Stage IIIA-N2 Research Articles

An Exploratory Phase 2 Study of Pemetrexed (Pem) and Cisplatin (Cis) As Preoperative Chemotherapy (Ct) in the Treatment of Stage Iiian2 Nonsquamous Non-Small Cell Lung Cancer (Ns Nsclc)

ABSTRACT Aim: This study was designed to evaluate the response rate of Pem-Cis as preoperative CT in patients with stage IIIAN2 NS NSCLC. The neoadjuvant setting provided the opportunity to obtain tumor tissue samples for exploratory analyses of specific biomarkers pre and post CT. Methods: This single arm, multicenter Phase II study evaluated 3 cycles of preoperative Pem-Cis CT followed by surgery in patients with stage IIIAN2 NS NSCLC and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Patients received Pem 500 mg/m2 + Cis 75 mg/m2 IV on Day 1 Q3W with vitamin and dexamethasone supplementation and then underwent surgery. The primary endpoint was the overall response rate (ORR: complete response [CR] + partial response [PR]) after 3 CT cycles. A total of 33 patients were planned for enrolment. Secondary endpoints included pathological complete resection rate after surgery, tumor downstaging, and association between ORR and biomarker mRNA and protein expression (TS, TTF 1, E2F1, ERCC1, and BRCA1). Results: Patient enrolment was stopped early due to difficulties in identifying suitable patients. Of 19 enrolled patients (median age 62 years male/female 68%/32%, ECOG PS 0/1 79%/21%, adenocarcinoma 90%), 17 (89.5%) completed CT, and 15 (78.9%) completed CT and surgery. The ORR was 41.2% (95% CI: 18.4, 67.1%), all PRs. Of 17 patients with available scans 10 (58.8%) experienced tumor downstaging (stage IIIAN2 to IIIA, II, or I). Out of 15 patients undergoing surgery, 14 had a pathological complete resection resulting in a complete resection rate of 93.3% (95% CI: 68.1, 99.8%). No new safety signals were identified. Other efficacy outcomes are still immature. Conclusions: Pre-operative CT with Pem-Cis is active in patients with stage IIIAN2 NS NSCLC. The ORR of 41.2% is consistent with previous reports in this patient population. Assessment of the associations between ORR and baseline biomarker expression is ongoing. Disclosure: M. Das: MD is an employee and stock holder of Eli Lilly and Company; V. Soldatenkova: VS is an employee and stock holder of Eli Lilly and Company; C.M. Visseren-Grul: CVG is an employee and stock holder of Eli Lilly and Company; G. Scagliotti: GS has participated on advisory boards for Eli Lilly and Company, Astra Zeneca, Pfizer, and Roche. All other authors have declared no conflicts of interest.

Lung cancer: is surgery an option for persisting N2 after induction therapy?

Induction chemotherapy followed by surgical resection has been a treatment option for stage IIIA3 N2 non-small cell lung cancer since publication of some small randomised trials during the 1990s. Later on other studies suggested a poor prognosis in cases of persistent N2 disease, so surgical treatment for these patients was not recommended. This study analyses the outcome of patients with persisting N2 disease and tries to identify prognostic parameters within that group of patients. We conducted a retrospective cohort study with 50 patients after induction therapy for stage IIIA N2 NSCLC. We analysed the influence of the postoperative lymph node involvement as well as the number of involved lymph nodes on the overall survival. 50 patients with potentially resectable stage IIIA N2 were included in the analysis. In 25 cases (50 %) a persisting N2 remained after induction therapy with cisplatin/gemcitabine, 11 patients had a mediastinal downstaging. 14 patients did not qualify for surgery because of disease progression or comorbidities. The resection consisted in 29 cases of a lobectomy or bilobectomy; two times pneumonectomy was necessary and 4 segmentectomies and one atypical resection were performed. The median survival of patients with persisting N2 (ypN2) was 14.6 months, if mediastinal downstaging was achieved (ypN0/1) it was 22.3 months (p = 0.172). The number of involved mediastinal lymph nodes was a significant prognostic factor. If less than 6 lymph nodes were involved the mean survival was 17.5 months, while it was 8.6 months in patients with more than 6 involved lymph nodes (p < 0.01). The median survival for patients with persisting N2 disease is less favourable compared to patients with mediastinal downstaging. However, the long-term survival for patients with less than 6 involved lymph nodes is 17.5 months. Therefore surgical resection for these patients seems to be justified. After induction therapy a rigorous restaging should be performed to rule out persisting multilevel N2 disease.

Current status of induction treatment for N2-Stage III non-small cell lung cancer.

Locally advanced non-small cell lung cancer (NSCLC), particularly clinical Stage IIIA NSCLC with mediastinal lymph node metastasis, is known to be quite heterogeneous, comprising approximately one-fourth of cases of NSCLC. In this subset, patients with a minor tumor load in the mediastinal lymph nodes, such as microscopically or pathologically proven N2 in the resected specimens, are treated with surgery followed by adjuvant chemotherapy. Meanwhile, the current standard of care for patients with bulky or infiltrative N2 disease is concurrent chemoradiotherapy. The potential role of surgery in multi-modality treatment for clinical N2-Stage IIIA remains controversial. Several prospective clinical trials of this subset have been conducted; however, the heterogeneity of the N2 status and differences in chemotherapy regimens and/or radiation modalities between clinical trials make the results difficult to compare. No optimal chemotherapy regimen has been established to control possible micrometastasis, and radiotherapy is often used to achieve maximum local disease control and minimize post-surgical complications. This review summarizes the findings of prospective clinical trials that assessed the role of surgery in treating clinical N2-Stage IIIA patients within the last two decades and discusses the present status of induction treatment followed by surgery for clinical N2-Stage IIIA NSCLC.

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.

A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.

7508 Background: Prophylactic cranial irradiation (PCI) significantly decreases the incidence of brain metastases in patients with non-small cell lung cancer (NSCLC), but its impact on survival is ...

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.

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

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 efficacy and safety of gefitinib following adjuvant chemotherapy in patients with EGFR mutation are unknown. In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either exon 19 deletion or L858R point mutation) were assigned randomly to receive pemetrexed (500mg/m(2)) and carboplatin (AUC=5), administered every 21days for 4 cycles, followed with or without gefitinib (250mg/day) for 6months. The primary end point was disease-free survival (DFS). From August 2008 to September 2011, 60 patients were included in our center. DFS was significantly longer among those who received pemetrexed and carboplatin (PC)-gefitinib than among those who received PC alone [hazard ratio (HR), 0.37; 95% confidence interval (CI) 0.16-0.85; P=0.014; median, 39.8 vs. 27.0months]. The rates of 2-year DFS were 78.9% in the PC-gefitinib group and 54.2% in the PC alone group. The rates of 2-year overall survival (OS) were 92.4% in the PC-gefitinib group and 77.4% in the PC alone group (HR, 0.37; 95% CI 0.12-1.11, P=0.076). The most common adverse event was rash (43.3%, 13/30) in the PC-gefitinib group and the administration of gefitinib following chemotherapy was well tolerated. The administration of gefitinib following PC adjuvant therapy shows significant improvement in DFS in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.

The Prognosis According to Patterns of Mediastinal Lymph Node Metastasis in Pathologic Stage IIIA/N2 Non-Small Cell Lung Cancer

BackgroundThe aim of this study is to evaluate prognostic factors for survival in pathologic stage IIIA/N2 non-small-cell lung cancer (NSCLC), to identify the prognostic significance of the metastatic patterns of mediastinal lymph nodes (MLNs) relating to survival and to recurrence and metastasis.MethodsA total of 129 patients who underwent radical resection for pathologic stage IIIA-N2 NSCLC from July 1998 to April 2011 were retrospectively reviewed. The end points of this study were rates of loco-regional recurrence and distant metastasis, and survival.ResultsThe overall 5-year survival rate was 47.4%. A univariate analysis showed that age, pathologic T stage, and adjuvant chemotherapy were significant prognostic factors, while in multivariate analysis, pathologic T stage and adjuvant chemotherapy were significant prognostic factors. The metastasis rate was higher in patients with multistation N2 involvement and with more than 3 positive MLNs. Further, non-regional MLN metastasis was associated with a higher loco-regional recurrence rate.ConclusionPathologic T stage and adjuvant chemotherapy were independent prognostic factors for long-term survival in pathologic stage IIIA/N2 NSCLC. The recurrence and the metastasis rate were affected by the metastatic patterns of MLNs. These results may be helpful for planning postoperative therapeutic strategies and predicting outcomes.

Long-term survival of stage T4N0-1 and single station IIIA-N2 NSCLC patients treated with definitive chemo-radiotherapy using individualised isotoxic accelerated radiotherapy (INDAR)

BackgroundNon-small cell lung cancer (NSCLC) stage T4N0-1 or single nodal station IIIA-N2 are two stage III sub-groups for which the outcome of non-surgical therapy is not well known. We investigated the results of individualised isotoxic accelerated radiotherapy (INDAR) and chemotherapy in this setting. MethodsAnalysis of NSCLC patients included in 2 prospective trials (NCT00573040 and NCT00572325) stage T4N0-1 or IIIA-N2 with 1 pathologic nodal station, treated with chemo-radiotherapy (CRT) using INDAR with concurrent or sequential platinum-based chemotherapy. Overall survival (OS) was updated and calculated from date of diagnosis (Kaplan–Meier). Toxicity was scored following CTCAEv3.0. To allow comparison with other articles the subgroups were also analysed separately for toxicity, progression free and overall survival. Results83 patients (42 T4N0-1 and 41 IIIA-N2) were identified: the median radiotherapy dose was 65Gy. Thirty-seven percent of patients received sequential CRT and 63% received concurrent CRT. At a median follow-up of 48months the median OS for T4N0-1 patients was 34months with 55% 2-year survival and 25% 5-year survival. For stage IIIA-N2 at a median follow-up of 50months the median OS was 26months with 2- and 5-year survival rates of 53% and 24%, respectively. ConclusionChemo-radiation using INDAR yields promising survival results in patients with single-station stage IIIA-N2 or T4N0-1 NSCLC.

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.

Endobronchial/Endoesophageal Ultrasound (EBUS/EUS) Guided Fine Needle Aspiration (FNA) and 18F-FDG PET/CT Scanning in Restaging of Locally Advanced Non-small Cell Lung Cancer (NSCLC) Treated with Chemo-radiotherapy: A Mono-institutional Pilot Experience.

Chemo-radiotherapy is standard treatment of stage IIIA-N2 bulky or IIIB non-small cell lung cancer (NSCLC). Surgical resection of residual disease in downstaged patients may improve overall survival. In this setting, restaging disease is still a challenge. 18F-FDG PET/CT represents the gold standard although accuracy results are disappointing. Endoscopic bronchial/ esophageal ultrasound (EBUS/EUS)-guided fine needle aspiration (FNA) may confirm lymph node (LN) involvement. We analyzed 16 patients with stage IIIA-N2 bulky or IIIB NSCLC treated with chemo-radiotherapy. At restaging, all patients performed EBUS/EUS with FNA and PET/CT scan and results were compared. Patients underwent PET/CT scan 43 days (range: 24-89) and EBUS/EUS 42 days (range: 14-71) after therapy. Overall, 7 EBUS and 9 EUS procedures were performed: no complications resulting from the procedure occurred. In 6 patients EBUS/EUS did not reveal any suspicious lesions; in 2 the exam showed enlarged mediastinal LN that were biopsied, but with no evidence of tumor cells; in 2 the sample was not considered diagnostic; 6 had persistent mediastinal LN involvement. PET/CT scan showed 4 cases of complete metabolic response, 9 partial metabolic response, 2 stable metabolic disease and one progressive metabolic disease. Notably, all 7 patients with .80% decrease in SUV with respect to basal value showed a pathological complete response or negative EBUS/EUS. EBUS/EUS could be used to complement PET/CT scanning to verify mediastinal LN clearance. Further prospective trials are warranted to confirm the utility of EBUS/EUS together with PET/CT in restaging locally advanced NSCLC.

Value of surgery for stage IIIa non-small cell lung cancer

背景与目的对于Ⅲ期非小细胞肺癌（non-small cell lung cancer, NSCLC），目前普遍倡导手术、化疗、放疗的多学科综合治疗，但许多研究者对是否应该手术提出了质疑。该研究探讨了手术对于Ⅲ期NSCLC患者的价值。方法回顾性分析2002年3月-2012年10月北京协和医院收治的经病理学确诊的Ⅲ期NSCLC患者310例。根据最初确诊时是否手术可分为手术组和非手术组。Ⅲa期根据N分期的不同可分为T4N0/T3-4N1M0期和T1-3N2M0期。采用χ2检验比较计数资料，Kaplan-Meier方法比较总生存期（overall survival, OS）和无进展生存期（progression free survival, PFS），并绘制生存曲线。结果ECOG评分0分和Ⅲa期NSCLC患者更倾向于手术治疗。Ⅲa期手术与非手术组的中位OS分别为38.9个月和21.8个月，中位PFS分别为19.2个月和11.9个月。两组OS的差异有统计学意义（P=0.041），PFS的差异无统计学意义（P=0.209）。Ⅲa期中的T4N0/T3-4N1M0期手术与非手术组的中位OS分别为48.7个月和20.1个月，中位PFS分别为14.6个月和10.5个月，两组OS和PFS的差异均无统计学意义（P>0.05）；T1-3N2M0期手术与非手术组中位OS分别为38.9和30.8月，中位PFS分别为19.8个月和12.7个月，两组OS和PFS的差异亦无统计学意义（P>0.05）。肿瘤最大径和辅助化疗对Ⅲa-N2期患者的OS和PFS的影响有统计学意义，而肿瘤的病理类型仅影响患者的OS（P < 0.05）。结论ECOG评分0分和Ⅲa期NSCLC患者更适于手术治疗。手术可延长Ⅲa期尤其是T4N0/T3-4N1M0期NSCLC患者的OS，但对PFS无改善作用。肿瘤最大径和辅助化疗对Ⅲa-N2期患者的OS和PFS均有明显影响，而肿瘤的病理类型只影响其OS。

Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: A meta-analysis

BackgroundWe hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). MethodsTo investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. Non-individual patient data were used to model the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection. ResultsOf the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 (p=0.01) and 0.76 (p=0.02) for PORT vs. controls, respectively).Four trials (357 patients) were suitable to assess LR rates in stage III NSCLC treated with surgery, in most cases after induction chemotherapy. LR as first relapse was 30% (105/357) after 5years. In the modeling part, PORT with linear accelerators was estimated to reduce LR rates to 10% as first relapse and to increase the absolute 5-year OS by 13%. ConclusionsThis modeling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.

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

What outcome after the prescription of neoadjuvant chemotherapy in lung cancer?

The treatment of patients with locally advanced non-small-cell lung cancer is controversial. Surgery remains the gold standard, even in this group. Neoadjuvant chemotherapy could allow surgical resection in patients initially judged inoperable. From January 2009 to May 2010, neoadjuvant chemotherapy was indicated in 27 patients with NSCLC (25 men, 2 women). Their mean age was 65 years. The stages were: IIB in 5, IIIA in 17 (6 in stage IIIAN2), IIIB in 2, and IV in 3. 23 patients received neoadjuvant chemotherapy, 2 refused induction treatment, and 2 had impaired status. The neoadjuvant chemotherapy regimen was gemcitabine-cisplatin in 17 patients and vinorelbine-cisplatin in 6. Only 5 patients underwent complete surgical treatment after induction: 1 in stage IIB, 1 in stage IIIAN0, 1 in IIIB, and 2 in stage IV (1 operated brain metastasis, and 1 operated adrenal metastasis). Surgical treatment was not achieved after neoadjuvant chemotherapy in 18 patients because of progressive disease. Neoadjuvant chemotherapy offers several potential benefits, but it may delay surgery or eliminate eligibility as a surgical candidate. Rigorous patient selection for this type of multimodal treatment is essential.

Improved Survival Associated with Neoadjuvant Chemoradiation in Patients with Clinical Stage IIIA(N2) Non–Small-Cell Lung Cancer

Optimal management of clinical stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial. This study examines whether neoadjuvant chemoradiation plus surgery improves survival rates when compared with other recommended treatment strategies. Adult patients from the National Cancer Database, with clinical stage IIIA-N2 disease definitively treated between 1998 and 2004 at American College of Surgeons Commission on Cancer accredited facilities, were included in the study. Treatment was defined as neoadjuvant chemoradiation plus either lobectomy (NeoCRT+L) or pneumonectomy (NeoCRT+P), lobectomy plus adjuvant therapy (L+AT), pneumonectomy plus adjuvant therapy (P+AT), and concurrent chemoradiation (CRT). Median follow-up and overall survival (OS) were defined from date of diagnosis to last contact. Five-year OS was estimated using Kaplan-Meier methods. Cox proportional hazard regression was used to estimate hazard ratios and 95% confidence intervals (CIs), adjusting for sociodemographic, clinical, and facility characteristics. Median follow-up was 11.8 months for 11,242 eligible patients. Five-year OS was 33.5%, 20.7%, 20.3%, 13.35%, and 10.9% for NeoCRT+L, NeoCRT+P, L+AT, P+AT, and CRT, respectively (p < 0.0001). On multivariable analysis, the estimated hazard ratio was 0.51 (CI: 0.45-0.58) for NeoCRT+L; 0.77 (0.63-0.95) for NeoCRT+P; 0.66 (0.59-0.75) for L+AT; 0.69 (0.54-0.88) for P+AT; and 1.0 (reference) for the CRT group. Comorbidity did not attenuate the relationship between treatment and survival. This large study demonstrates that patients with clinical stage IIIA-N2 NSCLC, who underwent neoadjuvant chemoradiation followed by lobectomy, were associated with an improved survival.

Prognostic factors after complete resection of pN2 non–small cell lung cancer

This retrospective, multicenter study aimed to determine prognostic factors of completely resected pathologic N2 stage IIIA non-small cell cancer (NSCLC). From 25 participating hospitals, 496 patients (325 men and 171 women; median age, 65 years) who underwent complete resection without preoperative treatment for pT1-3 N2 M0, stage IIIA NSCLC between2000 and 2004 were enrolled. Lobectomy/bilobectomy was performed in 462 patients and pneumonectomy in 34. Some kind of adjuvant chemotherapy was administered to 296 patients. Survivals were calculated using the Kaplan-Meier method, and prognostic factors were determined using the Cox proportional hazards model. Five-year overall survival (OS) and disease-free survival (DFS) were 44.8% and 24.2%, respectively. pT classification (hazard ratio (HR), pT1/pT2/pT3=1/1.32/2.03), single or multiple N2 metastases (HR, single/multiple=1/1.36), and skip or nonskip N2 metastasis (HR, skip/nonskip=1/1.30) were found to be independent prognostic factors for DFS. Sex (HR, female/male=1/1.36), performance status (HR, PS-0/PS-1=1/1.37), tumor diameter (HR, 1.12 per 1-cm increase), pT-factor (HR, pT1/pT2/pT3=1/1.37/2.22), and extent of N2 metastasis (HR, localized/extended=1/1.39) were shown to be independent prognostic factors for OS. We found that pT classification was a significant prognostic indicator for OS and DFS whereas tumor diameter, performance status, and sex were ones for OS. Single N2 metastasis and skip N2 metastasis were demonstrated as favorable prognostic factors for DFS, limited N2 metastasis was one for OS, and these should be considered as stratification factors for trial on adjuvant therapy.

Concurrent chemoradiation (CChRT) with bi-weekly docetaxel and cisplatin and thoracic radiotherapy for stage III non-small cell lung cancer (NSCLC): A phase II study from the Galician Lung Cancer Group.

7549 Background: CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly docetaxel (D) and cisplatin (C) and thoracic radiotherapy. Methods: 50 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 &gt; 1.1, V20 &lt; 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 14,5 months. Results: The p characteristics were: mean age 59,1 years (34-75); male/female 44/6; squamous/adeno/large cell carcinoma: 52%/34%/14%; stage IIIAN2 14 p (28%) and stage IIIB 36 p (72%). All p were evaluable for response and toxicity. RR: 4 CR, 36 PR (RR 80%; 95% CI:69-91), 4 SD (8%) and 6 PD (12%). The median PFS was 13 months (95% CI:8-18) and median OS was 19 months (95% CI:14-24). The PFS and OS at 1/2 years were 52%/30% and 79%/40% respectively. A total of 50 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 2/16; anemia 12/0; nausea/vomiting 28/2; diarrhea 22/4; there were two episodes of febrile neutropenia. Main toxicities per p in CChRT (D-C doses: 192, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28/6; anemia 60/0; esophagitis 52/4 and pneumonitis 34/0; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p. Conclusions: CChRT with bi-weekly docetaxel and cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.

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.