Stage IIIA-N2 Non-small Cell Lung Research Articles

Radiation Therapy–First Strategy After Surgery With or Without Adjuvant Chemotherapy in Stage IIIA-N2 Non-Small Cell Lung Cancer

Postoperative radiation therapy (PORT) and postoperative chemotherapy (POCT) can be administered as adjuvant therapies in patients with non-small cell lung cancer (NSCLC). The aim of this study was to present the clinical outcomes in patients treated with PORT-first with or without subsequent POCT in stage IIIA-N2 NSCLC. From January 2002 to November 2014, the conditions of 105 patients with stage IIIA-N2 NSCLC who received PORT-first with or without subsequent POCT were analyzed. PORT was initiated within 4 to 6 weeks after surgical resection. Platinum-based POCT was administered 3 to 4 weeks after the completion of PORT. We analyzed the outcomes and the clinical factors affecting survival. Of 105 patients, 43 (41.0%) received POCT with a median of 4 cycles (range, 2-6 cycles). The follow-up times ranged from 3 to 123 months (median, 30 months), and the 5-year overall survival (OS) was 40.2%. The 5-year OS of patients treated with PORT and POCT was significantly higher than that of patients with PORT (61.3% vs 29.2%, P<.001). The significant prognostic factors affecting OS were the use of POCT (hazard ratio [HR] = 0.453, P=.036) and type of surgery (pneumonectomy/lobectomy; HR = 2.845, P<.001). PORT-first strategy after surgery appeared not to compromise the clinical outcomes in the treatment of stage IIIA-N2 NSCLC. The benefit of POCT on OS was preserved even in the PORT-first setting. Further studies are warranted to compare the sequencing of PORT and POCT, guaranteeing the proper use of POCT.

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.

Volume-Based Assessment With 18F-FDG PET/CT Improves Outcome Prediction for Patients With Stage IIIA-N2 Non-Small Cell Lung Cancer.

We evaluated the prognostic impact of volume-based assessment by pretreatment (18)F-FDG PET/CT in patients who had clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection. We reviewed 161 consecutive patients who had stage IIIA-N2 NSCLC treated with neoadjuvant CCRT followed by surgery. In all cases, N2 disease was pathologically confirmed by mediastinoscopic biopsy, endobronchial ultrasound-guided transbronchial needle aspiration, or video-assisted thoracoscopic surgery. We measured the total metabolic tumor volume (total MTV) and the maximum standardized uptake value (SUVmax), including a primary tumor and metastatic nodes on the pretreatment scan. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method. The association of PET parameters with OS and DFS was determined by univariable and multivariable analyses performed using the Cox regression model. A higher total MTV was significantly associated with poor DFS (hazard ratio [HR], 1.82; p = 0.036) and OS (HR = 2.97; p = 0.012) in the multivariable analysis. In contrast, a higher SUVmax was not significantly associated with poor DFS and OS. Patients with a high total MTV (> 22 cm(3)) had a median survival time that was significantly shorter than that of patients with a low total MTV (median DFS, 11.3 vs 42.0 months, respectively [p < 0.001]; median OS, 38.3 months vs not reached [p < 0.001]). Kaplan-Meier curves showed significant differences on the basis of total MTV in patients with or without mediastinal downstaging after CCRT. Patients with a high total MTV had significantly worse DFS when they had post-neoadjuvant pathologic (yp) stage 0-II disease (p = 0.020) or yp stage III disease (p = 0.036). Higher total MTV was also associated with worse OS in patients with yp stage 0-II disease (p = 0.013) or yp stage III disease (p = 0.007). A higher pretreatment total MTV is associated with worse outcome, independent of yp stage, in patients with stage IIIA-N2 NSCLC treated with neoadjuvant CCRT followed by surgery.

Postoperative radiotherapy for completely resected stage IIIA-N2 non-small cell lung cancer

Current studies show that postoperative adjuvant radiotherapy (PORT) may improve local control and overall survival for ⅢA-N2 NSCLC. With modern radiotherapy technology and techniques, the adverse effect of PORT is moderate and tolerated. Besides, modern PORT doesn′t decrease the survival. Investigation concerning postoperative target volume for PORT is rare, so that definite agreement has not been reached. Available informations suggest that clinical target volume should include bronchial stump, involved lymph nodes, ipsilateral hilar nodes, subcarinal nodes and ipsilateral lower paratracheal nodes. Key words: Carcinoma, non-small-cell lung; Surgical procedures, operative; Radiotherapy

Selection of proper candidates with resected pathological stage IIIA-N2 non-small cell lung cancer for postoperative radiotherapy.

BackgroundTo establish a prediction model in selecting fit patients with resected pIIIA-N2 non-small cell lung cancer (NSCLC) for postoperative radiotherapy (PORT), and evaluate the model in clinical practice.MethodsBetween January 2003 and December 2005, 221 patients with resected pIIIA-N2 NSCLC were retrospectively analyzed. The effect of PORT on overall survival (OS) of patients with different clinicopathological factors was evaluated and the results were used to establish a prediction model to select patients fit for PORT.ResultsCompared with the control, PORT significantly improved the OS of patients with a smoking index ≤400 (P = 0.033), cN2 (P = 0.003), pT3 (P = 0.014), squamous cell carcinoma (SCC) (P = 0.013), or ≥4 positive nodes (P = 0.025). Patients were divided from zero to all five factors into low, middle, and high PORT index (PORT-I) groups (scored 0–1, 2, and 3–5, respectively). PORT did not improve OS (3-year, P = 0.531), disease free survival (DFS) (P = 0.358), or loco-regional recurrence free survival (LRFS) (P = 0.412) in the low PORT-I group. PORT significantly improved OS (P = 0.033), and tended to improve DFS (P = 0.064), but not LRFS (P = 0.287) in the middle PORT-I group. PORT could significantly improve OS (P = 0.000), DFS (P = 0.000), and LRFS (P = 0.006) in the high PORT-I group.ConclusionThe prediction model is valuable in selecting patients with resected pIIIA-N2 NSCLC fit for PORT. PORT is strongly recommended for patients with three or more of the five factors of smoking index ≤400, cN2, pT3, SCC, and ≥4 positive nodes.

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

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

81O - Erlotinib as Neoadjuvant Treatment in Endobronchial Ultrasound Confirmed Stage IIIA-N2 Non-Small Cell Lung Cancer (NSCLC) Patients with Epidermal Growth Factor Receptor (EGFR) Mutation (EXON 19 OR 21) (NCT01217619, ESTERN): a Prospective, Single Arm, Phase Ii Clinical Trial

81O - Erlotinib as Neoadjuvant Treatment in Endobronchial Ultrasound Confirmed Stage IIIA-N2 Non-Small Cell Lung Cancer (NSCLC) Patients with Epidermal Growth Factor Receptor (EGFR) Mutation (EXON 19 OR 21) (NCT01217619, ESTERN): a Prospective, Single Arm, Phase Ii Clinical Trial

Analyses of risk factors for postoperative recurrence after curative resection of stage III A-N2 non-small cell lung cancer

To explore the patterns of mediastinal lymph node metastases and prognostic factors of recurrence in patients undergoing curative resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). A total of 92 patients underwent curative operation and pathologically diagnosed as stage IIIA-N2 NSCLC were retrospectively reviewed. The clinicopathological data were compared between the recurrence and non-recurrence groups. And the potential prognostic factors were included for multivariate analysis using Cox proportional hazard model. The 3 and 5-year recurrence rates were 61.0% and 70.2% respectively. For univariate analysis, the prognostic factors were number of metastatic lymph nodes, positive lymph node ratio, number of metastatic mediastinal lymph nodes (MLN), positive MLN ratio, number of MLN metastasis > 3, multiple station metastasis, trans-regional metastasis and multi-zonal metastasis. A multivariate analysis using Cox regression identified 2 independent factors of prognosis: trans-regional MLN metastasis (P = 0.035) and number of MLN metastasis >3 (P = 0.045). The recurrence risk of patients with trans-regional MLN metastasis was 2.0 times higher than those with regional MLN metastasis while the recurrence risk of patients with number of MLN metastasis >3 was 2.2 times higher than those with number of MLN metastasis of 1-3. Recurrence risk of stage IIIA-N2 non-small cell lung cancer (NSCLC) after curative resection may be estimated by location and number of MLN metastasis. And the subgroup with trans-regional MLN metastasis and number of MLN metastasis >3 carries the highest risk of recurrence.

Predictive factors for survival in stage IIIA N2 NSCLC patients treated with neoadjuvant CCRT followed by surgery.

To assess the impact of imaging, surgical, histopathologic and patient-related factors on the risks of recurrence and overall survival (OS) in stage IIIA-N2 non-small cell lung cancer (NSCLC) patients undergoing definitive resection after neoadjuvant concurrent chemoradiotherapy (CCRT). We retrospectively examined 104 consecutive patients with stage IIIA-N2 NSCLC who received neoadjuvant CCRT followed by surgery between 2008 and 2011. While reviewing the clinical and surgical data, we also assessed histopathologic and imaging (CT and PET/CT) factors. Disease-free survival (DFS) and OS were estimated with predictors for recurrence and survival. The 3-year OS for patients with and without recurrence was 37.1 and 63.3 %, respectively (p < 0.001). Size decrease of target lesion(s) ≥36 % on post-neoadjuvant CCRT CT (p = 0.048) and viable tumor size on surgical specimen <9.4 mm (p = 0.035) were related to longer OS. Regarding shorter DFS, tumor size on post-neoadjuvant CCRT CT (p = 0.046), SUV(max) of the primary tumor (p = 0.011), male gender (p = 0.023), total tumor size on surgical specimen (p = 0.041) and viable tumor size on surgical specimen (p = 0.043) were the significant predictors. OS is prolonged with greater extent of size decrease of target lesion(s) on post-neoadjuvant CCRT CT and smaller viable tumor size on surgical specimen. Larger tumor size on post-neoadjuvant CCRT CT, higher SUV(max), male gender, larger total tumor size and larger viable tumor size on surgical specimen may herald the higher probability of recurrence and the necessity of more attention.

Survivin mRNA Level in Blood Predict the Efficacy of Neoadjuvant Chemotherapy in Patients with Stage IIIA-N2 Non-Small Cell Lung Cancer.

In a previous study, survivin mRNA expression in non-small cell lung cancer (NSCLC) tissue had been demonstrated to be associated with unfavorable prognosis of patients treated with chemotherapy. In this study, we investigated the survivin mRNA levels in blood of patients with stage IIIA-N2 NSCLC and their association with the efficacy of neoadjuvant chemotherapy (NCT) and disease-free survival (DFS) and overall survival (OS). Blood specimens were collected from 56 patients with stage IIIA-N2 NSCLC before (N0) and after the complete of NCT (N1). Survivin mRNA was measured by real-time quantitative-PCR assay. Receiver operating characteristics curve analysis was undertaken to determine the best cutoff value for survivin mRNA. Results showed that high blood survivin mRNA levels at N0 and N1 were significantly associated with clinical (P = 0.01 and P = 0.008, respectively) and pathologic response (both P = 0.004, respectively). Moreover, the change of blood survivin mRNA levels in these NSCLC patients is associated with the clinical and pathologic response to NCT. Patients with high survivin mRNA levels at N0 and N1 had significantly shorter DFS and OS than those with low survivin mRNA levels (P = 0.021 and P = 0.014, respectively for DFS; P = 0.009 and P = 0.005, respectively for OS). Multivariate analysis demonstrated that high blood survivin mRNA level was an independent predictor for worse DFS and OS in the NSCLC patients receiving NCT. In conclusion, survivin mRNA level in blood from stage IIIA-N2 NSCLC patients receiving NCT is predictive of cancer outcome.

The prognostic significance of proliferative indices in surgically resected IIIA-N2 non-small cell lung cancer after induction chemotherapy.

The aim of this study was to assess the prognostic significance of Mib1 expression, Mitosis (Mi) and Apoptosis (Ai) in residual tumour cells after induction chemotherapy in surgically resected IIIA-N2 patients. Between January 2002 and November 2008, we reviewed 50 consecutive patients (39 males) with histologically proven stage IIIA-N2 non-small cell lung cancer (NSCLC), who underwent radical resection following induction chemotherapy. Five-year survival in the series was evaluated in relation to lymph node downstaging, histology, extent of resection, number of chemotherapy cycles, pT status, sex and age. It was then also evaluated in relation to the proliferative indexes (Mi, Ap and Mib 1 expression), dividing the patients into two groups according to whether they were above or below the 50th percentile for each parameter. The associations between mortality and the abovementioned prognostic factors were explored using the Kaplan-Meier method, the log-rank test, and Cox regression analysis. The monovariate analysis confirmed the positive prognostic role of lymph node downstaging in terms of 5-yr survival: 31% vs. 12% (P=0.018). However Mi and Mib1 expression under the 50th percentile were also associated with better 5-yr survival: respectively 46% vs. 5% (P=0.007) and 40% vs. 6% (P=0.017). Neither apoptosis nor the other prognostic factors showed any statistical impact on long-term survival. The multivariate analysis showed Mi to be an independent prognostic factor (P=0.005). Although lymph node downstaging has been considered the principal prognostic factor after induction chemotherapy and surgical resection, Mi and Mib1 expression in residual tumor can predict long-term survival more accurately.

Neoadjuvant use of Tyrosine Kinase Inhibitors

Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) have a 5-year overall survival (OS) of only 10%-15%, and it decreases to 2-5% in patients with mediastina N2 bulky disease. The efficacy of surgery in this stage is limited and remains controversial. In 4 different studies with a total of 1180 patients who underwent surgical resection, 5-year survival was 14-30% [1-4]. To improve this rate and supported by the introduction of new chemotherapeutic agents, induction chemotherapy (CT) has been added to the treatment approach in this stage. The theoretical advantages of induction CT include: in vivo assessment of response to CT, which would help identify patients who might benefit from adjuvant CT; early treatment of micro metastasis to increase control of distant metastases; reduction of drug resistance due to early exposure to chemotherapeutic agents and increased surgical resect ability, due to enhance of response rates that also allows preservation of healthy lung parenchyma.

Postoperative Radiation Therapy for Elderly Patients With Resected Pathological Stage IIIA-N2 Non-Small Cell Lung Cancer

Postoperative Radiation Therapy for Elderly Patients With Resected Pathological Stage IIIA-N2 Non-Small Cell Lung Cancer

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

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

A favorable population among clinical stage IIIA-N2 non-small cell lung cancer: The importance of the location of the primary tumor and involved nodes.

7575 Background: The number of station of involved N2 nodes has been considered to be one of the most important prognostic factors for lung cancer. However most reports detailed with not clinical nodal status, but pathological nodal status. We investigated the relationship between prognosis and the location of the primary tumor and involved nodes. Methods: A retrospective study was conducted on 1257 patients with primary lung cancer, which was resected between 1996 and 2009. Among them, 79 patients (6.3%) had cN2, c-stage IIIA, pN2 and NSCLC. Mediastinal lymph node with a diameter of 10mm or more in the short axis was diagnosed as metastasis. We defined cN2α as only involvement of upper mediastinal lymph node (UMLN) in main tumor located on upper lobe or as that of lower mediastinal lymph node (LMLN) in main tumor located on lower lobe. And we did cN2β as involvement of LMLN in main tumor located on upper lobe with or without metastatic UMLN or as that of UMLN in main tumor located on lower lobe with or without metastatic LMLN. We analyzed preoperative clinical factors and investigated overall and disease-free survival. Results: The overall 5-year survival rate was 30.2% and median follow-up was 52.8 months. The disease-free 5-year survival rate was 22.2%. The differences in survival between cN2α and cN2β were statistically significant (29.5% vs. 0%, p-value=0.0007), whereas no significant differences was found between cN2 single station and multiple station (23.3% vs. 19.4%, p-value=0.1220). Multivariate analysis with cox’s hazard model disclosed that cN2α was independent good disease-free prognostic factor(HR: 0.426, 95%CI: 0.193-0.941). The sensitivity, specificity and positive predictive value for pN2 single station based on cN2 single station were 71.4%, 49.1% and 34.9% (p=0.1269). Conclusions: Clinical mediastinal lymph node status based on the location of the primary tumor and involved nodes was an important preoperative prognostic factor. Thus this factor should be taken into consideration for planning and evaluating clinical trials. Another fruit of the study was that clinical single nodal N2 was not always pathological single N2 disease.

Prognostic analysis of curative surgery for stage IIIA-N2 non-small cell lung cancer

To investigate the survival and prognostic factors in patients undergoing potentially curative resection of stage IIIA-N2 non-small cell lung cancer. Clinical data of eighty-nine patients, who underwent curative operation from January 2003 to April 2007 in the Peking University First Hospital and were pathologically diagnosed as stage IIIA-N2 NSCLC, were reviewed. The patients were followed up until death or the cut-off date. The overall 3-year and 5-year survival rates were calculated, and Cox proportional hazard model was used to determine the clinical and pathological risk factors and evaluate their influence on the survival. The three-year and five-year survival rates were 51.7% and 31.5%, respectively. The univariate Cox regression analysis revealed five significant factors associated with prognosis: the arm of age < 55, T3 stage, lymphovascular invasion (LVI), multiple positive N2 station and the number of positive N2 nodes > 3 were found to be at increased risk of tumor-related death, and those risk factors were confirmed especially in the age ≥ 55 group. Multivariate Cox regression analysis indicated three independent prognostic factors: T3 stage, LVI and multiple positive N2 station. The results of this preliminary study show that T3 stage, lymphovascular invasion and N2 level (single or multiple station) are associated with the prognosis of stage IIIA-N2 NSCLC patients after potentially curative resection, and the characteristics of age < 55 and the number of positive N2 nodes > 3 may imply worse prognosis.

Hyperfractionated Irradiation with 3 Cycles of Induction Chemotherapy in Stage IIIA‐N2 Lung Cancer

The purpose of the present study was to improve the prognosis of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). To achieve that goal, we performed induction chemoradiotherapy followed by surgery. The criteria for this phase II study were ≤75-year-old patients with pathologically diagnosed stage IIIA-N2 NSCLC who had performance statuses of 0 or 1 with good organ function. Three cycles of chemotherapy with paclitaxel and carboplatin were carried out, with concurrent hyperfractionated irradiation (42 Gy). After re-evaluation, pulmonary resections were considered unless patients showed progressive disease. The primary endpoint was overall survival (OS), and the secondary endpoints were disease-free survival (DFS) and absence of toxicity. All 22 patients enrolled in this study completed the induction chemoradiotherapy without any severe complications. In these 22 patients, the 2- and 5-year OS were 81 and 47%, respectively. There were no therapy-related deaths. Surgery was subsequently performed in 19 patients (86%). Pathological complete responses were seen in 6 patients (27%), while node downstaging was obtained in 10 patients (45%). In the 19 patients who underwent surgery, the 2- and 5-year OS rates were 83 and 62%, respectively, and the 2-year DFS rate was 63%. All 6 patients with pathological complete responses survived without disease. Patients with residual multiple-station N2 showed worse OS and DFS rates than did those with downstaged and single-station N2 (P=0.026 and P<0.0001, respectively). This trimodal therapy was effective and well tolerated, and it is an acceptable therapeutic option for patients with locally advanced stage IIIA-N2 NSCLC. Patients without persistent multiple-station N2 showed promising survival.

Risk factors of brain metastases in completely resected pathological stage IIIA-N2 non-small cell lung cancer

BackgroundBrain metastases (BM) is one of the most common failures of locally advanced non-small cell lung cancer (LA-NSCLC) after combined-modality therapy. The outcome of trials on prophylactic cranial irradiation (PCI) has prompted us to identify the highest-risk subset most likely to benefit from PCI. Focusing on patients with completely resected pathological stage IIIA-N2 (pIIIA-N2) NSCLC, we aimed to assess risk factors of BM and to define the highest-risk subset.MethodsBetween 2003 and 2005, the records of 217 consecutive patients with pIIIA-N2 NSCLC in our institution were reviewed. The cumulative incidence of BM was estimated using the Kaplan–Meier method, and differences between the groups were analyzed using log-rank test. Multivariate Cox regression analysis was applied to assess risk factors of BM.ResultsFifty-three (24.4 %) patients developed BM at some point during their clinical course. On multivariate analysis, non-squamous cell cancer (relative risk [RR]: 4.13, 95 % CI: 1.86–9.19; P = 0.001) and the ratio of metastatic to examined nodes or lymph node ratio (LNR) ≥ 30 % (RR: 3.33, 95 % CI: 1.79–6.18; P = 0.000) were found to be associated with an increased risk of BM. In patients with non-squamous cell cancer and LNR ≥ 30 %, the 5-year actuarial risk of BM was 57.3 %.ConclusionsIn NSCLC, patients with completely resected pIIIA-N2 non-squamous cell cancer and LNR ≥ 30 % are at the highest risk for BM, and are most likely to benefit from PCI. Further studies are warranted to investigate the effect of PCI on this subset of patients.

Erlotinib as neoadjuvant treatment in patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation (NCT01217619, ESTERN).

e17551 Background: Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year survival rate. Tyrosine kinase inhibitor monotherapy have been demonstrated a significant improvement in OR rate and PFS as first-line treatment for metastatic NSCLC patients with EGFR mutation. The objective of trial is to explore the efficacy and safety profile of erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with EGFR mutation. The purpose of this neoadjuvant regime is to down-stage and increase complete resection rate in this patients setting. Methods: This is a single arm, one center, phase II study of erlotinib as neoadjuvant treatment in patients with Endobronchial Ultrasound (EBUS) confirmed stage IIIA-N2 NSCLC with activating EGFR mutation in exon 19 or 21. The primary endpoint is to evaluate radical resection rate. The secondary endpoint is pathological complete resection rate (pCR), objective response rate (ORR), disease free survival (DFS), overall survival (OS), quality of life (QoL) and safety profile. A total of 44 patients will be enrolled. Patients with IIIA-N2 NSCLC with pathologically confirmed ipsilateral mediastinal metastasis by EBUS. The biopsy specimen shows EGFR mutation in exon 19 or 21. All patients will be treated by erlotinib 150mg orally per day for 56 days. Patients will be assessed by Chest CT for the efficacy evaluation in day 29 and right after day 56. Patients get benefit from neoadjuvant treatment and evaluated as technically resectable will receive surgery. All the post-operative patients will receive standard adjuvant treatment. The adjuvant regime is decided by the investigator for the patients’ benefits. After adjuvant treatment patients will enter nomal follow-up including regular chest CT and ultrasound examination Results: Current enrollment: The study has enrolled 5 patients. One male patient, aged 47, with stable disease after neoadjuvant treatment, got right upper lobe resection on 17 Jan 2012. Conclusions: Erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR mutation is feasible.

A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.

7039 Background: Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587) . Study Design: Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: Response to Induction Therapy; Estimated enrollment: 5 cases with partial response in the erlotinib arm. Results: From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30-42 days), while 12 cases harboring wild-type EGFR received the GC regimen (3 cycles). The primary end point of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) for the GC arm (P=0.49). The pathological N2 complete response rates were 17% for the erlotinib arm and 25% for the GC arm (P=0.64). In the erlotinib arm, the most common failure model after initial therapy was distant metastases (9/10), especially brain metastases (3/9). The median progression free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P=0.27). The median overall survival was 27 months for the erlotinib arm and 23 months for the GC arm (P=0.52). In addition, four cases in the erlotinib arm got partial response to the 2nd EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR mutations (NCT01407822) is currently recruiting participants.