Impact of skip mediastinal lymph node metastasis on outcomes after resection for primary lung cancer.

OBJECTIVES: Patients with non-small cell lung cancer and nodal disease are a heterogeneous group with varied patterns of disease. The aim of this study was to assess long-term outcomes of patients with skip N2 disease in comparison to those with N1 or non-skip N2 disease. MATERIALS AND METHODS: A retrospective review of 445 patients undergoing anatomical lung resection for primary lung cancer between 2012 and 2019 with post-operative histological confirmation of nodal disease was undertaken. Log rank analysis was used to assess differences in estimated median overall survival according to nodal status. Multivariable Cox regression analysis was performed to determine whether skip N2 disease was independently associated with overall survival. RESULTS: Mean patient age was 67.0 years (standard deviation ± 9.2 years) and 48.1% (n = 214) were male. In total, 20.7% (n = 92) of patients had N1 disease, 32.1% (n = 143) had skip N2 disease and 47.2% (n = 210) had non-skip N2 disease. Post-operative upstaging took place in 33.0% (n = 147) of patients. Median follow-up time was 35 months (interquartile range 14-68 months). Skip N2 patients had significantly longer estimated median overall survival in comparison to their non-skip N2 counterparts (47 months vs 28 months, log rank analysis p = 0.029) and non-skip N2 disease remained independently associated with reduced overall survival after multivariable analysis (hazard ratio 1.421, 95% confidence interval 1.060-1.907, p = 0.019). CONCLUSION: Skip N2 disease is a positive prognostic factor for patients with N2 lung cancer, suggesting that lung cancer staging guidelines should consider separating N2 disease into additional subgroups in order to improve prognostic accuracy.

Minimally invasive surgery vs. open thoracotomy for non-small-cell lung cancer with N2 disease: a systematic review and meta-analysis.

Background: This meta-analysis aimed to investigate the effectiveness and safety of minimally invasive surgery [MIS, including robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS)] and open thoracotomy (OT) for non-small cell lung cancer (NSCLC) patients with N2 disease. Methods: We searched online databases and studies from the creation of the database to August 2022, comparing the MIS group to the OT group for NSCLC with N2 disease. Study endpoints included intraoperative outcomes [e.g., conversion, estimated blood loss (EBL), surgery time (ST), total lymph nodes (TLN), and R0 resection], postoperative outcomes [e.g., length of stay (LOS) and complication], and survival outcomes [e.g., 30-day mortality, overall survival (OS), and disease-free survival (DFS)]. We estimated outcomes using random effects meta-analysis to account for studies with high heterogeneity (I2 > 50 or p < 0.05). Otherwise, we used a fixed-effect model. We calculated odds ratios (ORs) for binary outcomes and standard mean differences (SMDs) for continuous outcomes. Treatment effects on OS and DFS were described by hazard ratio (HR). Results: This systematic review and meta-analysis of 15 studies on MIS vs. OT for NSCLC with N2 disease included 8,374 patients. Compared to OT, patients that underwent MIS had less estimated blood loss (EBL) (SMD = - 64.82, p < 0.01), shorter length of stay (LOS) (SMD = -0.15, p < 0.01), higher R0 resection rate (OR = 1.22, p = 0.049), lower 30-day mortality (OR = 0.67, p = 0.03), and longer overall survival (OS) (HR = 0.61, P < 0.01). The results showed no statistically significant differences in surgical time (ST), total lymph nodes (TLN), complications, and disease-free survival (DFS) between the two groups. Conclusion: Current data suggest that minimally invasive surgery may provide satisfying outcomes, a higher R0 resection rate, and better short-term and long-term survival than open thoracotomy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022355712.

Upfront surgery for N2 NSCLC: a large retrospective multicenter cohort study.

BACKGROUND: The optimal sequence and combination of surgery, chemotherapy and radiotherapy in patients with N2 non-small cell lung cancer (NSCLC) remain undefined. The aim of our study was to compare two treatment options for N2 NSCLC-induction therapy with subsequent surgery versus upfront surgery with adjuvant treatment. METHODS: We retrospectively reviewed 405 patients with N2 disease in two centers, between January 2010 and December 2016. They were divided into two groups: the Induction Group, composed of patients who received neoadjuvant chemotherapy, and the Upfront surgery Group, composed of patients who underwent surgery as first-line therapy. Propensity score-matched (PSM) analysis was performed, and 52 patients were included in each group. Primary endpoints were: recurrence, overall survival (OS) and disease-free survival (DFS). RESULTS: After the PSM, no differences were observed in general characteristics, perioperative results, rates and severity of complications, and histopathology results. Seventeen patients (32.7%) of the induction group and 21 (40.4%) of the upfront surgery group had mediastinal lymph nodal involvement with skipping (p = 0.415). Recurrence rate was not different between the two groups (57.7% vs 50.0%, p = 0.478). No differences were observed in terms of OS (40.98 ± 35.78 vs 37.0 ± 40.69 months, p = 0.246) and DFS (29.67 ± 36.01 vs 27.96 ± 40.08 months, p = 0.697). The multivariable analysis identified the pT stage and skipping lymph node metastasis as independent predictive factors for OS. CONCLUSIONS: Upfront surgery followed by adjuvant therapy does not appear inferior in terms of recurrence, OS and DFS, compared to induction chemotherapy with subsequent surgery.

Reaching multidisciplinary consensus on the management of non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer.

INTRODUCTION: The optimal management of patients with non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer (NSCLC) remains controversial. In this modified Delphi study from France, we aimed to generate agreement through multidisciplinary decision-making on the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC. METHODS: An expert panel of 30 physicians from different specialities completed two Delphi rounds of a 76-item questionnaire, pertaining to: pathological confirmation of N2 disease; initial treatment approach; treatment approach in case of disease progression/stability following neoadjuvant chemotherapy; treatment approach taking into account various patient and tumour characteristics. Each questionnaire item was scored using a 9-point Likert scale. Consensus in agreement was achieved if ≥ 80 % of responses to a questionnaire item were scored between 7 and 9 and if the median value of the score to the item was ≥ 7. RESULTS: Regarding the pathologic confirmation of N2 disease, agreement (up to 100 %) was reached on endobronchial ultrasound/endoscopic ultrasound as the preferred method of initial mediastinal staging for paratracheal lymph nodes. There was also panellist agreement (up to 93 %) on the adoption as first-line treatment of surgery and (neo)adjuvant chemotherapy in patients with single-station disease, and of concurrent chemoradiotherapy followed by adjuvant immunotherapy in those with multi-station N2 disease. Panellists further agreed on the use of a non-surgical strategy, i.e., concurrent chemoradiotherapy with adjuvant immunotherapy, in patients with single-station N2 disease in case of: involvement of ≥ 2 mediastinal lymph nodes; disease progression following neoadjuvant chemotherapy; compromised cardiopulmonary function if compatible with radiotherapy; anticipated right pneumonectomy. CONCLUSIONS: This Delphi study reinforces the importance of multidisciplinary discussions leading to the best individual approach to the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC, a challenging heterogeneous population.

Integral mediastinal staging in patients with NON-SMALL cell lung cancer and risk factors for occult N2 disease.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), the presence of abnormal hiliar lymph nodes (clinical N1; cN1), central tumor location and/or tumor size (diameter >3 cm) increases the risk of occult mediastinal metastasis (OMM). This study investigates prospectively the diagnostic value of an integral mediastinal staging (IMS) strategy that combines EndoBronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) and Video-Assisted Mediastinoscopy (VAM) in patients with NSCLC at risk of OMM. METHODS: Patients with NSCLC and radiologically normal mediastinum assessed non-invasively by positron emission tomography and computed tomography of the chest (PET-CT), and OMM risk factors (cN1, central tumor and/or >3 cm) underwent EBUS-TBNA followed by VAM if the former was negative. Those with negative IMS underwent resection surgery of the tumor. RESULTS: EBUS-TBNA identified OMM in 2 out of the 49 patients evaluated (4%) and VAM in 1 of the 47 patients with negative EBUS (2%). Two patients with a negative IMS had OMM at surgery. Overall, the prevalence of OMM was 10%. EBUS-TBNA has a sensitivity of 40%, a negative predictive value (NPV) of 93.6%, and negative likelihood ratio of 0.60 (95%CI:0.30-1.16). The risk of not diagnosing OMM after EBUS was 6% and after IMS was 4.4%. CONCLUSION: Integral mediastinal staging in patients with NSCLC and clinical risk factors for OMM, does not seem to provide added diagnostic value to that of EBUS-TBNA, except perhaps in patients with cN1 disease who deserve further research.

Does mediastinal lymph node involvement influence the surgical outcome in malign pleural mesothelioma?

BACKGROUND: This study examined the effect of metastatic mediastinal lymph node involvement on the prognosis of patients with malignant pleural mesothelioma (MPM) who underwent extrapleural pneumonectomy (EPP) or extended pleurectomy (E/P) and also to assess the effect of metastatic mediastinal lymph node involvement on the prognosis of patients with MPM in these group of patients. METHODS: This retrospective study included 84 patients with MPM (66 men [78.6%] and 18 women [21.4%]) who underwent EPP (n = 44) or E/P (n = 40) at our institution between January 2001 and July 2019. Survival analyses were performed according to histopathology, nodal status, and surgical approach. RESULTS: In the EPP group, patients with T2-N2 status had a significantly better mean survival (17 ± 2.1 months) than patients with T3-N2 (7.3 ± 1.6 months) or T4-N2 (3.2 ± 1.1 months) status (p = .001). In the E/P group, patients with T2-N2 status had a mean survival of 18 ± 1.1 months, while patients with T3-N2 and T4-N2 status had mean survival durations of 6.6 ± 1.6 and 4.8 ± 1.2 months, respectively (p = .159). In both treatment groups, the survival rates of patients with epithelial tumors were better than those of patients with non-epithelial tumors, independent of N status. None of the patients with N2 disease survived until 5 years postoperatively. CONCLUSION: In summary, our results suggested that mediastinal lymph node metastasis negatively influenced the prognosis of patients with T3 MPM, regardless of treatment by EPP or E/P. Under these circumstances, preoperative cervical mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration may be considered for patients with high-stage MPM who are scheduled for surgery with curative intent. In our study, N2 status was spotted as a significant factor affecting survival, nevertheless its significance in survival of pleural mesothelioma patients should be analyzed in multi-centered studies.

Impact of fibrinogen levels and modified Glasgow prognostic score on survival of stage III/N2 non-small cell lung cancer patients treated with neoadjuvant therapy and radical resection.

PURPOSE: The prognostic value of pretreatment and preoperative fibrinogen plasma levels and the modified Glasgow prognostic score (mGPS) in stage III/N2 non-small cell lung cancer (NSCLC) patients who receive neoadjuvant treatment followed by radical surgery is yet unclear. METHODS: Fibrinogen levels and mGPS of 84 patients with initial stage III/N2 NSCLC, who received neoadjuvant therapy followed by complete surgical resection from 2002 to 2014 were retrospectively analyzed and correlated with clinical parameters and overall survival (OS). Data were analyzed using log-rank and Cox regression analysis adjusted for clinical and pathological factors. RESULTS: Median serum fibrinogen level after neoadjuvant treatment was 439 mg/dL (IQR 158 mg/dL). Elevated fibrinogen levels (> 400 mg/dL) after neoadjuvant treatment were significantly associated with poorer OS (28.2 months vs. 60.9 months, HR 0.562, p = 0.048). Importantly, a decrease in fibrinogen levels after neoadjuvant treatment (n = 34) was found to be an independent predictor for favorable OS in multivariate analysis (HR 0.994, p = 0.025). Out of 80 patients, 55, 19 and 6 patients had a mGPS of 0, 1 and 2, respectively. Moreover, elevated mGPS after neoadjuvant treatment (mGPS 1-2) showed a non-significant trend for poorer OS compared to mGPS 0 (28.2 vs. 46.5 months, HR 0.587, p = 0.066). CONCLUSION: Elevated fibrinogen levels after neoadjuvant therapy prior to surgery in stage III/N2 NSCLC patients are associated with significant disadvantage for OS. A decrease in fibrinogen levels after neoadjuvant therapy was found to be a predictor for superior OS in this retrospective patient cohort.

Oncological outcomes following minimally invasive surgery for pathological N2M0 colorectal cancer: A propensity score-matched analysis.

INTRODUCTION: Whether minimally invasive surgery (MIS) is safe and effective for patients with N2M0 colorectal cancer (CRC) remains controversial. This study aimed to compare short- and long-term outcomes between MIS and open surgery (Open) groups for patients with pathological (p)N2M0 CRC, and evaluate the oncological outcomes of MIS for pN2M0 CRC. MATERIALS AND METHODS: We retrospectively analyzed 125 consecutive patients with pN2M0 CRC who underwent curative surgery between 2010 and 2017, using propensity score-matching (PSM) analysis. RESULTS: Median follow-up was 59.4 months. After PSM, we enrolled 68 patients (n = 34 in each group). The conversion rate was 9.6% for the entire patient cohort and 5.9% for the matched cohort. In colon cancer (CC), short-term outcomes were similar between groups. On the other hand, in rectal cancer (RC), estimated blood loss, rate of anastomosis leakage, and length of postsurgical stay were lower in the MIS group than the Open group. R0 resection was achieved in all patients with MIS. No surgical mortality was encountered in any group. No significant differences were found between groups in terms of 3-year local recurrence rate, overall survival, cancer-specific survival, or recurrence-free survival among the entire patient cohort or the matched cohort, regardless of the primary tumor site (CC or RC). Surgical approach (MIS vs Open) had no significant influence on survival outcomes. CONCLUSIONS: MIS is a safe and effective option for patients with pN2M0 CRC, with acceptable short- and long-term outcomes comparable to the open approach. MIS can be considered for patients with pN2M0 CRC.

Neoadjuvant chemoradiotherapy is superior to chemotherapy alone in surgically treated stage III/N2 non-small-cell lung cancer: a retrospective single-center cohort study.

BACKGROUND: There is lack of consensus whether neoadjuvant chemoradiotherapy (CHT/RT) is superior to neoadjuvant chemotherapy (CHT) alone in patients with potentially resectable stage III/N2 non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively evaluated clinical parameters and outcomes in patients with clinical stage III/N2 NSCLC treated with neoadjuvant CHT/RT versus CHT followed by surgery. Nearest-neighbor propensity score (PS) matching was used to correct for pretreatment differences. RESULTS: A total of 84 patients were enrolled. Thirty-four (40%) and 50 (60%) patients received CHT/RT or CHT followed by curative-intent surgery, respectively. Overall 90-day mortality and morbidity were 0% versus 0.04% and 21% versus 18%, respectively, with no significant difference between the CHT/RT and the CHT-alone cohorts (P = 0.51 and P = 0.70). In the PS-matched cohort, complete pathological response was recorded in 25% after CHT/RT versus 0% after CHT at the time of surgery. Patients receiving neoadjuvant CHT/RT exhibited significantly better 5-year disease-free survival (DFS) [45% versus 16% CHT group; hazard ratio (HR) 0.43, P = 0.04]; 5-year overall survival (OS) was 75% after CHT/RT and 21% after CHT (HR 0.37, P = 0.001). CHT/RT more often induced pathological mediastinal downstaging (P = 0.007), but CHT/RT remained the only independent factor for DFS and OS and did not depend on mediastinal downstaging. CONCLUSIONS: In this retrospective PS-matched long-term analysis, neoadjuvant CHT/RT conferred improved DFS and OS compared with CHT alone in stage III/N2 NSCLC. These highly challenging results require confirmation in well-designed randomized controlled trials conducted at highly specialized thoracic oncology centers.

Importance of tumor size in resectable stage III-N2 non-small cell lung cancer.

OBJECTIVE: The 8th TNM edition classifies stage III-N2 disease as IIIA and IIIB based on a tumor size cutoff of 5 cm. However, the importance of tumor size on survival in patients with resectable stage III-N2 disease has not been analyzed systematically. METHODS: Survival analysis based on tumor size (>5 cm vs ≤ 5 cm) for 255 consecutive patients with nonbulky (maximal lymph node diameter of 1.5 cm) stage III-N2 non-small cell lung cancer treated with surgery in our institution. RESULTS: Ninety patients (35.3%) underwent induction chemoradiation therapy (n = 72, 28%) or induction chemotherapy (n = 18, 7%), and 165 patients underwent primary surgery followed by adjuvant chemotherapy (n = 52, 32%), adjuvant chemoradiation therapy (n = 47, 29%), or adjuvant radiation therapy (n = 14, 13.2%). After a median follow-up of 6.5 years, the overall survival was 46.5% at 5 years and 28.9% at 10 years. In tumors 5 cm or less, there was no difference in survival between patients treated with induction or adjuvant therapy. However, in tumors greater than 5 cm, the survival was significantly better after induction therapy compared with adjuvant therapy or surgery alone. Pathologic multi-station N2 disease was more frequently detected in tumors greater than 5 cm (31% vs 18% in tumors ≤5 cm, P = .042), and the rate of R1 resection was lower after induction therapy (2.2% vs 8.5% in primary surgery, P = .048). CONCLUSIONS: These results support the redefinition of tumors greater than 5 cm with resectable N2 disease to stage IIIB. This change should help to refine the multimodality approach for stage III-N2 lung cancer.

Postoperative radiotherapy for patients with completely resected stage IIIA-N2 non-small cell lung cancer: opt-in or opt-out.

The role of adjuvant radiotherapy in completely resected pIIIA-N2 non-small cell lung cancer (NSCLC) has long been debated. Evidence from previous retrospective and prospective studies showed that postoperative radiotherapy could reduce the incidence of local recurrence and prolong disease-free survival, while two recently reported randomized controlled trials (lung ART and PORT-C) both demonstrated no survival benefit of postoperative radiotherapy. The great gap between our knowledge and reality has made us rethink the value of postoperative radiotherapy. In this mini review, we elaborate on the role of postoperative radiotherapy in completely resected pIIIA-N2 NSCLC.

Utility of PET-CT in non-small cell lung cancer clinical stage IB-IIA according to AJCC 8th edition staging system: an alternative to invasive mediastinal staging?

OBJECTIVE: Mediastinal nodal staging in lung cancer is essential to determine treatment strategy and prognosis. There are controversies as to whether a mediastinal negative result in PET-CT may spare the invasive staging of the mediastinum. The main endpoint is to evaluate the negative predictive value (NPV) of PET-CT in non-small cell lung cancer (NSCLC) clinical stage IB-IIA without clinical nodal involvement. The secondary endpoint is to evaluate the prevalence of mediastinal and hilar nodal affection in this population. METHODS: We performed an observational descriptive study from January 2010 to January 2020, including 76 patients with clinical stage IB-IIA, who underwent pulmonary resection with systematic nodal sampling (pre-determined lymph node stations based on tumour location) for primary NSCLC. Clinically, nodal involvement was defined as any lymph node greater than 1 cm in the short axis on a CT or with metabolic uptake greater than 2.5 SUV on PET-CT. The prevalence of nodal metastases was recorded. RESULTS: Fifty six patients had clinical stage IB and 20 had clinical stage IIA. Mean tumour size was 3.74 ± 0.5 cm. Lobectomy was the resection procedure most frequently performed. Of the 76 patients with clinical N0 by PET-CT who underwent surgical resection, 10 (13.1%) were upstaged to pN1 and none were upstaged to pN2. NPV of PET-CT for overall nodal metastasis was 87% (95% CI: 0.79-0.94). NPV of PET-CT for N2 metastasis was 100%. CONCLUSION: PET-CT might be an alternative to invasive mediastinal staging in patients with NSCLC clinical stage IB-IIA who are surgical candidates. Further prospective multi-institutional studies are necessary to verify the external validity of our study.

Perioperative safety and feasibility outcomes of stage IIIA-N2 non-small cell lung cancer following neoadjuvant immunotherapy or neoadjuvant chemotherapy: a retrospective study.

BACKGROUND: We sought to determine the perioperative safety and feasibility outcomes of stage IIIA (N2) non-small cell lung cancer (NSCLC) following neoadjuvant immunotherapy or neoadjuvant chemotherapy. METHODS: The clinical details of patients who attended the Affiliated Hospital of Qingdao University between January 2019 and December 2020 were retrospectively evaluated. Eligible patients had pathologically proven stage IIIA (N2) NSCLC and were randomly prescribed neoadjuvant therapy. Those in the neoadjuvant immunotherapy group received two cycles of nivolumab (3 mg/kg) and those in the control group received neoadjuvant chemotherapy (1,000 mg/m2 gemcitabine and 80 mg/m2 cisplatin). All patients were scheduled to undergo surgery. The primary endpoint was the risk of major complications within 30 days of surgery and the secondary endpoints were interval to surgery and 30-day mortality. RESULTS: A total of 107 eligible patients were evaluated of whom 25 were allocated to the neoadjuvant immunotherapy group and 82 to the neoadjuvant chemotherapy group. The median interval to surgery was similar in the two groups at 29.2 days [95% confidence interval (CI), 27.1 to 31.4 days] in the immunotherapy group and 28.7 days (95% CI, 27.6 to 29.8 days) in the chemotherapy group (P=0.656). While treatment-related adverse events were reported in most patients, all 25 patients completed two cycles of neoadjuvant immunotherapy and 80 of 82 patients completed two cycles of neoadjuvant chemotherapy, although one patient in the latter group died within 30 days of surgery. There was no statistically significant difference between the groups in the probability of grade 3 or higher postoperative complications within 30 days after surgery (P=0.757). CONCLUSIONS: Most patients achieved the primary and secondary endpoints of the study. However, the major pathological response (MPR) showed statistically significant differences between the neoadjuvant immunotherapy and neoadjuvant chemotherapy groups.

Postoperative long-term survival of non-small cell lung cancer patients with skip-N2 metastases.

OBJECTIVE: Radical lymphadenectomy is crucial in operations for non-small cell lung cancer (NSCLC). Usually pN1 and pN2 lymph nodes are affected consecutively (N1N2). Nevertheless, pN2 metastases may also occur in the absence of pN1 as skip-N2 metastases (N0N2). Here we compare the long-term survival of N1N2- and N0N2 patients. MATERIALS AND METHODS: 464 patients underwent surgery for NSCLC at our institution between 2012 and 2017. We retrospectively reviewed data of pN2 stage patients (n = 68). Patients with N1N2 (n = 39) were compared to N0N2 (n = 29) patients. 1-, 3-and 5-year survival rates were measured. Survival was assessed by Kaplan-Meier curves and the cox proportional hazards model was used to identify prognostic factors for overall survival. All patients received adjuvant chemoradiation therapy according to European guidelines. RESULTS: The baseline characteristics did not differ between groups. We observed no differences in the histology, localization, or gender in our cohort. N0N2 patients showed significantly better 1- (N1N2: 82.4% vs. N0N2 100%; p = 0.001), 3- (14.7% vs. 63.6%; p=<0.001) and 5-year (9.4% vs. 43.8%; p = 0.001) survival rates. Tumor size (Hazard ratio (HR) 1.46, Confidence interval (CI 95%) 1.03-2.04; p = 0.03) and the occurrence of N1N2 (HR 4.26, CI 2.04-8.91; p < 0.0001) were independent prognostic factors for worse long-term survival. The Kaplan-Meier curves showed a reduced overall survival for N1N2 patients (log-rank N1N2, N0N2 p < 0.0001). CONCLUSION: N1N2 patients have a significantly worse prognosis compared to N0N2 patients. This will aid to classify the heterogeneous pN2-NSCLC patient population more precisely. Further, multimodal therapy should be considered for N1N2 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.

Minimal invasive surgery in locally advanced N2 non-small cell lung cancer.

Locally advanced lung cancer, defined by nodal involvement in upper mediastinal stations (N2) (stage IIIA-N2), includes a wide spectrum of patients with multiple therapeutic alternatives. Such heterogeneity is explained, at least in part, by tumor size and magnitude of mediastinal nodal involvement. In this setting, many variants can influence the prognosis, such as the specific nodal stations compromised, the burden of mediastinal disease, and the presence of skip metastasis. In the surgical field, the advent of minimally invasive techniques, including video-assisted thoracoscopic and robotic surgery, have revolutionized the management of early-stage lung cancer, but implementations of these approaches in the locally advanced setting have been erratic. This review attempts to highlight the most relevant scientific data of the surgical management of locally advanced lung cancer patients, analyzing not only the medical evidence but also the cost-effectiveness and accessibility.

High-dose neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery in potentially-resectable stage IIIA-N2 NSCLC. A multi-institutional retrospective study by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

BACKGROUND: The optimal induction treatment in potentially-resectable stage IIIA-N2 NSCLC remains undefined. AIM: To compare neoadjuvant high-dose chemoradiotherapy (CRT) to neoadjuvant chemotherapy (CHT) in patients with resectable, stage IIIA-N2 non-small-cell lung cancer (NSCLC). METHODS: Retrospective, multicentre study of 99 patients diagnosed with stage cT1-T3N2M0 NSCLC who underwent neoadjuvant treatment (high-dose CRT or CHT) followed by surgery between January 2005 and December 2014. RESULTS: 47 patients (47.5%) underwent CRT and 52 (52.5%) CHT, with a median follow-up of 41 months. Surgery consisted of lobectomy (87.2% and 82.7%, in the CRT and CHT groups, respectively) or pneumonectomy (12.8% vs. 17.3%). Nodal downstaging (to N1/N0) and Pathologic complete response (pCR; pT0pN0) rates were significantly higher in the CRT group (89.4% vs. 57.7% and 46.8% vs. 7.7%, respectively; p < 0.001)). Locoregional recurrence was significantly lower in the CRT group (8.5% vs. 13.5%; p = 0.047) but distant recurrence rates were similar in the two groups. Median PFS was 45 months (CHT) vs. "not reached" (CRT). Median OS was similar: 61 vs. 56 months (p = 0.803). No differences in grade ≥3 toxicity were observed. On the Cox regression analysis, advanced pT stage was associated with worse OS and PFS (p < 0.001) and persistent N2 disease (p = 0.002) was associated with worse PFS. CONCLUSIONS: Compared to neoadjuvant chemotherapy alone, a higher proportion of patients treated with preoperative CRT achieved nodal downstaging and pCR with better locoregional control. However, there were no differences in survival. More studies are needed to know the optimal treatment of these patients.

Skip N2 Metastasis in Pulmonary Adenocarcinoma: Good Prognosis Similar to N1 Disease.

INTRODUCTION: The prognostic effect and mechanism of skip N2 lung cancer remain unclear. Our study aimed to elucidate the influence of skip N2 on overall survival (OS) and disease-free survival (DFS) compared with N1 and non-skip N2 in patients with lung adenocarcinoma. PATIENTS AND METHODS: Patients with lung adenocarcinoma and lymph node involvement between May 2011 and December 2015 were retrospectively analyzed. The outcomes of skip N2 patients were compared with N1 and non-skip N2 patients. Prognosis was further investigated according to the N status in different adenocarcinoma subtypes. Univariate and multivariate analyses were carried out to define independent risk factors for OS and DFS. RESULTS: A total of 456 patients with lung adenocarcinoma, 169 with N1 disease, 81 with skip N2 disease, and 206 with non-skip N2 disease, were enrolled in this study. All tumors were invasive adenocarcinoma, and the predominant subtypes were acinar in 252, papillary in 42, solid in 119, micropapillary in 20, and invasive mucinous adenocarcinoma in 23 patients. The DFS and OS of N1 and skip N2 diseases were similar and significantly better than those of patients with non-skip N2 disease. The prognosis according to lymph node status was significantly different in acinar-predominant subtypes in terms of both OS and DFS. CONCLUSIONS: Skip N2 disease has a similar prognosis to N1 disease and is significantly better than that of non-skip N2 disease in relation to OS and DFS. Skip N2 has a prognostic advantage in patients with the acinar-predominant subtype.

Adherence to the mediastinal staging guideline and unforeseen N2 disease in patients with resectable non-small cell lung cancer: Nationwide results from the Dutch Lung Cancer Audit - Surgery.

OBJECTIVES: Invasive mediastinal staging is advised by guidelines in patients with resectable non-small cell lung cancer (NSCLC) and suspicious lymph nodes (cN1-3) or for central, FDG-non-avid or peripheral tumours >3 cm. Our objective was to assess current guideline adherence and consequent unforeseen N2 disease (uN2) in NSCLC patients having various indications for mediastinal staging. MATERIALS AND METHODS: We analysed the Dutch Lung Cancer Audit - Surgery data of all patients who underwent a primary lung resection with lymph node dissection for NSCLC in 2017-2018. Based on the 2015 ESTS-ERS-ESGE guideline we assessed the use of initial endosonography and confirmatory mediastinoscopy as well as uN2 rates. RESULTS: A total of 2238 patients were analysed. 43 % (95 %-CI: 41-45) underwent initial endosonography followed by a confirmatory mediastinoscopy in 44 % (95 %-CI:40-47) of them, resulting in a 19 % (95 %-CI: 17-20) rate of properly staged patient according to the guidelines. uN2 was demonstrated in 12.5 % (95 %-CI: 9.7-16.0) of correctly staged patients compared to 10.9 % (95 %-CI: 9.6-12.4) who were not (p = .36). The highest uN2 rate was found in cN1-3 patients who were not staged (23.0 %, 95 %-CI: 16.4-31.2) compared to 13.0 % (95 %-CI: 9.7-17.1) who were (p = .01). CONCLUSION: Guideline adherence in Dutch NSCLC patients with an indication for invasive mediastinal staging is poor. The highest uN2 rate was found in unstaged cN1-3 patients, suggesting that this subgroup may benefit from an appropriate staging conform guidelines.

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.