N2-positive Non-small Cell Lung Cancer Research Articles

Outcomes Of Surgically Treated N2-Positive Non-Small Cell Lung Cancer.

The role of surgery in the treatment of stage IIB/IIIA lung cancer is still a matter of debate. To assess the outcomes of N2-positive patients, we performed a retrospective 10-year study including all patients with histologically proven N2 disease submitted to lung resection surgery by the same surgical team in three different hospitals. Demographic, clinical, surgical and survival data were collected from patients' clinical registries. Patients were divided into groups according to evidence of neoadjuvant chemotherapy and number of positive N2 stations. Outcomes regarding survival time within and between groups were calculated and compared. Sixty-four patients were included in our study, with a mean age of 62,2 years. Surgery was performed by uniportal VATS in 43.8% of cases. A mean of 3 nodal stations were sampled and 35 patients (54.7%) had one single positive N2 station. Post-operative complications occurred in 27% of patients but no post-operative mortality was recorded. Twenty-seven patients (42.2%) were submitted to neoadjuvant chemotherapy. Survival time within this group was of 67,7±10,5 months, which was not statistically different from those who performed upfront surgery (survival time 48±5,2 months). Patients with single N2 positive stations had a longer survival time than those with multiple N2 positive stations (p<0.05). Within the group of patients with single N2 disease (n=35), no difference in survival time was found regarding neoadjuvant therapy. Surgery is effective in selected patients with N2 disease, in particular those with single-N2 positive stations. Neoadjuvant chemotherapy may not grant survival benefit. Adequate pre-operative staging is essential.

The Survival Efficiency of Initial Surgical Treatment in Stage IIIa-N2 Positive Non-Small Cell Lung Cancer

​ Objective: The role of surgical treatment in the multimodal treatment of stage IIIA-N2 positive non-small cell lung cancer (NSCLC) patients is a matter of debate. We aim to investigate initial surgical treatment's survival efficiency in patients with IIIA N2 positive NSCLC.Methods: The patients treated for stage IIIA N2 positive NSCLC in a single center between January 2009 and December 2014 were retrospectively analyzed. A total of 134 patients with 5 cm tumors in diameter or less and without involvements of the chest wall, mediastinal pleura, phrenic nerve, recurrent laryngeal nerve, pericardium, heart, diaphragm, vertebra, esophagus, large vessel invasion, and satellite nodule were detected. Of these patients, initial surgical treatment before chemoradiotherapy was performed in 72 (Group 1), while definitive concurrent chemoradiotherapy was performed in 62 patients (Group 2). Each patient's gender, age, physical performance status, tumors size, pathological diagnosis, lung resection types, and long-term survival data were evaluated.Results: No statistically significant difference was found in patients' gender, physical performance, tumor size, and tumor histology. Survival rates were higher among patients aged ≤65 years and higher in Group 1 than Group 2. While one-, three, five-, and seven-year survival rates were detected as 86.1%, 62.5%, 41.6%, and 31% in Group 1, respectively, the rates were observed to be as 77.4%, 30.6%, 10.8%, and 6.7% in Group 2, respectively. However, no difference was seen between patients' survival rates with single and multiple ipsilateral mediastinal lymph node metastases.Conclusion: Despite those advocating surgical treatment after neoadjuvant chemotherapy in treating stage IIIA N2 positive patients, others supporting surgical treatment should initially be performed. When conducted as the first step, surgical treatment achieves significant increases in survival.

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non–small-cell Lung Cancer: SQUAT trial (WJOG 12119L)

IntroductionWe describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non–small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). Patients and MethodsKey inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. ConclusionThis trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

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

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. 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. 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). 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.

Trimodality Therapy in the Treatment of Stage III N2-Positive Non-Small Cell Lung Cancer: A National Cancer Database Analysis.

Significant controversy remains regarding the care of patients with clinical stage III (N2-positive) NSCLC. Although multimodality therapy is effective, the roles of surgery, chemotherapy, and radiotherapy are not fully defined and the optimal treatment approach is not firmly established. We analyzed outcomes and predictors associated with trimodality therapy (TT) in the National Cancer Database. The NCDB was queried from 2004 to 2014 for patients with NSCLC diagnosed with stage III (N2) disease and treated with chemotherapy and radiation (CRT). Three cohorts of patients were studied: CRT only/no surgery (NS), CRT plus lobectomy (LT), and CRT plus pneumonectomy (PT). The univariate and multivariable analyses (MVA) were conducted using Cox proportional hazards model and log-rank tests. A total of 29,754 patients were included in this analysis: NS 90.1%, LT 8.4%, and PT 1.5%. Patient characteristics: median age 66 years; male 56% and white 85%. Patients treated at academic centers were more likely to receive TT compared with those treated at community centers (odds ratio: 1.85 [1.53-2.23]; p < .001). On MVA, patients that received TT were associated with better survival than those that received only CRT (hazard ratio: 0.59 [0.55-0.62]; p < .001). The LT group was associated with significantly better survival than the PT and NS groups (median survival: 62.8 months vs. 51.8 months vs. 34.2 months, respectively). In patients with more than two nodes involved, PT was associated with worse survival than LT and NS (median survival: 51.4 months in LT and 39 months in NS vs. 37 months in PT). The 30-day and 90-day mortality rates were found to be significantly higher in PT patients than in LT. TT was used in less than 10% of patients with stage III N2 disease, suggesting high degree of patient selection. In this selected group, TT was associated with favorable outcomes relative to CRT alone. This analysis demonstrates that trimodality therapy could benefit a selected subset of patients with stage III (N2) disease. This plan should be considered as a treatment option following patient evaluation in a multidisciplinary setting in experienced medical centers with the needed expertise.

Unsuspected N2-positive non-small cell lung cancer after complete resection: is there a place for multimodal adjuvant therapy?

Unsuspected N2 disease after surgical resection is found in a substantial proportion of patients with locally advanced non-small cell lung cancer (NSCLC) despite adequate preoperative mediastinal staging. This situation is challenging for clinicians, as optimal adjuvant strategies remain controversial and such patients are at risk of local recurrence and distant metastasis (1,2).

Loss of Muscle Mass is a Novel Predictor of Postoperative Early Recurrence in N2-Positive Non-Small-Cell Lung Cancer.

Background: We often experienced early recurrence in patients with completely resected N2-positive non-small-cell lung cancer (NSCLC). Loss of muscle mass is a poor prognostic factor in patients with several stages of NSCLC. This study aimed to investigate the relationship between preoperative loss of muscle mass and postoperative early recurrence in patients with N2-positive NSCLC.Methods: We retrospectively analyzed 47 male patients with completely resected pathological N2-positive NSCLC. Early recurrence was defined as that diagnosed within 1 year after the operation. We used the L3 muscle index (cross-sectional area of muscle at the L3 level, normalized for height) as a clinical measurement of loss of muscle mass (cutoff value, 52.4 cm2/m2).Results: In all, 18 patients with early recurrence had significantly poorer outcomes compared with those without (P <0.01). In univariate analysis, loss of muscle mass (P = 0.023), carcinoembryonic antigen (CEA) level >5.0 ng/mL (P = 0.002), and absence of postoperative chemotherapy (P = 0.042) were predictors of postoperative early recurrence. In multivariate analysis, loss of muscle mass (P = 0.004) and CEA level >5.0 ng/mL (P = 0.001) were independent predictors.Conclusions: Loss of muscle mass is an independent predictor of postoperative early recurrence in pathological N2-positive NSCLC patients.

P1.08-004 Adjuvant Chemoradiotherapy vs. Chemotherapy for Completely Resected Unsuspected N2-Positive Non-Small Cell Lung Cancer

P1.08-004 Adjuvant Chemoradiotherapy vs. Chemotherapy for Completely Resected Unsuspected N2-Positive Non-Small Cell Lung Cancer

1288PD - Randomized phase ii trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer

1288PD - Randomized phase ii trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer

Clinical outcomes of surgery after induction treatment in patients with pathologically proven N2-positive stage III non-small cell lung cancer.

To assess the effect of preoperative neoadjuvant therapy on resectability, downstaging, and the prognosis in patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). Eighty-four patients who underwent resections after induction therapy [76 with neoadjuvant chemotherapy (CTx) and 8 with induction chemoradiotherapy (CRTx)] for clinically evident [larger than 1 cm on computed tomography (CT)] and pathologically confirmed ipsilateral N2 positive NSCLC (stage IIIA) between January 2009 and July 2013 were reviewed retrospectively. Partial response (PR) was observed in 39 patients (46.4%). Standard lobectomy was performed in 63 cases (75.0%), and extensive resection was conducted in 21 cases (25.0%), including four pneumonectomies. Pathologic nodal downstaging (pN2 to pN0-1) was confirmed in 38 cases (45.2%). After induction therapy plus resection, 5-year progression-free survival (PFS) and overall survival (OS) in cases with radical resections were 37.9% and 34.2%, respectively. Patients who underwent lobectomy or pathologic nodal downstaging had better prognosis than those who had extensive resection or persistent N2 in PFS (P=0.036; P=0.025) and OS (P=0.023; P=0.024). On univariate analysis, lobectomy and pathological nodal downstaging were favourably predictive factors both in PFS and OS. Cox multivariate analyses identified only pathologic nodal downstaging to predict better PFS, and lobectomy to be significantly prognostic for OS. These data suggest that neoadjuvant therapy was feasible, and helpful for tumor and pathologic nodal downstaging with promising rates of survival in patients with stage IIIA-N2 NSCLC. After induction therapy, patients with potentially radical lobectomy were more likely to benefit from operation. Pathological nodal downstaging of pN2 to pN0-1, rather than clinical response was predictive of a favorable outcome, and was correlated with a better chance of survival.

Prognostic factors in resectable pathological N2 disease of non-small cell lung cancer.

N2-positive non-small cell lung cancer (NSCLC) exhibits extremely low survival rates. The role of surgery in operable locally advanced N2 NSCLC remains controversial. In this study, we tried to analyze the role of surgery in resectable N2 NSCLC and the relationship between survival and clinico-pathologic factors from a pathologic point of view. 108 resectable pathologic N2-positive NSCLC patients, diagnosed from January 2005 to July 2012, were enrolled in this study. We retrospectively reviewed the medical records, image studies, and pathology reports to collect the clinico-pathologic factors in these patients. Those who received lobectomy (p = 0.002) and had a metastatic lymph node ratio less than 0.4 (p = 0.01) had a better overall survival rate. In addition, our study also showed that perineural invasion may play a significant role in disease-free survival (p = 0.01) CONCLUSIONS: Metastatic lymph node ratio greater than 0.4 and non-anatomic resection were poor prognostic factors for disease-free survival. Anatomic resection for selected N2 patients may play a crucial role in the overall survival rate. Perineural invasion showed an adverse impact on disease-free survival, but further investigation is warranted.

P6. Induction chemo- or chemoradiotherapy followed by resection for N2 positive NSCLC—a retrospective study

Background Advanced stage non-small cell lung cancer (NSCLC) is a fatal disease, characterized by mediastinal lymph node involvement (N2) and/or locally advanced tumor. In these patients the role of surgical resection—combined with induction treatment—remains controversial. We aimed to assess the clinical outcome of patients undergoing induction chemo- or chemoradiotherapy for N2 positive NSCLC.

Epidermal growth factor receptor mutation and treatment outcome of mediastinoscopic N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery

Epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) is a strong predictive factor for a favorable response to EGFR tyrosine kinase inhibitors, however, its prognostic role in locally advanced stage is unclear. The aim of this study was to analyze the association of EGFR mutational status and clinical outcome after neoadjuvant chemoradiotherapy (CRT) followed by surgical resection in mediastinoscopically proven N2(+) NSCLC patients. We retrospectively identified 168 patients diagnosed between 1998 and 2006. EGFR mutational status was identified in 107 patients. Response and survival after neoadjuvant CRT followed by surgery were compared according to EGFR mutational status. 83 patients (77.6%) were found to have wild type EGFR, while exon 19 deletions or L858R missense mutations in the EGFR gene were detected in 19 patients. There was no significant difference in overall survival; however, the 5-year PFS rate in EGFR mutant patients (8.4%) were significantly lower than in the EGFR wild-type patients (33.6%; p=0.005). In multivariate analysis, EGFR mutation was a significant prognostic factor for a higher risk of distant recurrence/progression than the EGFR wild type (HR=7.183, p=0.005). In locally advanced mediastinoscopic N2-positive NSCLC, EGFR mutation was associated with more frequent distant relapses and worse 5-year PFS rate after neoadjuvant CRT followed by surgery, which might suggest that systemic control might be important in patients with the EGFR mutation. Therefore, the role of TKI for adjuvant EGFR TKI to decrease disease recurrence in distant sites should be further investigated.

The association of epidermal growth factor receptor (EGFR) mutation and survival in N2(+) non-small cell lung cancer patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy.

7034 Background: Epidermal growth factor receptor (EGFR) mutation is reported to be associated with radiosensitivity of non-small cell lung cancer (NSCLC) in vitro. The aim of this study is to analyze the association of clinical outcome to neoadjuvant concurrent chemoradiotherapy (CCRT) with EGFR mutation status in N2(+) NSCLC patients. Methods: We retrospectively identified 161 patients with mediastinoscopy-proven N2(+) NSCLC who were treated with platinum-based neoadjuvant concurrent chemoradiotherapy at Samsung Medical Center between 1998 and 2006. In 98 patients with remaining tumor tissue, EGFR mutation was assessed by both peptide nucleic acid (PNA)-mediated PCR clamping method and sequencing simultaneously. 88 patients were finally included in analysis, excluding 4 patients with indeterminate EGFR mutation results and 6 patients who didn’t proceed to operation by reason of other than disease progression. Results: Among 88 patients, EGFR mutation (exon 19 deletions or L858R) was detected in 13 patients (14.8%), and KRAS mutation in 2 patients (2.3%). After neoadjuvant concurrent chemotherapy, 5 patients showed progressive disease, pathologic downstaging of lymph nodes (LN) to N0 or N1 was achieved in 44 patients (50%), and pathologic CR in 13 patients (14.8%). Achievement of pathologic CR or pathologic downstaging of LNs were not associated with EGFR mutation status. With a median follow-up of 73.8 months, there were no significant difference in overall survival or progession free survival between EGFR mutation and negative patients (28.2 months vs 33.6 months, p=0.125; 15.2 months vs. 18.0 months, p=0.631), respectively. Conclusions: In N2-positive NSCLC patient, EGFR mutation didn’t show any significant clinical benefit to neoadjuvant CCRT in terms of response rate, PFS or OS. Further study should be needed to confirm and elucidate the association between EGFR mutation status and radiosensitivity in NSCLC patients.

ERCC1 expression as a prognostic marker in N2(+) nonsmall‐cell lung cancer patients treated with platinum‐based neoadjuvant concurrent chemoradiotherapy

Excision repair cross-complementation Group 1 (ERCC1) overexpression is associated with resistance to cisplatin-based chemotherapy in patients with nonsmall-cell lung cancer (NSCLC). A preliminary study also suggested that ERCC1 expression is associated with radioresistance in lung cancer cells. The aim of this study was to evaluate the clinical implications of ERCC1 expression in stage IIIA N2-positive NSCLC patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Sixty-eight patients with mediastinoscopy-proven N2-positive NSCLC were enrolled between August 1997 and September 2003. ERCC1 expression was assessed by immunohistochemistry from pretreatment mediastinoscopic biopsy specimens. ERCC1 expression was positive in 31 of 68 specimens (46%). Among 14 patients who obtained pathologic complete response, 6 were positive for ERCC1 expression and 8 were negative (P = .818). On univariate analysis, with median follow-up of 61.8 months (range, 34.3-108.8 months), progression-free survival was 15.9 months for ERCC1-positive and 29.5 months for ERCC1-negative patients (P = .062), and there was a statistically significant difference in overall survival between ERCC1-negative tumors and ERCC1-positive tumors (89.2 vs 26.0 months, P = .014). On multivariate analysis, ERCC1 negativity (P = .041) and achieving mediastinal nodal clearance (downstage to pathological N0 or N1) after neoadjuvant CCRT followed by surgery (P = .005) were significant independent prognostic factors for the prolongation of survival. These results suggest that N2-positive NSCLC patients with ERCC1 negative tumors show a survival benefit from neoadjuvant CCRT with a platinum-containing regimen.

Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer?

Neoadjuvant treatment followed by surgery is currently being investigated for locally advanced non-small cell lung cancer (NSCLC). This study reports efficacy, toxicity and feasibility of neoadjuvant chemotherapy with concurrent radiotherapy (CCRT) in stage IIIA, N2 positive NSCLC. From March 2001 to February 2004, 52 patients with histologically confirmed stage IIIA, N2 positive NSCLC were registered. Patients received preoperative CCRT that consisted of weekly paclitaxel plus platinum chemotherapy and concurrent radiotherapy followed by surgery. Overall response rate was 76.9% (95% CI, 64-88%). The major grade 3-4 toxicities were radiation esophagitis (15.4%) and neutropenia (11.5%), and treatment-related mortality rate was 1.9%. Forty-two of 52 patients (80.8%) subsequently underwent surgical resection and 35 of 52 patients (67.3%) underwent complete resection. Among them, pathological complete response was obtained in 4.8%. Pathological downstaging rate to N0-1 and stage 0-II at surgery were 69.0% and 66.7%, respectively. The perioperative major morbidity rate was 23.8% and perioperative mortality was 2.4%. At a median follow-up of 33.9 months (range: 16.4-49.9), the median progression-free survival and overall survival were 16.5 months (95% CI, 6.2-26.8) and 25.6 months (95% CI, 14.6-36.6), respectively. Multivariate analyses identified that patients achieved mediastinal nodal clearance (downstage to pathological N0 or N1) after CCRT (p=0.02) and age at diagnosis<60 years (p=0.01) showed significantly improved survival. Neoadjuvant CCRT showed a high overall response rate with tolerable toxicity profile. Downstaging after CCRT may increase the rate of complete tumor resection and result in survival benefit in stage IIIA, N2 positive NSCLC patients.

Randomized trial of chemoradiotherapy to 61 Gy [no S] versus chemoradiotherapy to 45 Gy followed by surgery [S] using cisplatin etoposide in stage IIIa non-small cell lung cancer (NSCLC): intergroup trial 0139, RTOG (9309)

Purpose/Objective: Optimal treatment for IIIa, N2 positive NSCLC needs definition from large randomized trials. Small phase III trials support the use of chemotherapy followed by [S]. Increasingly concurrent chemoradiotherapy produces substantial 2- and 3-year survival. SWOG 8805, a large phase II study employing cisplatin [P] etoposide [E] and 45 Gy thoracic radiotherapy (TRT) followed by resection demonstrated that patients achieving nodal complete response (CR) survived quite well. Intergroup 0139 tested the hypothesis that PE + concurrent 61 Gy TRT may be adequate, but [S] following induction therapy might either improve survival or increase morbidity/mortality. Study endpoints are progression free, median and overall survival, as well as pattern of failure.

Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival

Background. This study was undertaken to determine the predictive value of nodal status at resection in regards to long-term outcome of patients undergoing neo-adjuvant therapy and resection for stage IIIA N2-positive non-small cell lung cancer (NSCLC). Methods. We reviewed the medical records of all patients found on surgical staging to have N2-positive NSCLC and who underwent induction therapy followed by resection between 1988 and 1996 at our hospital. Complete follow-up information was examined utilizing Kaplan-Meier survival analysis and Cox proportional hazards multivariate analysis. Results. One hundred three patients (59 men) with stage IIIA N2-positive NSCLC received neoadjuvant therapy before surgical resection. Preoperative therapy consisted of platinum-based chemotherapy (76), radiotherapy (18), or chemoradiation (9). Operations included pneumonectomy (38), bilobectomy (6), and lobectomy (59). There were four deaths and seven major complications. Eighty-five patients were followed until death. Median survival among 18 living patients is 60.9 months (range 29 to 121 months). Twenty-nine patients were downstaged to N0 and had 5-year survival of 35.8% (median survival 21.3 months). Seventy-four patients with persistent tumor in their lymph nodes (25 N1 and 49 N2) had significantly worse, 9%, 5-year survival, p = 0.023 (median survival 15.9 months). Other negative prognostic factors were adenocarcinoma and pneumonectomy. Conclusions. Patients with N2-positive NSCLC whose nodal disease is eradicated after neoadjuvant therapy and surgery enjoy significantly improved cancer-free survival. These data support surgical resection for patients downstaged by induction therapy; however, patients who are not downstaged do not benefit from surgical resection. Direct effort should be made to improve the accuracy of restaging before resection.