Resected Stage IIIA-N2 Non-small Cell Lung Cancer Research Articles

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

ObjectivesThis 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. MethodsThe 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. ResultsA 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. ConclusionsIn 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.

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.

Postoperative Radiation Therapy for Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer: A Population Study from 1988 to 2014 Using the Surveillance, Epidemiology, and End Results Database

The use of postoperative radiotherapy(PORT) after resection of stage IIIA-N2 non-small-cell lung cancer(NSCLC) remains controversial. Large real-world data studies are absent regarding the value of PORT across different time periods as all treatment methods develop. We explored the effects of PORT on the survival of patients with resected stage IIIA-N2 NSCLC and assessed the temporal changes spanning 27 years. Within the Surveillance, Epidemiology, and End Results Database, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumectomy and coded as receiving PORT or never receiving radiation therapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival rates were assessed with Kaplan-Meier method, log-rank test and multivariable hazard ratios were estimated from Cox proportional hazards models. A total of 5568 patients (718, 2020, 2830 in period 1, 2, 3 respectively) were included, 45.4% of which received PORT. The yearly PORT use varied largely with the highest 74.4% in 1994 and the lowest 27.8% in 2005. Overall survival(OS) was significantly improved over the periods ( p<0.001) in the whole cohort, PORT group and non-PORT group, respectively. Median survivals in the three periods were 20 vs 14, 26 vs 24, 39 vs 33 months for PORT vs non-PORT group. The use of PORT had significant impact on survival in period 1(p<0.001) and 3(p=0.001) but not in period 2(p=0.256). However, in subgroup analysis, the OS benefit of PORT was significantly in each period in patients with 50% or more lymph node ratio(LNR, defined as number of positive nodes/ number of resected nodes): Period 1: hazard ratio(HR), 0.646; 95% confidence interval(CI): 0.482-0.865, p=0.003. Period 2: HR, 0.846; 95% CI: 0.717-0.998, p=0.047. Period 3: HR, 0.773; 95% CI: 0.634-0.942, p=0.011). This population-based study demonstrates significant improvements in OS of these selected resected stage IIIA-N2 NSCLC patients from 1988-2014. The benefits of PORT are not significantly in each time period but are lasting and stable throughout the years in patients with LNR of 50% or more, although other integrated factors such as the progress of surgery and medication may contribute to a better survival. Further investigations in other cohorts and prospective studies are warranted.

Propensity score-matching analysis of postoperative radiotherapy for stage IIIA-N2 non-small cell lung cancer using the Surveillance, Epidemiology, and End Results database

BackgroundTo investigate the effects of postoperative radiotherapy (PORT) on the survival of patients with resected stage IIIA-N2 non-small cell lung cancer (NSCLC).MethodsA total of 3,334 patients with resected stage IIIA-N2 NSCLC in 2004 to 2013 were identified in the Surveillance, Epidemiology, and End Results database and stratified according to use of PORT. Propensity score-matching (PSM) methods were used to balance the baseline characteristics of patients who did (n = 744) or did not (n = 744) undergo PORT. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared between these two patient groups.ResultsAfter PSM, PORT increased OS (hazard ratio, 0.793; p = 0.001) and LCSS (hazard ratio, 0.837; p = 0.022) compared with no PORT. The OS benefit for PORT was mainly seen in patients aged <60 years (5-year OS, 35.4% versus 28.9% for PORT versus no PORT, respectively; p = 0.026) and in those who underwent lobectomy (5-year OS, 43.5% versus 34.5% for PORT versus no PORT, respectively; p = 0.001). The LCSS benefit for PORT was significant in patients undergoing lobectomy (5-year LCSS, 48.3% versus 42.3% for PORT versus no PORT, respectively; p = 0.036).ConclusionsThe survival benefits of PORT were primarily observed in patients with resected stage IIIA-N2 NSCLC who were <60 years of age or had undergone lobectomy.

The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients.

To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.

Prognostic Significance of the Number of Metastatic pN2 Lymph Nodes in Stage IIIA-N2 Non–Small-Cell Lung Cancer After Curative Resection

IntroductionThere have been controversies regarding the prognostic relevance of the number of positive N2 nodes in pathologic stage IIIA-N2 non–small-cell lung cancer (NSCLC). We examine prognosis of patients with pathologic stage IIIA-N2 with classifying the number of positive N2 nodes into subgroups. MethodsFrom January 1997 to December 2004, 250 patients were diagnosed with pathologic stage IIIA-N2 disease. All patients underwent mediastinal lymph node dissection. After excluding 44 patients with preoperative chemotherapy, incomplete resection, and postsurgical mortality, 206 patients were included in the analysis. Patients were classified according to the number of positive N2 lymph nodes (N2a: 1 [n = 83], N2b: 2-4 [n = 82], N2c: ≥ 5 [n = 41]), and its correlation with survival outcomes were investigated. ResultsWith a median follow-up of 96.3 months, 5-year disease-free survival (DFS) was 27.2% (95% confidence interval [CI], 21.6-33.7), and 5-year overall survival (OS) was 37.7% (95% CI, 31.5-44.7) in all patients. The number of metastatic N2 lymph nodes was associated with DFS (P < .001) and OS (P = .01). In the N2a, N2b, and N2c groups, 5-year DFS rates were 38%, 24%, and 5%, respectively, and 5-year OS rates were 47%, 35%, and 24%, respectively. In a multivariate analysis, the number of metastatic N2 lymph nodes was an independent prognostic factor for DFS and OS. ConclusionStratification of patients according to the number of metastatic N2 lymph nodes may improve the accuracy of prognostic prediction among patients with curatively resected stage IIIA-N2 NSCLC.

Pemetrexed-Carboplatin Adjuvant Chemotherapy With or Without Gefitinib in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Harbouring EGFR Mutations: A Randomized, Phase II Study

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of gefitinib following adjuvant chemotherapy in patients with EGFR mutation are unknown. In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either exon 19 deletion or L858R point mutation) were assigned randomly to receive pemetrexed (500mg/m(2)) and carboplatin (AUC=5), administered every 21days for 4 cycles, followed with or without gefitinib (250mg/day) for 6months. The primary end point was disease-free survival (DFS). From August 2008 to September 2011, 60 patients were included in our center. DFS was significantly longer among those who received pemetrexed and carboplatin (PC)-gefitinib than among those who received PC alone [hazard ratio (HR), 0.37; 95% confidence interval (CI) 0.16-0.85; P=0.014; median, 39.8 vs. 27.0months]. The rates of 2-year DFS were 78.9% in the PC-gefitinib group and 54.2% in the PC alone group. The rates of 2-year overall survival (OS) were 92.4% in the PC-gefitinib group and 77.4% in the PC alone group (HR, 0.37; 95% CI 0.12-1.11, P=0.076). The most common adverse event was rash (43.3%, 13/30) in the PC-gefitinib group and the administration of gefitinib following chemotherapy was well tolerated. The administration of gefitinib following PC adjuvant therapy shows significant improvement in DFS in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.

Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: A randomized phase II study.

7519 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The BR.19 trial exploring the role of adjuvant gefitinib in resected early stage NSCLC (stage IB 49%, II 38%, III 13%) did not show significant progression-free survival (PFS) or overall survival (OS) improvement in all patients. The efficacy of gefitinib following adjuvant chemotherapy in patients with EGFR mutation is unknown. Methods: In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned to receive pemetrexed (500mg/m2) and carboplatin (AUC=5), administered every 21 days for 4 cycles, followed with (n=30) or without (n=30) gefitinib (250mg per day) for 6 months. The primary end point was PFS. The second end point was OS. Results: From August 2008 toSeptember 2011, 60 patients (35 males and 25 females) were included in our center. Of the 60 patients (56 adenocarcinomas, 2 squamous cell carcinomas, 2 adenosquamous carcinomas), 20 patients (33.3%) had exon 19 deletion mutation, 40 (66.7%) patients had exon 21 L858R point mutation. The most common adverse event was rash (43.3%, 13 of 30) in the pemetrexed and carboplatin (PC)-gefitinib group and the addition of gefitinib to chemotherapy was well tolerated. The PFS was significantly longer among those who received PC-gefitinib than among those who received PC alone (median,39.8 months vs 27.0 months; hazard ratio [HR],0.369; 95% confidence interval [CI], 0.161-0.847; P=0.014). There was no significant difference in OS between the two group(median,41.6 months vs 32.6 months,P=0.066). The rates of 2-year PFS and OS were 78.9% and 92.4% in PC-gefitinib group, and 54.2% and 77.4% in PC alone group, respectively. Conclusions: The addition of gefitinib to pemetrexed and carboplatin adjuvant therapy showed significant improvement in PFS for patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.

Prognostic Significance of Reversion-Inducing Cysteine-Rich Protein With Kazal Motifs Expression in Resected Pathologic Stage IIIA N2 Non–Small-Cell Lung Cancer

Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase inhibitor, and experimental studies have shown that RECK can suppress tumor progression through angiogenesis inhibition. We have already revealed that enhanced RECK expression is significantly correlated with a favorable prognosis in non-small-cell lung cancer (NSCLC). In this study, further analyses focused on pN2 disease were conducted to assess the clinical significance of RECK expression. A total of 118 patients with completely resected pathologic stage IIIA N2 NSCLC were retrospectively examined. RECK expression in the primary tumor, along with involved N2 nodes, was examined immunohistochemically. RECK expression in the primary tumor was strong in 53 patients (44.9%) and was weak in the other 65 patients. The 5-year survival rate of patients with RECK-strong tumor (42.9%) was significantly higher than that of patients with RECK-weak tumor (23.1%; P = .017). Reduced RECK expression significantly correlated with a poor prognosis for patients with a single N2 node involved (P = .019), but not for patients with multiple N2 nodes involved (P = .440). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031). RECK expression in involved N2 nodes was significantly higher than in primary tumors (P < .001). RECK status was a novel prognostic factor in pathologic stage IIIA N2 NSCLC.