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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 73 months. 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. CONCLUSIONS: 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.

Adjuvant therapy following induction therapy and surgery improves survival in N2-positive non-small cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate treatment strategies and factors influencing overall survival (OS) and disease-free survival (DFS) in resectable, non-small cell lung cancer (NSCLC) with mediastinal (N2) lymph node metastasis. METHODS: All patients undergoing surgery for NSCLC with N2 disease between 2006 and 2016 were included. Treatment approaches included surgery only, neoadjuvant therapy followed by surgery, surgery followed by adjuvant therapy, and neoadjuvant therapy followed by surgery and adjuvant therapy (triple therapy). Patient clinical and pathologic data were retrospectively collected. RESULTS: A total of 281 patients were included in the study. In total, 209 patients had neoadjuvant therapy, 47.4% of which went on to received additional adjuvant therapy. The pathologic complete response rate was 12.9%. The treatment strategy which included triple therapy was isolated as a significant contributor to improved OS and DFS. Nodal downstaging (N0) after induction therapy conferred an OS benefit (38.3% vs. 15.6%, p = .03). Patients with single-station N2 disease experienced higher DFS. Video-assisted thoracic surgery (VATS) lobectomy completion rates were higher at the end of the study period compared to the beginning (p < .001). CONCLUSIONS: Patients who undergo neoadjuvant therapy for N2-positive NSCLC may benefit from additional adjuvant therapy. Single-station N2 disease confers higher DFS. VATS completion rates for lobectomy increase as experience increases.

Outcomes of initial surgery in patients with clinical N2 non-small cell lung cancer who met 4 specific criteria.

PURPOSE: The role of surgery for patients with non-small cell lung cancer (NSCLC) with clinical mediastinal lymph node metastasis (N2) remains controversial. We specified 4 criteria for performing initial surgery in these patients (single-station N2, non-bulky N2, N2 with regional mode of spread, and N2 without N1) and examined the outcomes to validate the treatment options. METHODS: Between September 2002 and December 2010, of 1290 patients who underwent complete resection for NSCLC, 808 patients underwent initial standard resection, including 779 patients with cN0-1 and 29 with cN2. We compared the outcomes, and evaluated patients with cN2-pN2. RESULTS: The median follow-up was 45.5 months (3-119 months). Seventy (9.0 %) and 24 (82.8 %) patients had p-N2 in the cN0-1 and cN2 groups, respectively (p < 0.0001). The 5-year disease-free survival (DFS) rates in the cN0-1 and cN2 groups were 73.3 and 50.6 %, respectively (p = 0.0053), and the 5-year overall survival (OS) rates were 81.3 and 71.1 %, respectively (p = 0.051). The 5-year DFS and OS of patients with cN2-pN2 were 52.5 and 72.6 %, respectively. CONCLUSIONS: Patients with clinical N2 disease based on our criteria represent a highly specific group with a favorable prognosis. Resection should therefore be the initial treatment for these patients.

Surgical outcomes after initial surgery for clinical single-station N2 non-small-cell lung cancer.

OBJECTIVE: Single-station N2 (Stage IIIA) non-small-cell lung cancer has been reported to have a relatively favorable prognosis after surgery. However, most previous studies examined surgical outcomes in N2 disease by pathologic nodal status but not by clinical nodal status. The objective of this study was to clarify the surgical outcomes in clinical single-station N2 non-small-cell lung cancer patients. METHODS: A total of 125 consecutive patients with clinical single-station N2 non-small-cell lung cancer were treated in our institution between 1992 and 2008. Among them, 97 (78%) patients underwent thoracotomy, and were included in this retrospective study. We defined clinical single-station N2 node as a node measuring 1-2 cm in a single mediastinal station observed on contrast-enhanced computed tomography. The median follow-up period was 5.9 years (range, 1.8-12.6). RESULTS: Eighty-eight (91%) patients underwent lung resection. Of them, 17 (19%) had true (pathologic) single-station N2 disease. Twenty-eight (32%) had pathologic multistation N2 and 43 (49%) had pN0-1 disease with favorable prognoses. The overall survival of the clinical single-station N2/pathologic N2 patients after initial surgery was unsatisfactory with a 5-year overall survival of 23.6%, but their prognoses were heterogeneous. True single-station pathologic N2 status (hazard ratio = 0.35, P = 0.008) and negative subcarinal node status (hazard ratio = 0.34, P = 0.022) were independent favorable prognostic factors after initial resection for clinical single-station N2/ pathologic N2 patients. The patients with both factors revealed a relatively favorable 5-year overall survival of 43.8%. CONCLUSION: Clinical single-station N2 status does not always correspond with pathologic true N2 status. From a prognostic point of view, initial surgery for clinical single-station N2 patients is indicated if their true single-station N2 status and negative subcarinal involvement are preoperatively confirmed.

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.

The Significance of Skip Mediastinal Lymph Node Metastasis in the Prognosis of Patients with Resected Non-Small-Cell Lung Carcinoma: Is It Really a Better N2 Disease Subtype?

OBJECTIVE: In this study, we aimed to reveal the prognostic differences between skip and non-skip metastasis mediastinal lymph node (MLN) metastasis. METHODS: A total of 202 patients (179 males and 23 females; mean age, 59.66 ± 9.89 years; range: 29-84 years) who had ipsilateral single-station MLN metastasis were analyzed in two groups retrospectively between January 2009 and December 2017: "skip ipsilateral MLN metastasis" group (sN2) (n = 55,27.3%) [N1(-), N2(+)], "non-skip ipsilateral MLN metastasis" group (nsN2) (n = 147,72.7%) [N1(+), N2(+)]. RESULTS: The mean follow-up was 42.63 ± 34.91 months (range: 2-117 months). Among all patients, and in the sN2 and nsN2 groups, the median overall survival times were 63.5 ± 4.56, 68.8 ± 7, and 59.3 ± 5.35 months, respectively, and the 5-year overall survival rates were 38.2%, 46.3%, and 36.4%. CONCLUSION: Skip metastasis did not take its rightful place in TNM classification; thus, further studies will be performed. To detect micrometastasis, future studies on skip metastasis should examine non-metastatic hilar lymph nodes (LNs) through staining methods so that heterogeneity in patient groups can be avoided, that is, to ensure that only true skip metastasis cases are included. Afterwards, more accurate and elucidative studies on skip metastasis can be achieved to propound its prognostic importance in the group of N2 disease.

How Effective Is Neoadjuvant Therapy Followed by Surgery for Pathologic Single-Station N2 Non-Small Cell Lung Cancer?

The optimal treatment strategy for pathologic single-station N2 (pN2a1) non-small cell lung cancer (NSCLC)-surgery first followed by adjuvant treatment (SF) or neoadjuvant therapy followed by surgery (NS)-remains unclear. We compared disease-free survival (DFS) and overall survival (OS) after NS versus SF for pN2a1 NSCLC. We retrospectively identified patients with pN2a1 NSCLC resected between 2000 and 2018. Patients in the SF group had cN0 disease and were treated with surgery before adjuvant chemotherapy; patients in the NS group had known preoperative nodal disease, cN2 disease, and were treated with neoadjuvant therapy before surgery. The matching-weights procedure was applied to generate a cohort with similar characteristics between groups. DFS and OS were calculated using the Kaplan-Meier approach and compared between groups using weighted log-rank test and Cox proportional hazards models. We identified 227 patients with pN2a1 disease: 121 treated with SF and 106 with NS. After the matching-weights procedure, 5- and 10-year DFS were 45% and 27% for SF versus 26% and 21% for NS (log-rank P = 0.056; hazard ratio [HR], 1.61; 95% confidence interval [CI], 0.98-2.65); 5- and 10-year OS were 49% and 30% for SF versus 43% and 20% for NS (log-rank P = 0.428; HR, 1.24; 95% CI, 0.67-2.28). SF and NS for pN2a1 NSCLC resulted in similar survival. A study comparing SF for known preresectional pN2a1 with occult pN2a1 disease could be a next step. Further investigation of SF for known N2a1 versus occult pN2a1 disease could power a clinical trial focused on N2a NSCLC.

Validation of the Proposed cN2 Subclassification in the Eighth Edition of the IASLC Staging System: A Prospective Phase II Multicenter Study.

INTRODUCTION: Surgery for N2 stage IIIA NSCLC is not recommended in major guidelines. Nevertheless, it has been noted that single-station N2 may have a better prognosis than multistation N2 and that surgery can be performed as the main therapeutic option. METHODS: We conducted a prospective phase II study for single-station clinical N2 (cN2) NSCLC to evaluate the efficacy and safety of surgical resection without induction therapy. Complete resection with lobectomy, bilobectomy, or pneumonectomy followed by ipsilateral mediastinal lymphadenectomy was performed in 32 of 34 enrolled patients, whereas the remaining two patients underwent incomplete resection. Three-quarters of the patients underwent subsequent adjuvant chemotherapy. RESULTS: The 5-year overall survival rate was 58.5% (95% confidence interval: 41.9-75.4) for all 34 patients, and eight patients (23.5%) with pN0 or pN1 seemed to have been enrolled. The 5-year overall survival rates for single-station cN2 without and with hilar node enlargement were 81.3% and 37.5%, respectively (p = 0.025). Surgical mortality was 0% for all, and no considerable perioperative complications were noted; however, two patients died of interstitial pneumonia and unknown cause within 3 months after surgical resection. CONCLUSIONS: This is the very first prospective study on the surgical approach for cN2 NSCLC, and our result partially validated the proposed classification of the N descriptor in the new staging system. The treatment for single-station cN2 without hilar node enlargement would better if it were similar to that for cN1 disease. Induction chemotherapy or chemoradiotherapy may not be needed for such an entity.

Is the prognosis of occult N2 disease similar to that of positive positron emission tomography-computed tomography (PET/CT) scan single-station N2 disease in patients with non-small cell lung cancer treated by surgical resection?

OBJECTIVE: A retrospective study, using a prospective database, was conducted on patients treated with surgery in order to analyze the prognosis between two groups: NSCLC (non-small cell lung cancer) patients with occult N2 disease and patients with single station N2 disease observed on pre-operative integrated PET/CT scan. METHODS: A total of 772 patients underwent surgical treatment for lung cancer from January 2007 to December 2014. All of them had an integrated PET/CT scan in the pre-operative work-up and a pulmonary resection plus mediastinal lymphadenectomy were performed in all cases. In the selected cases, no one received induction treatment. All patients from both groups had N2 disease after examination of the histopathology specimen. Clinical and pathological characteristics, disease free survival, and overall survival, were analyzed in both groups. RESULTS: A total of 34 cases presented occult N2 disease, whereas 11 cases showed single station N2 disease on pre-operative PET/CT scan. Mean disease free survival and mean overall survival for occult N2 disease compared to single-station N2 disease on PET/CT scan was 36.0 months (95% CI: 24.9-47.1) and 38.9 months (95% CI: 20.6-57.1), p=.586; and 52.3 months (95% CI: 38.9-65.7) and 38.2 months (95% CI: 21.9-54.5), p=.349, respectively. CONCLUSION: The prognosis of patients with single-station N2 disease on PET/CT scan treated by surgical resection and mediastinal lymphadenectomy as first line treatment was similar to those with occult N2 disease. More studies are needed to support our findings.