Pathological N2 Non-small Cell Lung Research Articles

P3.01-89 Upfront Surgery Versus Neoadjuvant Treatment Followed by Surgery in Pathologic N2 Non-Small Cell Lung Cancer

P3.01-89 Upfront Surgery Versus Neoadjuvant Treatment Followed by Surgery in Pathologic N2 Non-Small Cell Lung Cancer

Association between clinicopathological factors and postoperative radiotherapy in patients with completely resected pathological N2 non-small cell lung cancer.

The function of postoperative radiotherapy (PORT) in patients with completely resected pathologically N2 (pN2) non-small cell lung cancer (NSCLC) remains controversial due to a lack of prospective studies. The present study aimed to evaluate the efficacy of PORT in completely resected pN2 NSCLC when using modern radiation techniques, and to determine the associations between clinicopathological factors and PORT and survival rates. Following patient selection, 246 out of 269 consecutive patients with pN2 NSCLC were enrolled in the present study, with 88 patients having received postoperative chemotherapy (POCT) and PORT, 90 having received adjuvant chemotherapy, 1 having received adjuvant radiotherapy and the remaining 67 having received no adjuvant therapy. Overall survival (OS), local recurrence-free survival (LRFS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The median age of the patients was 59 years, overall, 175 (71.1%) of the patients were male and the median radiation dose was 50.4 Gy. The median follow-up duration was 38.3 months. The 1-, 3- and 5-year OS rates were 98.9, 71.3 and 54.9%, and 93.0, 58.4 and 36.7% (P=0.011) in the PORT and non-PORT group, respectively. The 1-, 3- and 5-year LRFS rates were 95.5, 84.6 and 78.0%, and 86.6, 70.6 and 52.8% (P<0.001) in the PORT and non-PORT groups, respectively. The 1-, 3- and 5-year DFS rates were 86.5, 55.2 and 37.9%, and 80.9, 40.3 and 26.8% (P=0.132) in the PORT and non-PORT groups, respectively. Univariate analysis revealed that the OS rate was significantly increased in patients with peripheral tumors (P=0.029), pT1-2 (P=0.015), one N2 lymph node (LN) metastasis (P=0.001), single N2 station metastasis (P=0.030), no bronchial involvement (P=0.025), use of PORT (P=0.011) and POCT (P=0.003). Multivariate analysis revealed that PORT (HR, 0.755; 95% CI, 0.498-0.986; P=0.047), POCT (HR, 0.645; 95% CI, 0.420-0.988; P=0.044), bronchial involvement (HR, 1.453; 95% CI, 1.002-2.107; P=0.049) and ≥2 N2 metastases (HR, 1.969; 95% CI, 1.228-3.157; P=0.005) were significant independent predictors of OS. Subgroup analysis demonstrated an increased OS rate with PORT only in the patients with positive bronchial involvement and ≥2 N2 LN metastases. The results revealed that PORT may improve the LRFS and OS rates in completely resected pN2 NSCLC, and that the patients with positive bronchial involvement and ≥2 N2 LN metastases may receive more benefit from PORT.

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

BackgroundPostoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS).MethodsWithin the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation.ResultsOS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3).ConclusionsIn Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).

P2.01-018 Risk Factors in Patients with Pathological N1 or N2 Non-Small Cell Lung Cancer

Pathological (p) N1 or N2 non-small cell lung cancer (NSCLC) patients may experience poor prognosis despite complete resection; therefore, adjuvant chemotherapy is recommended for them. In this study, we investigated the risk factors for pN1 or N2 NSCLC. From March 2005 to December 2015, we retrospectively reviewed 93 patients with completely resected pN1 or N2 NSCLC. Patients with synchronous or metachronous multiple lung cancer, malignancies from other organs, or who received neoadjuvant chemoradiotherapy were excluded. Clinicopathological factors analyzed included: age, sex, serum carcinoembryonic antigen levels, surgical procedures, histology, size of invasive tumor, pathological N status, pleural invasion, lymphatic invasion, vascular invasion, and histological grade. Univariate and multivariate analyzes of disease-free survival and overall survival were conducted. The study group comprised 93 patients (64 men, 29 women; age range: 38–86 years; mean: 68±9.9 years). The median follow-up period was 35.1 months. The preoperative serum carcinoembryonic antigen level was elevated in 36 patients. Complete resection was performed in all patients, comprising pneumonectomy in two patients (including sleeve pneumonectomy), bilobectomy in three, and lobectomy in 87 (including lobectomy with bronchoplasty or resection adjacent organs). Adenocarcinoma, squamous cell carcinoma, and other histology were observed in 59, 22, and 12 patients, respectively. The maximum diameter of invasive diameter was >30 mm in 39 patients and ≤30 mm in 54. There were 52 patients with pN1 and 41 with pN2. Forty-four were with pleural invasion, 52 with lymphatic invasion, and 48 with vascular invasion. Multivariate analysis showed histology to be an independent factor for recurrence, whereas older age (>70 years), pleural invasion, and adjuvant chemotherapy were independent factors for poor survival. There were 24 patients with no adjuvant chemotherapy, 10 could not receive it because of poor postoperative performance status, and 3 were ineligible because of older age. The 5-year overall survival in patients with adjuvant chemotherapy was 61.8%, compared with 23.8% for those without (p =0.002). Older age, pleural invasion, and adjuvant chemotherapy were found to be independent factors for poor survival in pN1 or N2 NSCLC. Adjuvant chemotherapy is a potential consideration for pN1 or N2 patients. Surgery to maintain performance status may be useful in relation to undergoing adjuvant chemotherapy.

P3.01-080 Overall Survival (OS) of Pathological N2 Non-Small Cell Lung Cancer (NSCLC) After Surgical Resection

P3.01-080 Overall Survival (OS) of Pathological N2 Non-Small Cell Lung Cancer (NSCLC) After Surgical Resection

MTE05.01 Where is the Place of Surgery for N2 Disease?

MTE05.01 Where is the Place of Surgery for N2 Disease?

Lymph node ratio as a prognostic factor in patients with pathological N2 non-small cell lung cancer.

BackgroundThe aim of this study was to investigate whether the lymph node ratio (LNR) was associated with the prognosis of patients, who underwent surgery for pathological N2 non-small cell lung cancer (NSCLC).MethodsA total of 182 patients were diagnosed with pathological N2 disease and underwent complete resection surgeries with systematic lymphadenectomies. We counted the number of positives and removed lymph nodes to calculate a ratio between them (LNR). We also investigated the association between skip mediastinal lymph node metastasis and survival.ResultsUnivariate analysis of survival in patients with N2 NSCLC showed that the T factor, clinical N factor, and LNR were significant prognostic factors. Multivariate analyses showed that the clinical N stage and LNR were significant independent prognostic factors for patients with pathological N2 NSCLC. Patients with a clinical lymph node status of 0 (cN0) and LNR ≤0.22 showed a significantly higher survival rate than patients with a cN1-2 and LNR ≥0.22 and 5-year survival rates were 47.1 and 10.3%, respectively (p < 0.0001).ConclusionsLNR is an important prognostic factor for poor outcome following surgery in patients with N2 disease. The combination of the LNR and cN status provides a valuable prognostic tool.

Mediastinal lymphadenectomy fulfilling NCCN criteria may improve the outcome of clinical N0-1 and pathological N2 non-small cell lung cancer.

This retrospective study investigated whether mediastinal lymphadenectomy compliant with the National Comprehensive Cancer Network (NCCN) criteria will improve the oncological outcomes of clinical early-stage lung cancer. From 2003-2010, 712 consecutive cases of clinical N0/1 were included for retrospective analysis, including 152 confirmed cases of pN2 and 560 of pN0-1 disease following surgery. Group A was defined as the cases fulfilling NCCN lymphadenectomy criteria (≥ three stations of N2 nodes dissection) and group B included all other cases. The groups were stratified according to pN status and the outcomes were assessed. Five-year overall survival (OS) and 5-year disease-free survival (DFS) were significantly different between group A versus B [72%±2% vs. 63%±4% (OS), P=0.014; 58.0%±2% vs. 49%±4% (DFS), P=0.038] in the whole cohort. After stratification by pN status, this difference was remained in pN2 subgroup [50%±5% vs. 25%±9% (OS), P=0.006; 31.0%±4% vs. 13%±7% (DFS), P=0.014], but not in pN0-1 subgroups. Cox regression analysis showed that performing a lymphadenectomy fulfilling NCCN criteria was a significant prognostic factor for OS either in the whole cohort [P=0.003, hazard ratio (HR): 0.598, 95% confidence interval (CI): 0.425-0.841] or in patients of pN2 status (P=0.038, HR: 0.559, 95% CI: 0.323-0.968). Cases with ≥4 N2 stations dissected did not achieve better survival benefit compared to those harvesting 3 stations in cN0/1-pN2 group (P=0.152). Mediastinal lymphadenectomy fulfilling NCCN criteria appears to improve the survival of unexpected N2 group (cN0/1-pN2) among early-stage lung cancer patients. More extended N2 node dissection may not further improve the outcome in this group.

89P - Clinical Factors of Nodal Upstaging in Pathologic N1 Or N2 Non-Small Cell Lung Cancer

89P - Clinical Factors of Nodal Upstaging in Pathologic N1 Or N2 Non-Small Cell Lung Cancer

Risk factors for recurrence after complete resection of pathological stage N2 non-small cell lung cancer.

BackgroundTumor recurrence is the most common cause of treatment failure, especially after complete resection of pathological stage N2 non-small cell lung cancer (NSCLC). In this study, we investigated the clinicopathological characteristics in order to identify independent risk factors for postoperative recurrence.MethodsBetween January 2001 and December 2013, 96 patients who underwent surgical resection for pathological N2 NSCLC were retrospectively reviewed. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method to explore risk factors, while the Cox proportional hazard model was used to assess independent predictors.ResultsThe median and five-year RFS rates were 15 months and 27.4%, respectively. Univariate analysis showed a significantly poorer prognosis for non-regional N2 metastasis, more than three metastatic N2 lymph nodes, multiple N2 station, and multiple N2 zone involvement. Multivariate analysis demonstrated that non-regional N2 metastasis (hazard ratio [HR] 1.857, 95% confidence interval [CI] 1.061–3.249, P = 0.030) and more than three metastatic N2 lymph nodes (HR 2.555, 95% CI 1.164–5.606, P = 0.019) were independent risk factors for RFS. Additionally, the incidence of non-regional N2 metastasis was higher in patients with a primary tumor in the left lower (57.1%) or right lower lobe (48.1%), followed by left upper (31.8%), right middle (14.3%) and right upper lobe (7.7%).ConclusionThe combination of the distribution and number of metastatic N2 lymph nodes provides a more accurate prediction for N2 NSCLC regarding recurrence. Non-regional N2 metastasis could occur with a primary tumor in any lobe, but occurs more frequently in the lower lobe.

Significant prognostic factors for completely resected pN2 non-small cell lung cancer without neoadjuvant therapy.

To identify prognostic factors for pathologic N2 (pN2) non-small cell lung cancer (NSCLC) treated by surgical resection. Between 1990 and 2009, 287 patients with pN2 NSCLC underwent curative resection at the Cancer Institute Hospital without preoperative treatment. The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) rates were 46%, 55% and 24%, respectively. The median follow-up time was 80 months. Multivariate analysis identified four independent predictors for poor OS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.616; p = 0.003); ipsilateral intrapulmonary metastasis (HR, 1.042; p = 0.002); tumor size >30 mm (HR, 1.013; p = 0.002); and clinical stage N1 or N2 (HR, 1.051; p = 0.030). Multivariate analysis identified three independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (HR, 1.457; p = 0.011); ipsilateral intrapulmonary metastasis (HR, 1.040; p = 0.002); and tumor size >30 mm (HR, 1.008; p = 0.032). Multiple-zone mediastinal lymph node metastasis, ipsilateral intrapulmonary metastasis, and tumor size >30 mm were common independent prognostic factors of OS, CSS, and RFS in pN2 NSCLC.

Role of Postoperative Radiation Therapy After Curative Resection and Adjuvant Chemotherapy for Patients With Pathological Stage N2 Non-Small Cell Lung Cancer: A Propensity Score Matching Analysis

Role of Postoperative Radiation Therapy After Curative Resection and Adjuvant Chemotherapy for Patients With Pathological Stage N2 Non-Small Cell Lung Cancer: A Propensity Score Matching Analysis

Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National Cancer Database.

Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National Cancer Database.

Clinical Outcomes of Thoracoscopic Lobectomy for Patients With Clinical N0 and Pathologic N2 Non-Small Cell Lung Cancer

We compared the surgical outcomes in patients with clinical N0 and pathologic N2 (cN0-pN2) non-small cell lung cancer (NSCLC) who underwent video-assisted thoracoscopic surgery (VATS) lobectomy and open thoracotomy to evaluate the role of VATS lobectomy for cN0-pN2 disease. Between March 2006 and August 2011, 1,456 patients with clinical N0 NSCLC disease underwent lobectomy with systematic node dissection (SND) at Shanghai Chest Hospital. Of those patients, 157 were shown to have cN0-pN2 NSCLC. Of those, 67 patients underwent VATS lobectomy, and 90 patients underwent open lobectomy. SND was performed in all 157 patients. Clinicopathologic factors, local recurrence rates, and survival rates were compared. The two groups were similar in age, sex, and pulmonary function. The VATS approach was associated with significantly shorter chest tube duration and postoperative stay than was the thoracotomy approach. Operative mortality, morbidity, and recurrence did not differ between the two groups. There was no significant difference between the two types of operation in numbers of total lymph nodes removed (17.4 ± 6.1 in the VATS group vs 18.1 ± 7.2 in the open group, p = 0.78) and mediastinal lymph nodes removed (11.7 ± 5.6 in the VATS group vs 12.0 ± 5.1 in the open group, p = 0.84). Similarly, the two groups were not significantly different with regard to stations of total lymph nodes removed (7.6 ± 1.9 in the VATS group vs 7.8 ± 2.3 in the open group, p = 0.81) and mediastinal lymph nodes removed (4.5 ± 1.1 in the VATS group vs 4.7 ± 1.3 in the open group, p = 0.71). The rates of overall survival and disease-free 5-year survival were not significantly different between the two groups. The clinical outcomes of thoracoscopic lobectomy were comparable to those of thoracotomy for patients with cN0-pN2 NSCLC. Single-station N2 is a good prognostic factor for disease-free survival in these patients.

Survival impact of node zone classification in resected pathological N2 non-small cell lung cancer

We assessed the prognostic value of the 'Zone-classification' which has been proposed by the Japanese Association for Lung Cancer (JALC) for mediastinal nodal metastases in non-small cell lung cancer (NSCLC). Among 357 NSCLC patients who underwent curative surgery, 46 patients with pathological (p) N2 disease were divided into two groups as follows: 32 patients in whom the nearer zone was involved were classified as the pN2a-1 group, and 14 patients in whom the further mediastinal node station was involved were classified as the pN2a-2 group. The proportions of patients with non-adenocarcinoma histology, with multiple station metastases with the involvement of four or more nodes, and who underwent pneumonectomy, were higher in the pN2a-2 group. The 'Zone-classification' proved to be a significant prognostic factor in a univariate analysis (the 5-year overall survival rate, 7.1% for pN2a-2 versus 21.9% for pN2a-1; P < 0.01). A multivariate analysis confirmed that pN2a-2 sub-classification (hazard ratio 2.77; P = 0.03) and undergoing pneumonectomy (hazard ratio 4.86; P < 0.01) were independent and significant factors in predicting a poor prognosis. In pN2 NSCLC patients, the involved mediastinal zone according to the primary tumour site was important in prediction of survival.

Which subgroup of patients with pathologic N2 non-small cell lung cancer benefit from surgery?

Patients with pathologic N2 non-small cell lung cancer comprise a heterogeneous group. The objective of this study was to evaluate which subgroup of patients with pathologic N2 benefit from surgery in terms of survival probability. This retrospective study included 141 patients who had undergone major resection with pathologically proven N2 from 1990 to 2006 (103 with adenocarcinoma, 38 with squamous cell carcinoma). Patients undergoing preoperative induction therapy were excluded. Records were examined for age, gender, tumor size, surgical procedure, surgical side, clinical N status, primary tumor lobe, curative resection, and metastatic N2 stations. In patients with adenocarcinoma, surgical procedure, clinical N status, curative resection, and metastatic N2 stations were significant prognostic factors in univariate analysis. Age and curative resection were significant factors in patients with squamous cell carcinoma. In multivariate analysis, clinical N2 (P = 0.003), incomplete resection (P = 0.04), and multi-station N2 (P = 0.004) were significant adverse prognostic factors in patients with adenocarcinoma, whereas only incomplete resection (P = 0.002) was significant in patients with squamous cell carcinoma. For adenocarcinoma patients with pathologic N2, the 5-year survival rates were 58.8% for clinical N0-1 and single-station N2, 50% for clinical N2 and single-station N2, 23.9% for clinical N0-1 and multi-station N2, and 0% for clinical N2 and multi-station N2. Prognosis of patients with pathologic N2 can be grouped according to clinical N status and metastatic N2 stations in adenocarcinoma, but not in squamous cell carcinoma. Only adenocarcinoma patients with pathologic N2 appear to have heterogeneous subgroups with different prognoses.

Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer

Optimal surgical treatment for patients with stage IIIA N2 non-small cell lung cancer (NSCLC) remains a matter of debate, because of the outcomes. The outcomes may be affected from variations in patterns of lymph node metastasis. As the patterns of lymph node sub-classifications, multiple station metastases of mediastinal lymph nodes (MN2), highest metastasis of the mediastinal lymph nodes (HM), distribution of metastatic nodes (skip N2 or non-skip N2), and clinical (c-) N factor have been cited. We investigated these factors for patients with pathological stage IIIA (pIIIA) N2 NSCLC. We reviewed 121 consecutive patients with pIIIA N2 who underwent complete resection. Age, gender, tumor laterality, histology, lobe location of the tumor, c-T factor, pathological (p-) T factor, c-N factor, MN2, HM and skip N2 condition were used as prognostic variables. Overall five-year survival rate was 41.8%. Based on log-rank testing, c-T factor (P = 0.022), p-T factor (P = 0.0002), c-N factor (P = 0.009), HM (P = 0.019) and skip N2 (P = 0.030) were identified as significantly prognostic. Using these variables, p-T factor, c-N factor and skip N2 showed significance and independence on Cox multivariate analysis. The sub-classification of lymph node metastasis in patients with p-stage IIIA N2 NSCLC has clinical implications for the prognosis.

Nuclear survivin in pN2 nonsmall cell lung cancer: prognostic and clinical implications

Patients with N2 nonsmall cell lung cancer (N2-NSCLC) represent heterogeneous groups. Survivin is a member of the inhibitor of apoptosis family. If N2-NSCLC patients could be stratified, based on survivin expression and/or its relation to cell cycle proteins, into homogeneous subgroups, certain therapies could be selected for those patients. Survivin expression in 78 surgically resected primary pathological N2-NSCLC tumours was evaluated using immunohistochemistry. Relationships of survivin expression to overall survival, clinical features and expression of six cell cycle-related proteins (pRb, cyclin D1, p16(INK4A), p53, p21(Waf1) and Ki-67) were analysed. Nuclear survivin and the number of mediastinal lymph node (LN) stations were independent prognostic factors. The patient group with combined negative survivin/single mediastinal LN station were the most favourable prognostic group, and was related to the clinical nodal factor. Indeed, patients with negative survivin/low Ki-67 labelling indices had the best survival, especially in nonsquamous histopathology. The current authors conclude that nuclear survivin is strongly related to lymph node metastasis and proliferative potentials in pathological N2 nonsmall cell lung cancer patients. Pre-operative N2 nonsmall cell lung cancer patients with combined negative nuclear survivin and a single mediastinal lymph node station, or low proliferative indices, particularly in clinical N0-1 disease and nonsquamous histopathology, respectively, are expected to have a favourable post-operative prognosis and may be candidates for primary resection.

Is video-assisted thoracoscopic surgery a feasible approach for clinical N0 and postoperatively pathological N2 non-small cell lung cancer?☆

It remains controversial whether video-assisted thoracoscopic surgery (VATS) major pulmonary resection (VMPR) with systematic node dissection (SND) is a feasible approach for clinical N0 and pathological N2 non-small cell lung cancer (cN0-pN2 NSCLC). We compared the clinical outcome of patients who underwent VMPR with SND for cN0-pN2 NSCLC with the outcome of patients who underwent MPR with SND by thoracotomy. We conducted this study to determine the feasibility of VMPR for cN0 and pN2 NSCLC patients and intraoperative node staging by node sampling. Between 1997 and 2006, 770 patients underwent MPR with SND for NSCLC, wherein 450 patients had VMPR and 320 were subjected to open thoracotomy. There were 673 clinical N0 patients. Among them, we retrospectively reviewed 69 patients (10.3%) with cN0-pN2 NSCLC of which the greatest tumor dimension ranged from 20 to 50mm. These patients were divided into two groups: 37 patients under group V, who underwent VMPR, and 32 patients under group T, who underwent MPR by thoracotomy, for cN0-pN2 NSCLC. The majority of the patients underwent postoperative chemotherapy. There were no differences between the two groups regarding preoperative data or the number of nodes dissected. The rate of nodal metastasis (number of metastatic nodes/number of dissected nodes) was similar between the two groups (group V vs group T, 0.24 vs 0.24 in total nodes dissected, 0.24 vs 0.23 in mediastinal nodes dissected). The 3-year and 5-year recurrence-free survivals were similar (60.9% vs 49.6% and 60.9% vs 49.6%), as well. Most of the pattern of recurrence was due to remote metastasis. In like manner, the 3-year and 5-year survivals were similar (67.6% vs 57.7% and 45.4% vs 41.1%). This study demonstrates that VMPR with SND is a feasible surgical therapy for cN0-pN2 NSCLC without loss of curability. It is unnecessary to convert the VATS approach to thoracotomy in order to do SND even if pN2 disease is revealed during VMPR.

P2-173: Induction chemotherapy versus induction chemoradiotherapy for pathological N2 non-small cell lung cancer

P2-173: Induction chemotherapy versus induction chemoradiotherapy for pathological N2 non-small cell lung cancer