rates of the PORT patient group were 95.0, 63.2 and 48.2%, respectively, while those of the non-PORT group were 86.7, 58.3 and 34.5%, respectively, and there was no significant difference between the two groups (P=0.056). The 5-year local recurrence-free survival (LRFS) rate in the PORT group was significantly improved (P=0.001). The effects of PORT on OS and LRFS rates were analysed in patients with different clinicopathological features. For subgroups with multiple N2 stations, N2 positive lymph nodes ≥4 and squamous cell carcinoma, PORT significantly increased the OS and LRFS rates (P<0.05). In conclusion, there was no statistically significant improvement in the 5-year OS rate with PORT overall, but there may be subgroups, such as patients with multiple N2 stations, N2 positive nodes ≥4 and squamous cell carcinoma histology, that could be explored as potentially benefitting from improved 5-year OS and LRFS rates with PORT.

Postoperative radiotherapy with modern techniques does not improve survival for operable stage IIIA-N2 non-small cell lung cancer.

OBJECTIVES: This study aims to evaluate whether postoperative radiotherapy using newer techniques (intensity-modulated radiotherapy [IMRT]) is associated with improved survival for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) who underwent complete resection. METHODS: The overall survival of patients with stage IIIA-N2 NSCLC who received postoperative IMRT versus no postoperative IMRT following induction chemotherapy and lobectomy in the National Cancer Database from 2010-2018 was assessed via Kaplan-Meier analysis, Cox proportional hazards analysis and propensity score-matched analysis. Additional survival analyses were also conducted in patients with completely resected stage IIIA-pN2 NSCLC who had upfront lobectomy (without induction therapy) followed by adjuvant chemotherapy alone or adjuvant chemotherapy with postoperative IMRT. Only patients receiving IMRT, which is a newer, more conformal radiotherapy technique, were included. Patients with positive surgical margins were excluded. RESULTS: A total of 3203 patients with stage IIA-N2 NSCLC who underwent lobectomy were included. Five hundred eighty-eight (18.4%) patients underwent induction chemotherapy followed by lobectomy, and 2615 (82%) underwent lobectomy followed by chemotherapy. In unadjusted, multivariable-adjusted, and propensity score--matched analyses, there were no significant differences in overall survival between the patients who also received postoperative IMRT versus those who did not. CONCLUSIONS: In this national analysis, the use of postoperative IMRT was not associated with improved survival in patients with completely resected stage IIIA-N2 NSCLC with or without induction chemotherapy.

Randomized phase II trial of pemetrexed-cisplatin plus bevacizumab or thoracic radiotherapy followed by surgery for stage IIIA (N2) nonsquamous non-small cell lung cancer.

BACKGROUND: Personalized Induction Therapy-1 is a multicenter, randomized phase II selection design trial of the efficacy and safety of platinum-doublet induction chemotherapy plus angiogenesis inhibitors/concurrent thoracic radiotherapy (TRT) followed by surgery for stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients with pathologically proven stage IIIA (N2) nonsquamous NSCLC were assigned at random to 1 of 2 arms. Patients received (1:1) induction therapy with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 plus bevacizumab 15 mg/kg intravenously every 3 weeks for 3 cycles (bevacizumab arm) or concurrent TRT (45 Gy in 25 fractions; TRT arm) before surgery. The primary endpoint was the 2-year progression-free survival (PFS) rate. RESULTS: Eighty-two patients were treated, including 42 in the bevacizumab arm and 40 in the TRT arm. Thirty-eight patients (90%) in the bevacizumab arm and 37 patients (93%) in the TRT arm underwent surgery. The objective response rates in the 2 groups were 50% and 60%, respectively (P = .36). The 2-year PFS and overall survival rates were 37% (95% confidence interval [CI], 22.4%-51.2%) and 50% (95% CI, 33.8%-64.2%) (hazard ratio [HR], 1.34; P = .28), respectively, and 81% (95% CI, 64.7%-89.7%) and 80% (95% CI, 64.0%-89.5%) (HR, 1.10; P = .83), respectively. Although grade 5 toxicity did not occur during induction therapy, 2 patients in the bevacizumab arm died due to bronchopleural fistula. CONCLUSIONS: Although not significant, the 2-year PFS rate was higher in the TRT arm than in the bevacizumab arm. Fatal surgical complications were observed only in the bevacizumab arm. Therefore, pemetrexed-cisplatin with concurrent TRT was chosen as the investigational induction treatment strategy for future phase III trials.

The Prognostic Role of Blood Inflammatory Biomarkers and EGFR Mutation Status in Stage IIIA/N2 Non-Small Cell Lung Cancer Patients Treated With Trimodality Therapy.

OBJECTIVES: Various blood inflammatory biomarkers were associated with treatment response and prognosis of non-small cell lung cancer (NSCLC) in previous studies. In this study, we retrospectively evaluated the prognostic role of pretreatment blood inflammatory biomarkers and epidermal growth factor receptor (EGFR) mutation status in stage IIIA/N2 NSCLC patients with trimodality therapy. METHODS: Completely resected stage IIIA/N2 NSCLC patients with adjuvant chemotherapy and postoperative radiotherapy (PORT) were assessed in this study. Cutoff values of blood inflammatory factors were calculated by the R package SurvivalROC of R software. SPSS Statistics software was used for survival analyses. Kaplan-Meier survival curve and log-rank test were used to compare the survival difference between every two groups. Univariate and multivariate analyses of predictive factors were performed by Cox proportional hazards regression model. RESULTS: The univariate analysis showed that T stage (p=0.007), EGFR mutation status (p=0.043), lymphocyte-to-monocyte ratio (LMR) (p=0.067), and systemic immune-inflammation index (SII) (p=0.043) were significant prognostic factors of disease-free survival (DFS). In the multivariate analysis, T2 (HR=0. 885, 95% CI: 0.059-0.583, p=0.004), EGFR mutation-positive (HR=0.108, 95% CI: 0.023-0.498, p=0.004) and elevated pretreatment SII (HR=0.181, 95%CI: 0.046-0.709, p=0.014) were independently related to shorter DFS. High pretreatment neutrophil counts (HR=0.113, p=0.019) and high systemic inflammation response index (SIRI) (HR=0.123, p=0.025) were correlated with worse overall survival (OS) by the univariate analysis. In the multivariate analysis, only high pretreatment SIRI was an independent predictor for poorer OS (HR=0.025, 95% CI: 0.001-0.467, p=0.014). CONCLUSIONS: In conclusion, we identified that high pretreatment SII and SIRI were unfavorable prognostic factors in stage IIIA/N2 NSCLC patients treated with surgery, adjuvant chemotherapy and PORT. Patients with high pretreatment SII, high pretreatment SIRI, T2, and EGFR mutation-positive may need more forceful adjuvant treatment. Further prospective studies with large-scale are needed to validate our results and identify the proper cut-off values and optimum adjuvant treatment for distinct patient population.

Effects of postoperative radiotherapy on cardiovascular-pulmonary disease mortality in patients with stage IIIA-N2 resected NSCLC: analysis of the SEER database.

BACKGROUND: The role of postoperative radiotherapy (PORT) in cardiovascular-pulmonary disease mortality in patients with stage IIIA-N2 resected non-small cell lung cancer (NSCLC) remains uncertain. The purpose of this population-based analysis was to explore the effect of PORT on cardiovascular-pulmonary disease mortality in these patients. METHODS: Patients aged ≥ 18 years with stage IIIA-N2 resected NSCLC were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015 and were grouped according to the use of PORT. Propensity score matching (PSM) was used to account for differences in baseline characteristics between the Non-PORT and PORT groups. The cumulative risk for cardiovascular-pulmonary disease death was estimated using the cumulative incidence curve. Competing risk regression was used to run univariate and multivariate analyses to evaluate risk factors. RESULTS: A total of 3981 patients were included in the study population. Among them, 1446 patients received PORT, and 2535 did not. A total of 1380 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two groups. The cumulative incidence of cardiovascular-pulmonary mortality was 10.93% in the Non-PORT group compared with 9.85% in the PORT group. There was no significant difference in the cumulative risk between the two groups (HR 1.07, 95% CI 0.77-1.48, p = 0.703). Multivariate analysis indicated that PORT had no significant impact on increased risk, with an HR of 1.18 (p = 0.377). CONCLUSIONS: No significant differences between the PORT and Non-PORT groups were found in cardiovascular-pulmonary-specific modalities in this study. Further studies are required to validate these results. This study highlights the importance of long-term surveillance for NSCLC patients.

The Prognostic Role of PORT and EGFR Mutation Status in Completely Resected Stage IIIA/N2 Non-Small Cell Lung Cancer Patients with Postoperative Chemotherapy.

Background: The treatment choice for completely resected stage IIIA/N2 non-small cell lung cancer (NSCLC) patients is still controversial now. Our study aims to identify potential prognostic factors in stage IIIA/N2 NSCLC patients with complete surgical resection and postoperative chemotherapy. Methods: In this study, we screened the stage IIIA/N2 NSCLC patients diagnosed in the Affiliated Cancer Hospital of Zhengzhou University from 2015 to 2019. Completely resected patients with postoperative chemotherapy (PCT) were enrolled. The univariate and multivariate COX proportional hazards regression analyses were used to identify the prognostic factors. The Kaplan-Meier survival curve was used to compare the disease-free survival (DFS) and overall survival (OS) in the subgroup analyses. Results: 180 patients were collected, including 142 patients with PCT treatment alone and 38 patients with postoperative radiotherapy (PORT) treatment. The median DFS was 17.8 months (95% CI: 16.5-19.1 months) and the median OS was 50.6 months (47.4-53.9 months) in all the patients. The median DFS of the PORT group was significantly longer than the PCT group (38.7 vs 16.7 months, p < 0.001). Epidermal growth factor receptor (EGFR) mutation-positive patients had a worse DFS compared with EGFR mutation-negative patients (16.8 vs 18.0 months, p = 0.032). Possible prognostic factors were evaluated through univariate COX regression analysis. The further multivariate COX regression analysis showed that patients with PORT (HR: 0.318, 95% CI: 0.185-0.547, p < 0.001), EGFR mutation-negative (HR: 0.678, 95% CI: 0.492-0.990, p = 0.044), T1 (HR: 0.661, 95% CI: 0.472-0.925, p = 0.016), and lobectomy (HR: 0.423, 95% CI: 0.191-0.935, p = 0.034), had better DFS. The only independent prognostic factor of OS was the type of surgery (p = 0.013). Conclusion: PORT might improve the DFS of stage IIIA/N2 NSCLC patients with complete surgical resection and PCT, but it cannot increase OS. Besides, EGFR mutation status, T stage, and type of surgery are possible independent prognostic factors for DFS, and type of surgery is associated with OS. These factors remain to be clarified in further studies.

Risk of cardiac-related mortality in stage IIIA-N2 non-small cell lung cancer: Analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

BACKGROUND: In this study, we aimed to investigate the association between postoperative radiotherapy (PORT) and cardiac-related mortality in patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The United States (US) population based on the SEER database was searched for cardiac-related mortality among patients with stage IIIA-N2 NSCLC. Cardiac-related mortality was compared between the PORT and Non-PORT groups. Accounting for mortality from other causes, Fine and Gray's test compared cumulative incidences of cardiac-related mortality between both groups. Univariate and multivariate analysis were performed using the competing risk model. RESULTS: From 1988 to 2016, 7290 patients met the inclusion criteria: 3386 patients were treated with PORT and 3904 patients with Non-PORT. The five-year overall incidence of cardiac-related mortality was 3.01% in the PORT group and 3.26% in the Non-PORT group. Older age, male sex, squamous cell lung cancer, earlier year of diagnosis and earlier T stage were independent adverse factors for cardiac-related mortality. However, PORT use was not associated with an increase in the hazard for cardiac-related mortality (subdistribution hazard ratio [SHR] = 0.99, 95% confidence interval [CI]: 0.78-1.24, p = 0.91). When evaluating cardiac-related mortality in each time period, the overall incidence of cardiac-related mortality was decreased over time. There were no statistically significant differences based on PORT use in all time periods. CONCLUSIONS: With a median follow-up of 25 months, no significant differences were found in cardiac-related mortality between the PORT and Non-PORT groups in stage IIIA-N2 NSCLC patients.

Patient prognostic scores and association with survival improvement offered by postoperative radiotherapy for resected IIIA/N2 non-small cell lung cancer: A population-based study.

BACKGROUND: Currently, there is no consensus on the role of postoperative adjuvant radiotherapy (PORT) for resected stage IIIA/N2 non-small cell lung cancer (NSCLC). Our study sought to determine which patients may be able to benefit from PORT, based on a patient prognostic score. METHODS: A retrospective cohort study was conducted to identify patients diagnosed with IIIA/N2 NSCLC between 1988 and 2016 in the SEER database. Eligible patients were divided into the following two groups: PORT group and non-PORT group. We classified patient prognostic scores as an ordinal factor and stratified patients based on prognostic scores. A Cox proportional hazards model with propensity score weighting was performed to evaluate cancer-specific mortality (CSM) between the two groups. RESULTS: We identified 7060 eligible patients with IIIA/N2 NSCLC, 2833 (40.1%) in the PORT group and 4227 (59.9%) in the non-PORT group. Overall, the 10-year CSM rate in the weighted cohorts was 70.4% in the PORT group, 72.0% in the non-PORT group, and patients who received PORT had a lower CSM rate (p = 0.001). Compared with the non-PORT group, significant survival improvements in the PORT group were observed in patients with higher age, grade, T stage and lymph node ratio (LNR), and without chemotherapy. The improved survival of patients receiving PORT was significantly correlated with patient prognostic scores (p < 0.001). CONCLUSIONS: In our population-based study, the prognostic score was associated with the survival improvement offered by PORT in IIIA/N2 NSCLC, suggesting that prognostic scores and clinicopathological characteristics may be helpful in proper candidate selection for PORT.

Clinical impact of the tumor immune microenvironment in completely resected stage IIIA(N2) non-small cell lung cancer based on an immunoscore approach.

BACKGROUND: Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) comprises a heterogeneous population according to discrepancies in survival prognosis. Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs) are clinically significant, despite a lack of consensus regarding the immunoscore (IS) in NSCLC. Here, we determined the prognostic value of the immune microenvironment as an IS in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC. METHODS: Consecutive patients with pathologically confirmed stage IIIA(N2) NSCLC and who underwent complete resection (2005-2012) were retrospectively reviewed. Tissue microarrays (TMAs) were constructed from surgical paraffin-embedded primary lung tumor specimen. For each case, two representative regions from the tumor center (CT) and two from the invasive margin (IM) containing the highest density of lymphocytes were selected. Densities of CD3+, CD45RO+, and CD8+ lymphocytes were assessed using immunohistochemistry (IHC) by specialized pathologists according to predefined scoring scales. Patients were classified according to IS definition based on TIL type, density, and distribution, and relationships between IS and prognosis were evaluated. RESULTS: Patients (N = 288) with complete IHC-based TMA spots were included. Univariate analyses showed that CD3+ T cell density was associated with neither overall survival (OS) nor distant metastasis-free survival (DMFS), whereas CD45RO+ T cell density in the IM was a significant prognostic factor for DMFS (p = 0.02) and was predictive of OS (p = 0.05). Combined CD45RO+ and CD8+ cell infiltration in tumor regions (CT and IM) significantly improved IS prognostic impact. Multivariate analyses revealed IS as an independent prognostic predictor for both DMFS (p = 0.001) and OS (p = 0.002). CONCLUSION: The proposed IS might provide valuable prognostic information, including prediction of DMFS and OS in stage IIIA(N2) NSCLC patients. Larger patient cohorts are needed to validate this IS classification, which might assist with accurate risk stratification and treatment decisions.

Surgery for Locally Advanced and Oligometastatic Non-Small Cell Lung Cancer.

Locally advanced non-small cell lung cancer is a heterogeneous group of tumors that require multidisciplinary treatment. Although there is much debate with regard to their management, a multimodal treatment strategy for carefully selected patients that includes surgery can extend survival compared with nonoperative definitive therapy. As the role of targeted therapies and immune checkpoint inhibitors for these tumors becomes better defined, practices will continue to evolve.

Evaluation of Postoperative Radiotherapy Effect on Survival of Resected Stage III-N2 Non-small Cell Lung Cancer Patients.

Objective: The role of postoperative radiotherapy (PORT) in resected stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains controversial. This study aimed to explore the effect of PORT on survival of resected stage IIIA-N2 NSCLC patients. Methods: Resected stage IIIA-N2 NSCLC patients aged 18 years or older were identified from the SEER (Surveillance, Epidemiology, and End Results) database from 2010 to 2015. Cox regression analysis was used to identify factors including PORT associated with survival time. A subgroup analysis of patients stratified by number of lymph node metastases was also performed. Overall survival (OS) and overall mortality were compared among the different groups. Results: A total of 3,445 patients were included in the study. Multivariate Cox analysis showed that PORT had no significant impact on survival of patients with <6 positive lymph node [hazard ratio (HR) = 1.012, P = 0.858, 95% CI: 0.886-1.156]. Postoperative chemotherapy (POCT) (HR = 0.605, P < 0.001, 95% CI: 0.468-0.783) and PORT (HR = 0.724, P = 0.007, 95% CI: 0.574-0.914) are both favorable prognostic factors for stage IIIA-N2 patients with ≥6 positive lymph nodes. In 2,735 patients who featured <6 number of positive regional lymph nodes, patients who received PORT had better survival and lower 3-years and 5-years overall mortality rate than patients who underwent surgery only (41 vs. 28 months, P < 0.015). There was no significant difference in the survival of postoperative patients who underwent POCT in view of whether received PORT (44 vs. 53 months, P = 0.176). A total of 710 patients who featured ≥6 number of positive regional lymph node metastasis were divided into two groups by PORT. PORT did not prolong survival for postoperative patients who did not receive chemotherapy (12 vs. 15 months, P = 0.632). PORT showed a significant advantage in influencing OS in patients who received PORT combined with POCT as compared with those who received POCT only (32 vs. 25 months, P = 0.006). Conclusions: For IIIA-N2 patients with <6 lymph node metastases, use of PORT can be encouraged to improve survival. For patients with ≥6 positive lymph nodes, PORT combined with POCT significantly improved OS and decreased overall mortality.

Prognostic Value of Tumor Size in Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer.

The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to heterogeneous disease entity. The aim of this study was to evaluate the clinicopathologic features and prognostic factors of patients with completely resected stage IIIA-N2 NSCLC. We retrospectively evaluated 77 consecutive patients with pathologic stage IIIA-N2 NSCLC (AJCC eighth edition) who underwent surgical resection with curative intent in China Medical University Hospital between 2006 and 2014. Survival analysis was conducted, using the Kaplan-Meier method. Prognostic factors predicting overall survival (OS) and disease-free survival (DFS) were analyzed, using log-rank tests and multivariate Cox proportional hazards models. Of the 77 patients with pathologic stage IIIA-N2 NSCLC examined, 35 (45.5%) were diagnosed before surgery and 42 (54.5%) were diagnosed unexpectedly during surgery. The mean age of patients was 59 years, and the mean length of follow-up was 38.1 months. The overall one-, three-, and five-year OS rates were 91.9%, 61.3%, and 33.5%, respectively. Multivariate analysis showed that tumor size <3 cm (hazards ratio (HR): 0.373, p = 0.003) and video-assisted thoracoscopic surgery (VATS) approach (HR: 0.383, p = 0.014) were significant predictors for improved OS. For patients with surgically treated, pathologic stage IIIA-N2 NSCLC, tumor size <3 cm and the VATS approach seemed to be associated with better prognosis.

A biomarker-based prediction model for risk of locoregional recurrence in pathologic stage IIIA-N2 non-small cell lung cancer.

OBJECTIVE: To investigate risk factors for locoregional recurrence (LRR) of pathologic stage IIIA-N2 non-small cell lung cancer (pIIIA-N2 NSCLC) and construct a prediction model for risk score to determine a patient's risk for LRR and guide the selection of postoperative radiotherapy (PORT). METHODS: The clinical, pathologic, and biological data of 107 patients with pIIIA-N2 NSCLC treated at Fujian Provincial Hospital between May 2012 and December 2018 were analyzed retrospectively. None of the patients had positive surgical margins, and none received preoperative treatment or PORT. The Kaplan-Meier method was used for a univariate analysis of possible factors for locoregional recurrence-free survival (LRFS). The Cox regression model was used in a multivariate analysis to identify independent risk factors for LRFS, which were used to construct a prediction model for risk score. The concordance index was calculated to evaluate discrimination. RESULTS: The median follow-up time was 31.2 months. During the follow-up, 69 (64.5%) patients had LRR and/or distant metastasis (DM). Among them, 46 (43%) patients had LRR (with or without DM), and 56 (52.3%) patients had DM (with or without LRR). The 1-year LRFS, distant metastasis-free survival, disease-free survival, and overall survival rates were 78.2%, 78%, 69.8%, and 90.2%, respectively; the 3-year rates were 50.6%, 41.2%, 31.2%, and 66.3%, respectively. Multivariate analysis showed that surgical approach (hazard ratio [HR], 0.348; 95% confidence interval [CI], 0.175-0.693; P = 0.003), metastatic N2 lymph node ratio (HR, 3.597; 95% CI, 1.832-7.062; P = 0.000), epidermal growth factor receptor status (HR, 3.666; 95% CI, 1.724-7.797; P = 0.001), and lymphocyte-to-monocyte ratio (HR, 2.364; 95% CI, 1.221-4.574; P = 0.011) were independent risk factors for LRFS. These independent risk factors were used to construct a prediction model for risk score and stratify patients into the low-risk group (risk score: 0-2), medium-risk group (risk score: 3-5), and high-risk group (risk score: 6-13). The 1-year LRFS rates of these groups were 91.9%, 85.3%, and 54.6%, respectively; the 3-year LRFS rates were 71.4%, 57.3%, and 13.6%, respectively. These between-group differences were significant (P = 0.000). The prediction model showed good discrimination (concordance index = 0.747, 95% CI, 0.678-0.816). CONCLUSION: Our prediction model for risk score based on characteristics of pIIIA-N2 NSCLC patients may help clinicians predict a patient's risk for LRR. Further investigations of PORT with patients in different risk groups are warranted.

Postoperative Radiotherapy for Resected Stage IIIA-N2 Non-small-cell Lung Cancer: A Population-Based Time-Trend Study.

INTRODUCTION: The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27 years. METHODS: Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. RESULTS: 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). CONCLUSIONS: The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application.

The role of postoperative radiotherapy for completely resected pIIIA-N2 non-small cell lung cancer patients with different clinicopathological features: a systemic review and meta-analysis.

Background: The role of postoperative radiotherapy (PORT) in completely resected pathological stage IIIA-N2 (pIIIA-N2) non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis aimed to assess the effect of PORT in patients with pIIIA-N2 NSCLC on the basis of clinicopathological features. Methods: The PubMed, PubMed Central (PMC), Embase, Web of Science, and Cochrane Library were searched for relevant studies. The main outcomes were overall survival (OS) and disease-free survival (DFS), which were compared using the hazard ratio (HR). Results: One randomized trial and 12 retrospective studies were eligible for the analysis. PORT significantly improved both OS [HR = 0.85; 95% confidence interval (CI): 0.79-0.92] and DFS (HR = 0.57; 95% CI: 0.38-0.85) compared with non-PORT treatment in patients with multiple N2 metastases or multiple N2 station involvement. No significant difference in either OS (HR = 1.03; 95% CI: 0.86-1.24) or DFS (HR = 1.08; 95% CI: 0.70-1.65) was found between PORT and non-PORT groups for patients with single N2 station involvement. No significant heterogeneity was observed. No significant differences in OS were observed between PORT and non-PORT groups for patients of different ages, sex, tumor sizes or pT stages, and histological types. Conclusions: The findings of this meta-analysis supported a role for PORT in patients with completely resected pIIIA-N2 NSCLC having multiple N2 metastases and favored withholding PORT to patients with single N2 station involvement. Further prospective randomized controlled trials are needed to confirm the findings.

Male patients with resected IIIA-N2 non-small-cell lung cancer may benefit from postoperative radiotherapy: a population-based survival analysis.

AIM: Our analysis was performed to assess the efficacy of postoperative radiotherapy (PORT) on the survival for pathologic IIIA-N2 Non-small-cell lung cancer patients. PATIENTS & METHODS: We identified 2949 patients from 2004 to 2013 in the SEER database. Propensity score-matching was used to reduce the selection bias. Overall survival (OS), cancer-specific survival (CSS) and the factors associated with survival prognosis were evaluated. RESULTS: There was no significant difference in OS and CSS between PORT and non-PORT groups. However, subgroup analysis revealed an OS (p = 0.007) and CSS (p = 0.006) detrimental for male patients not receiving PORT. Multivariate analysis showed that old age, male sex, high pathologic grade, squamous carcinoma, bigger tumor size and larger number of positive lymph nodes had a negative impact on survival. CONCLUSION: PORT could improve OS and CSS in male patients with resected IIIA-N2 non-small-cell lung cancer.

A nomogram to predict the survival of stage IIIA-N2 non-small cell lung cancer after surgery.

OBJECTIVE: Postoperative survival of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is highly heterogeneous. Here, we aimed to identify variables associated with postoperative survival and develop a tool for survival prediction. METHODS: A retrospective review was performed in the Surveillance, Epidemiology, and End Results database from January 2004 to December 2009. Significant variables were selected by use of the backward stepwise method. The nomogram was constructed with multivariable Cox regression. The model's performance was evaluated by concordance index and calibration curve. The model was validated via an independent cohort from the Jiangsu Cancer Hospital Lung Cancer Center. RESULTS: A total of 1809 patients with stage IIIA-N2 NSCLC who underwent surgery were included in the training cohort. Age, sex, grade, histology, tumor size, visceral pleural invasion, positive lymph nodes, lymph nodes examined, and surgery type (lobectomy vs pneumonectomy) were identified as significant prognostic variables using backward stepwise method. A nomogram was developed from the training cohort and validated using an independent Chinese cohort. The concordance index of the model was 0.673 (95% confidence interval, 0.654-0.692) in training cohort and 0.664 in validation cohort (95% confidence interval, 0.614-0.714). The calibration plot showed optimal consistency between nomogram predicted survival and observed survival. Survival analyses demonstrated significant differences between different subgroups stratified by prognostic scores. CONCLUSIONS: This nomogram provided the individual survival prediction for patients with stage IIIA-N2 NSCLC after surgery, which might benefit survival counseling for patients and clinicians, clinical trial design and follow-up, as well as postoperative strategy-making.

Occult stage IIIA-N2 patients have excellent overall survival with initial surgery.

BACKGROUND: Patients may be found to have stage IIIA-N2 at the final pathology after the initial surgery. We want to determine the survival rate in this unique group of patients. METHODS: We reviewed all patients who underwent surgical resection for lung cancer from 2000 to 2011 who had pathologic stage N2 without induction therapy. We determined the clinicopathologic characteristics and survival rate in this unique group of patients. RESULTS: A total of 101 patients met the inclusion criteria. The average age of the group was 65 years old with 53 (53%) females. The chest computed tomography (CT) scans showed 30 patients (30%) with mediastinal lymphadenopathy (>1 cm) and 13 (13%) with multistation disease. The positron emission tomography-computed tomography (PET-CT) showed 24 patients (24%) with N2 positive uptake. Invasive mediastinal staging prior to surgery occurred in 43 patients (43%). Eighty-four patients underwent a lobectomy (83%), 7 with bilobectomy (7%), and 10 with pneumonectomy (10%). The most common pathology was adenocarcinoma with 73 patients (72%) and the second most common was squamous cell carcinoma with 22 patients (22%). Most of the patients completed the adjuvant chemoradiation therapy (86%). The 5-year survival rate was 48% and the 10-year survival rate was 24%. CONCLUSIONS: Pathologic stage IIIA-N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease process with a very small group of patients undergoing initial surgery. Patients with occult stage IIIA-N2 who undergo initial surgery have an excellent overall survival rate.

Optimal managements of stage IIIA (N2) non-small cell lung cancer patients: a population-based survival analysis.

BACKGROUND: This study aimed to investigate the optimal management of stage IIIA (cN2) non-small cell lung cancer (NSCLC) patients and determine potential predictive factors. METHODS: We extracted patients diagnosed as NSCLC stage IIIA (cN2) between 2004 and 2011 from Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients given different clinical managements by Kaplan-Meier method. Other variables such as age, sex and tumor size were analyzed to explore the factors associated with outcomes. RESULTS: A total of 98,700 IIIA-cN2 NSCLC patients were identified from SEER database. Survival of patients treated with surgery was better than that of patients treated by radiotherapy alone (P<0.001). Radiation prior to surgery significantly improved the survival in comparison with surgery alone (P<0.001). In the subgroups of OS analysis, age >65 (P=0.902), adenocarcinoma (P=0.279), tumor size ≤3 cm (P=0.170), well differentiated (P=0.360) patients, preoperative radiotherapy improved survival insignificantly compared with surgery alone. CONCLUSIONS: Preoperative radiation with surgery had the most encouraging survival outcomes in stage IIIA-cN2 NSCLC patients compared with radiation or surgery alone. No significant outcome improvement was shown between postoperative radiotherapy (PORT) and surgery alone.