Stage III-N2 Non-small Cell Lung Research Articles

What Is the Accuracy of Clinical Staging for Stage III-Single-station N2 NSCLC? A Multi-Centre UK Study

IntroductionSingle-station N2 (ssN2) versus multi-station N2 has been used as a selection criterion for treatment recommendations between surgical versus non-surgical multimodality treatment in stage III-N2 NSCLC. We hypothesized that clinical staging would be susceptible to upstaging on pathologic staging and, therefore, challenge this practice. MethodsA retrospective study of prospectively collected routine clinical data for patients with stage III-N2 NSCLC that had completed computed tomography (CT), positron emission tomography (PET), and staging endobronchial ultrasound (EBUS) and had been confirmed clinical stage III-ssN2 at multidisciplinary team discussion and went on to complete surgical resection as the first treatment to provide pathologic staging. The study was completed in two cohorts (A) across a single cancer alliance in England (Greater Manchester) January 1, 2015 to December 31, 2018 and (B) across five United Kingdom centers to validate the findings in part A January 1, 2016 to December 31, 2020. ResultsA total of 115 patients met the inclusion criteria across cohort A (56 patients) and cohort B (59 patients) across 15 United Kingdom hospitals. The proportion of cases in which clinical stage III-ssN2 was upstaged to pathologic stage III-multi-station N2 was 34% (19 of 56) in cohort A, 32% in cohort B (19 of 59), and 33% across the combined study cohort (38 of 115). Most patients had a single radiologically abnormal lymph node on CT and PET (88%, 105 of 115). In the majority, the reasons for missed N2 disease on staging EBUS were due to inaccessible (stations 5, 6, 8, 9) N2 nodes at EBUS (34%, 13 of 38) and accessible lymph nodes not sampled during staging EBUS as not meeting sampling threshold (40%, 15 of 38) rather than false-negative sampling during EBUS (26%, 10 of 38). ConclusionsDuring multidisciplinary team discussions, clinicians must be aware that one-third of patients with stage III-ssN2 on the basis of CT, PET, and staging EBUS do not truly have ssN2 and this questions the use of this criterion to define treatment recommendations.

Prognostic Significance of the Highest Mediastinal Lymph Node Involvement in Patients with Stage III-N2 Non-small Cell Lung Cancer.

Highest mediastinal lymph node (HMLN) involvement is a category of uncertain resection, yet the prognostic significance of HMLN involvement remains controversial. A total of 486 patients with pathological stage III-N2 disease who underwent radical resection were enrolled from January 2015 to December 2018. Patients were allocated into two groups-HMLN involvement (219 cases) and HMLN-negative (249 cases) groups. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of HMLN involvement on 5-year recurrence-free survival (RFS) and overall survival (OS). The proportion of patients with multiple N2 diseases (72.1% vs. 23.7%; p<0.001) and stage IIIA (87.2% vs. 77.5%; p<0.009) were greater in the HMLN-involvement group than in the HMLN-negative group, and the survival rates of the HMLN-involvement group were significantly lower than those of the HMLN-negative group (RFS: 27.2% vs. 49.8%, p<0.001; OS: 42.1% vs. 59.2%, p=0.001). HMLN status was an independent factor for OS only (RFS: adjusted hazard ratio [aHR] 1.26, 95% confidence interval CI 0.94-1.68; OS: aHR 1.45, 95% CI 1.07-1.99) in the entire stage III cohort. After stratification of patients according to stage, the involvement of HMLN decreased both RFS and OS in the stage IIIA group (RFS: aHR 1.46, 95% CI 1.06-2.02; OS: aHR 1.70, 95% CI 1.19-2.42); however, no such difference was observed within the stage IIIB group. HMLN involvement is a prognostic factor of deteriorating survival in highly advanced N2 disease only in patients with stage IIIA.

Surgery is a promising strategy for improving overall survival for stage III-N2 non-small cell lung cancer patients.

Surgery is commonly used to treat stage I lung cancer patients, whereas radiotherapy is applied to treat stage III lung cancer patients. However, few advanced-stage lung cancer patients benefit from surgery. This study aimed to investigate the efficacy of surgery for stage III-N2 non-small cell lung cancer (NSCLC) patients. A total of 204 patients with stage III-N2 NSCLC were included and divided into surgery (n=60) and radiotherapy (n=144) groups. The clinical characteristics [tumor node metastasis (TNM) stage, and adjuvant chemotherapy] and basic information (gender, age, and smoking/family history) of the included patients were evaluated. Furthermore, the patients' Eastern Cooperative Oncology Group (ECOG) scores and comorbidities were also evaluated, and the Kaplan-Meier approach was utilized to analyze their overall survival (OS). A multivariate Cox proportional hazards model was generated to analyze OS. There was a significant difference in disease stages (IIIa and IIIb) between the surgery and radiotherapy groups (P<0.001). Compared with the surgery group, there were more patients with ECOG scores of 1 and 2 and fewer patients with ECOG scores of 0 in the radiotherapy group (P<0.001). Moreover, there was a significant difference in comorbidities between the stage III-N2 NSCLC patients in the two groups (P=0.011). The OS rate was higher significantly in stage III-N2 NSCLC patients in the surgery group compared to that in the radiotherapy group (P<0.05). Kaplan-Meier analysis demonstrated that the OS of III-N2 NSCLC was markedly better in the surgery group compared to the radiotherapy group (P<0.05). The multivariate proportional hazards model showed that age, T stage, surgery, disease stage, and adjuvant chemotherapy were independent prognostic predictors for OS in stage III-N2 NSCLC patients. Surgery is associated with improved OS in stage III-N2 NSCLC patients and is recommended to treat these patients.

What is the optimal management of potentially resectable stage III-N2 NSCLC? Results of a fixed-effects network meta-analysis and economic modelling.

There is a critical need to understand the optimal treatment regimen in patients with potentially resectable stage III-N2 nonsmall cell lung cancer (NSCLC). A systematic review of randomised controlled trials was carried out using a literature search including the CDSR, CENTRAL, DARE, HTA, EMBASE and MEDLINE bibliographic databases. Selected trials were used to perform a Bayesian fixed-effects network meta-analysis and economic modelling of treatment regimens relevant to current-day treatment options: chemotherapy plus surgery (CS), chemotherapy plus radiotherapy (CR) and chemoradiotherapy followed by surgery (CRS). Six trials were prioritised for evidence synthesis. The fixed-effects network meta-analyses demonstrated an improvement in disease-free survival (DFS) for CRS versus CS and CRS versus CR of 0.34 years (95% CI 0.02-0.65) and 0.32 years (95% CI 0.05-0.58) respectively, over a 5-year period. No evidence of effect was observed in overall survival although point estimates favoured CRS. The probabilities that CRS had a greater mean survival time and greater probability of being alive than the reference treatment of CR at 5 years were 89% and 86% respectively. Survival outcomes for CR and CS were essentially equivalent. The economic model calculated that CRS and CS had incremental cost-effectiveness ratios of £19 000/quality-adjusted life-year (QALY) and £78 000/QALY compared to CR. The probability that CRS generated more QALYs than CR and CS was 94%. CRS provides an extended time in a disease-free state leading to improved cost-effectiveness over CR and CS in potentially resectable stage III-N2 NSCLC.

Machine Learning to Refine Selection Criteria of Post-Operative Radiotherapy for Resectable Stage III-N2 Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The role of post-operative radiotherapy (PORT) for completely resected N2 non-small cell lung cancer (NSCLC) is controversial, given the recently published LungART and PORT-C trials. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on the extent of nodal involvement. <h3>Materials/Methods</h3> Patients with completely resected N2 NSCLC were identified in the National Cancer Database diagnosed between 2004 and 2017. The query was subsequently limited to patients with pN2 disease, known pathologic T stage, and no evidence of distant metastasis. Patients were excluded if they had unknown follow-up, did not undergo surgery (lobectomy, bilobectomy, or pneumonectomy), did not undergo lymph node dissection, had positive margins, had unknown number of positive lymph nodes or total lymph nodes examined, or received neoadjuvant radiation. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation values (SHAP) were used to identify prognostic and predictive thresholds for the number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Multivariable (MVA) Cox proportional-hazards regression was used for confirmatory analysis. <h3>Results</h3> A total of 16,789 patients with completely resected N2 NSCLC were identified. Of the patients that met inclusion criteria, 6181 (36.8%) received PORT. When radiation treatment technique could be determined, about half received 3D conformal radiation therapy (18.7% of all patients) and about half received IMRT (19.9% of all patients). Median follow-up for the entire cohort was 32.0 months (0-183.1 months). Median OS of the whole population was 41.7 months (95%CI: 40.7-43.1). For patients who received PORT, median OS was 47.6 months (95%CI: 45.2-49.7). For patients who did not receive PORT, median OS was 38.6 months (95%CI: 37.1-39.9). Using SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On MVA, PORT was not significantly associated with OS (HR: 0.96; 95%CI: 0.92-1.01); (p=0.111). However, a subset analysis of patients with 3+ positive LNs revealed that PORT improved OS (HR: 0.91; 95%CI: 0.86-0.97; p=0.002). Patients with 3+ positive LNs had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 31% (95%CI: 29-32%) without PORT. Patients with 1-2 positive LNs had a 5-year OS of 49% (95%CI: 47-51%) with PORT compared to 44% (95%CI: 43-46%) without PORT. On a separate subset analysis, in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95%CI: 0.85-0.96; p=0.001). Patient with positive LNR of 0.34+ had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 29% (95%CI: 28-31%) without PORT. Patients with a positive LNR of 0.00-0.33 had a 5-year OS of 47% (95%CI: 45-49%) with PORT compared to 43% (95%CI: 42-44%) without PORT. <h3>Conclusion</h3> This study suggests that patients with 3+ positive LNs or a LNR of 0.34+ may present a subpopulation of patients who could benefit from PORT. These findings warrant further investigation in a future prospective study.

EP05.02-006 Neoadjuvant DS-8201 for Stage III Non-small Cell Lung Cancer with HER2 20ins

Stage III-N2 non-small cell lung cancer (NSCLC) represents a highly heterogeneous disease and requires multimodality management. Neoadjuvant therapy is indicated when upfront surgery is difficult with the aim of tumor shrinkage. Trastuzumab deruxtecan (i.e., DS-8201) is an emerging antibody-drug conjugate (ADC) which four topoisomerase I inhibitors are linked to a HER2-targeting antibody. Prior study has shown a 55% objective response rate (ORR) in previous treated metastatic HER2-mutant NSCLC with durable effect.

The effect of adjuvant chemoradiotherapy on survival after R0 resection for stage III-N2 nonsmall cell lung cancer: A meta-analysis.

Adjuvant chemotherapy is still the standard treatment for stage III-N2 nonsmall cell lung cancer after R0 resection, and it is still controversial whether conventional adjuvant radiotherapy is needed. We used meta-analysis to try to answer whether adjuvant postoperative chemoradiotherapy (POCRT) can bring survival benefits to patients with stage III-N2 nonsmall cell lung cancer after R0 resection. Up to June 25, 2021, the databases of PubMed, Embase, Cochrane Library, CNKI, and Wanfang were searched, and clinical studies on POCRT for stage III-N2 nonsmall cell lung cancer were included. RevMan5.4 software was used for meta-analysis. A total of 8959 patients were included in 5 randomized controlled trials and 17 retrospective studies. The results of the meta-analysis showed that POCRT could improve 3 and 5 years overall survival (OS) rate (OR = 1.52, 95%CI: 1.05-2.20; OR = 1.30, 95%CI: 1.16-1.46), 3 and 5 years disease-free survival (DFS) rate (OR = 1.34, 95%CI: 1.01-1.76; OR = 1.74, 95%CI: 1.43-2.12), and 5-year locoregional recurrence-free survival (LRFS) rate (OR = 2.69, 95%CI: 1.76-4.11) in patients with stage III-N2 nonsmall cell lung cancer compared with adjuvant postoperative chemotherapy (POCT) alone. But could not improve 5-year distant metastasis-free survival (DMFS) rate (OR = 1.14, 95%CI: 0.52-2.52). The results of subgroup analysis showed that postoperative sequential chemoradiotherapy could improve the 3 and 5 years OS rate (OR = 2.06, 95%CI: 1.22-3.46; OR = 1.39, 95%CI: 1.21-1.59). Three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) can improve the 3 and 5 years OS rate (OR = 1.80, 95%CI: 1.09-2.99; OR = 1.31, 95%CI: 1.04-1.66). In addition, POCRT could improve the 3-year OS rate (OR = 1.88, 95%CI: 1.21-2.92) in patients with N2 single-station lymph node metastasis compared with POCT alone. Compared with POCT alone, adjuvant POCRT can significantly improve the overall survival rate of patients with NSCLC after R0 resection of stage III-N2, especially in patients with N2 single-station lymph node metastasis. Accurate radiotherapy techniques such as 3DCRT or IMRT are recommended, and postoperative sequential chemoradiotherapy is the best treatment mode.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for patients with stage III-N2M0 non-small cell lung cancer (NSCLC): A population-based study.

8503 Background: Stage III-N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease with controversial management options. Induction therapy as part of multimodal treatment is the standard of care for Stage III-N2 NSCLC. We aim to investigate the effect of adding radiotherapy to neoadjuvant chemotherapy on survival outcomes. Methods: All adult NSCLC patients diagnosed between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database using ICD-O-3 histologic type coding. Inclusion criteria involved stage III NSCLC patients with ipsilateral lymph node involvement (N2), of any T stage, and with no known distant metastasis (M0). Our main sub-cohorts were patients who either underwent chemoradiotherapy (CRT) or chemotherapy (CT) in neoadjuvant settings. Our primary outcomes were overall survival (OS) and cancer-specific survival (CSS) in months. Cox proportional hazards model was used to analyze the effect of each treatment modality on OS and CSS in univariate and multivariate fashions. Multivariate analysis was adjusted for age, sex, marital status, T stage, resected lymph node status, tumor histology, primary site, laterality, and surgical procedure. Inverse probability treatment weighting (IPTW) was applied to create weighted samples based on study covariates. Results: Our analysis included 1175 patients; 799 (68.0%) underwent neoadjuvant CRT and 376 (32.0%) underwent neoadjuvant CT. Sample median age was 63 (IQR:56-69) years. T2 stage was the most prevalent (N =561, 47.7%), followed by T4 (N=243, 20.7%), T1 (N=228, 19.4%), and T3 (N=143, 12.2%). The main tumor histology was non-squamous cell carcinoma in 773 (65.8%) patients. The upper lobe was the most common primary tumor site (N =788, 67.1%). Patients underwent lobectomy (N=917, 78.0%), pneumonectomy (N=184, 15.7%), or sub-lobar resection (N=69, 5.9%). Adding radiotherapy to chemotherapy showed a slightly higher median OS than chemotherapy alone in neoadjuvant settings (51 vs. 47 months, respectively), and a higher median CSS (75 vs. 59 months, respectively). However, these differences were not statistically significant for OS or CSS (HR = 1.08, 95% CI: 0.91-1.28 and HR = 1.04, 95% CI: 0.89-1.21, respectively). After adjustment, age, T3-T4 stage, non-squamous histology, lower lobe primary site, positive resected lymph nodes, and pneumonectomy were all significant independent predictors for worse OS and CSS. IPTW analysis showed no remarkable survival advantage for CRT patients (HR = 1.15, 95% CI: 0.95-1.40 and HR= 1.12, 95% CI: 0.90-1.39) for OS and CSS, respectively. Conclusions: Adding radiotherapy to neoadjuvant CT did not result in significant survival benefits. Multiple prognostic factors should be taken into consideration when identifying the optimal choice and sequence of multimodal treatment for stage III-N2M0 NSCLC patients.

Machine learning to refine prognostic and predictive nodal burden thresholds for post-operative radiotherapy in completely resected stage III-N2 non-small cell lung cancer

BackgroundThe role of post-operative radiotherapy (PORT) for completely resected N2 non-small-cell lung cancer (NSCLC) is controversial in light of recent randomized data. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on extent of nodal involvement. Materials/MethodsPatients with completely resected N2 NSCLC were identified in the National Cancer Database. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation (SHAP) values were used to identify prognostic and predictive thresholds of number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Cox proportional hazards regression was used for confirmatory analysis. ResultsA total of 16,789 patients with completely resected N2 NSCLC were identified. Using the SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On multivariate analysis, PORT was not significantly associated with OS (p = 0.111). However, on subset analysis of patients with 3+ positive LNs, PORT improved OS (HR: 0.91; 95% CI: 0.86–0.97; p = 0.002). On a separate subset analysis in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95% CI: 0.85–0.96; p = 0.001). Patients with 3+ positive lymph nodes had a 5-year OS of 38% with PORT compared to 31% without PORT. Patient with positive lymph node ratio 0.34+ had a 5-year OS of 38% with PORT compared to 29% without PORT. ConclusionsPatients with a high lymph node burden or lymph node ratio may present a subpopulation of patients who could benefit from PORT. To our knowledge, this is the first study to use machine learning algorithms to address this question with a large national dataset. These findings address an important question in the field of thoracic oncology and warrant further investigation in prospective studies.

Validation of the IASLC Residual Tumor Classification in Patients With Stage III-N2 Non-Small Cell Lung Cancer Undergoing Neoadjuvant Chemoradiotherapy Followed By Surgery.

The aim of this study was to validate the International Association for the Study of Lung Cancer (IASLC) residual tumor classification in patients with stage III-N2 non-small cell lung cancer (NSCLC) undergoing neoadjuvant concurrent chemoradiotherapy (nCCRT) followed by surgery. As adequate nodal assessment is crucial for determining prognosis in patients with clinical N2 NSCLC undergoing nCCRT followed by surgery, the new classification may have better prognostic implications. Using a registry for thoracic cancer surgery at a tertiary hospital in Seoul, Korea, between 2003 and 2019, we analyzed 910 patients with stage III-N2 NSCLC who underwent nCCRT followed by surgery. We classified resections using IASLC criteria: complete (R0), uncertain (R[un]), and incomplete resection (R1/R2). Recurrence and mortality were compared using adjusted subdistribution hazard model and Cox-proportional hazards model, respectively. Of the 96.3% (n = 876) patients who were R0 by Union for International Cancer Control (UICC) criteria, 34.5% (n = 3O2) remained R0 by IASLC criteria and 37.6% (n = 329) and 28% (n = 245) migrated to R(un) and R1, respectively. Most of the migration from UICC-R0 to lASLC-R(un) and IASLC-R1/R2 occurred due to inadequate nodal assessment (85.5%) and extracapsular nodal extension (77.6%), respectively. Compared to R0, the adjusted hazard ratios in R(un) and R1/R2 were 1.20 (95% confidence interval, 0.94-1.52), 1.50 (1.17-1.52) ( P fortrend = .001) for recurrence and 1.18 (0.93-1.51) and 1.51 (1.17-1.96) for death ( P for trend = .002). The IASLC R classification has prognostic relevance in patients with stage III-N2 NSCLC undergoing nCCRT followed by surgery. The IASLC classification will improve the thoroughness of intraoperative nodal assessment and the completeness of resection.

Evaluation of Postoperative Radiotherapy Effect on Survival of Resected Stage III-N2 Non-small Cell Lung Cancer Patients

Objective: The role of postoperative radiotherapy (PORT) in resected stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains controversial. This study aimed to explore the effect of PORT on survival of resected stage IIIA-N2 NSCLC patients.Methods: Resected stage IIIA-N2 NSCLC patients aged 18 years or older were identified from the SEER (Surveillance, Epidemiology, and End Results) database from 2010 to 2015. Cox regression analysis was used to identify factors including PORT associated with survival time. A subgroup analysis of patients stratified by number of lymph node metastases was also performed. Overall survival (OS) and overall mortality were compared among the different groups.Results: A total of 3,445 patients were included in the study. Multivariate Cox analysis showed that PORT had no significant impact on survival of patients with <6 positive lymph node [hazard ratio (HR) = 1.012, P = 0.858, 95% CI: 0.886–1.156]. Postoperative chemotherapy (POCT) (HR = 0.605, P < 0.001, 95% CI: 0.468–0.783) and PORT (HR = 0.724, P = 0.007, 95% CI: 0.574–0.914) are both favorable prognostic factors for stage IIIA-N2 patients with ≥6 positive lymph nodes. In 2,735 patients who featured <6 number of positive regional lymph nodes, patients who received PORT had better survival and lower 3-years and 5-years overall mortality rate than patients who underwent surgery only (41 vs. 28 months, P < 0.015). There was no significant difference in the survival of postoperative patients who underwent POCT in view of whether received PORT (44 vs. 53 months, P = 0.176). A total of 710 patients who featured ≥6 number of positive regional lymph node metastasis were divided into two groups by PORT. PORT did not prolong survival for postoperative patients who did not receive chemotherapy (12 vs. 15 months, P = 0.632). PORT showed a significant advantage in influencing OS in patients who received PORT combined with POCT as compared with those who received POCT only (32 vs. 25 months, P = 0.006).Conclusions: For IIIA-N2 patients with <6 lymph node metastases, use of PORT can be encouraged to improve survival. For patients with ≥6 positive lymph nodes, PORT combined with POCT significantly improved OS and decreased overall mortality.

Systemic Inflammation-Immune Status Predicts Survival in Stage III-N2 Non-Small Cell Lung Cancer

Systematic inflammation-immune status has been thought to play a crucial role in tumorigenesis and progress. This study evaluated the prognostic value of systematic inflammation-immune status in patients with resected non-small cell lung cancer with pathological N2 nodal involvement (pN2-NSCLC). The relation between the preoperative systematic inflammation-immune score (SIS), defined as preoperative peripheral platelet count× neutrophil count/lymphocyte count, and prognosis was tested in a retrospective study of 660 consecutive patients with completed resected pN2-NSCLC and validated by a prospective study of 189 patients enrolled (NCT00880971). SIS of 650× 109 was an optimal cutoff point to stratify the patients with pN2-NSCLC into high (>650× 109) and low (≤650× 109) SIS groups in the training cohort. Univariate and multivariate analyses revealed that the SIS was an independent predictor for overall survival, disease-free survival, and distant metastasis-free survival. In the validation group, high SIS (>650× 109) predicted poor 5-year overall survival (hazard ratio [HR], 2.418; P=.006), disease-free survival (HR, 1.542; P= .042), and distant metastasis-free survival (HR, 1.682; P= .024). In addition to the number of positive lymph nodes, the area under the receiver operating characteristic curve of the SIS for outcomes was higher than the neutrophil count-to-lymphocyte count ratio, platelet count-to-lymphocyte count ratio, and other conventional clinicopathologic indices. The preoperative SIS is a more sensitive survival predictor than most of the other conventional clinical indices and may aid in more accurately stratifying patients for risk assessment and treatment decision.

P2.01-113 Prognostic Roles of Neoadjuvant and Adjuvant Chemotherapy for Treating Patients with Operable Stage III-N2 Non-Small Cell Lung Cancer (NSCLC)

P2.01-113 Prognostic Roles of Neoadjuvant and Adjuvant Chemotherapy for Treating Patients with Operable Stage III-N2 Non-Small Cell Lung Cancer (NSCLC)

Postoperative Radiotherapy for Surgically Resected ypN2 Non-Small Cell Lung Cancer

The role of postoperative radiotherapy (PORT) in patients with clinical stage III-N2 (cIII-N2) non-small cell lung cancer (NSCLC) treated with induction chemotherapy and surgical resection with persistent ypN2 disease is not well established. We retrospectively reviewed a prospectively maintained database for patients with cIII-N2 NSCLC who underwent induction chemotherapy followed by resection (2004-2016). Exclusion criteria included induction radiotherapy, non-biopsy-confirmed cN2 disease, incomplete resection, ypN0/1, and nonanatomic resection. The primary outcome was locoregional recurrence (LR); secondary outcomes were disease-free survival (DFS), lung cancer-specific death (LCSD), and overall survival (OS). Associations between variables and outcomes were assessed using Fine and Gray competing risk regression for LR/LCSD and Cox proportional hazard models for survival. Of the 501 patients identified with cIII-N2 disease, 99 met the inclusion criteria. Median follow-up was 25 months (range, 3-137 months). Sixty-nine patients (70%) received PORT. Sixty (61%) developed a recurrence: 3 (5%) with an initial isolated LR and 57 (95%) with an initial distant recurrence. On multivariable analysis, PORT was not associated with LR (HR, 0.51 [95% CI, 0.22-1.21], p= 0.13). PORT was also not associated with DFS (p= 0.6) or LCSD (p= 0.1). PORT was associated with improved 3-year OS (55% [95% CI, 42%-71%]) versus the no-PORT group (50% [95% CI, 34%-74%]) (p= 0.04). PORT is not independently associated with decreased LR or improved DFS/LCSD in this patient population. Given that the predominant failure pattern was distant recurrence, future clinical trials should focus on adjuvant systemic therapies, which may decrease distant recurrences in ypN2 patients.

A closer look at the safety and effectiveness of modern PORT in stage III-N2 non-small cell lung cancer.

We appreciate the interest of Dr. Fiorica in our study (1). The optimal treatment of patients with stage III locally advanced non-small-cell lung cancer (NSCLC) is still debatable. Regarding the high incidences and poor treatment outcomes (2), there is gaining interest in an optimization of the multimodality treatment for these patients.

P1.08-066 Prognostic Factors of Post-Recurrence Survival in Patients with Completely Resected Stage III-N2 Non-Small Cell Lung Cancer

Post-recurrence survival (PRS) after curative resection has been considered a multifactorial process dependent on clinicopathological, biological, and treatment modality in non-small cell lung cancer (NSCLC). The aim of this study is to investigate the prognostic factors for PRS in patients with completely resected stage III-N2 NSCLC. Two hundred forty-five patients who had complete resection for pathologic stage III-N2 NSCLC between 2003 and 2014 were enrolled. First, a number of clinicopathological factors were evaluated to find prognostic factors for recurrence by Cox proportional hazards models. Second, the following additional data were evaluated: presence of recurrent symptom, recurrence patterns, treatment modality, use of targeted agents, and recurrence-free interval. The prognostic effects of these factors were analyzed for PRS. One hundred twenty-four patients experienced recurrence during a median follow-up period of 36.3 months. Univariate analysis showed that vascular invasion, lymphatic invasion, tumor size, number of positive lymph nodes (LNs), and multistation N2 were poor prognostic factors for recurrence. Lymphatic invasion, tumor size, and number of positive LNs were even worse independent prognostic factors for recurrence by multivariate analysis. Of 124 recurred patients, 21 patients (17%) were symptomatic at the time of initial recurrence, and the remaining 103 patients (83%) were asymptomatic. In these asymptomatic patients, recurrence was detected by tumor markers in 3, computed tomography (CT) in 80, or positron emission tomography-CT (PET/CT) in 20 patients. The mean recurrence-free interval was 14.0 months (≤ 12 months in 72, > 12 months in 52 patients). The patterns of recurrence were presented as loco-regional recurrence in 37 (30%), distant metastasis in 33 patients (27%), and both in 54 patients (43%). The types of initial treatment included surgery in 15 (12%), chemotherapy in 68 (55%), radiotherapy in 19 (15%), and chemo-radiation in 16 patients (13%). The median duration of PRS was 30.5 (1-109) months and the 2-year and 5-year of PRS were 54% and 23%, respectively. Univariate analysis identified no symptom of recurrence, only LN metastasis without distant organ metastasis, treatment modality, and a longer recurrence-free interval as good prognostic factors, while no symptom and a longer recurrence-free interval were independent prognostic factors for PRS in a multivariate analysis. No symptom at the time of recurrence and a longer recurrence-free interval were significant predictors of better PRS in patients that have underwent complete resection of stage III-N2 NSCLC.

126P Outcome after post-operative radiotherapy (PORT) in ypN2 or R1/R2 versus no PORT in ypN0 stage III-N2 non-small cell lung cancer after induction chemotherapy and resection

126P Outcome after post-operative radiotherapy (PORT) in ypN2 or R1/R2 versus no PORT in ypN0 stage III-N2 non-small cell lung cancer after induction chemotherapy and resection

Postoperative Radiotherapy in Resected Ypn2 Stage Iii-N2 Non-Small Cell Lung Cancer: Can Modern Conformal Radiotherapy Compensate for the Poor Outcome?

ABSTRACT Aim: To investigate the effect of modern postoperative radiotherapy (PORT) ) on the 5-year overall survival (OS) in non-small cell lung cancer (NSCLC) patients with persistent N2 disease after induction chemotherapy. Methods: Patients with resectable pathologically proven N2 NSCLC who received induction chemotherapy followed by surgery were selected from a prospective database from September 1999 to December 2010. 103 patients without progressive disease after chemotherapy underwent resection. 95% of patients were staged with FDG-PET and 85% underwent brain imaging. In case of incomplete resection or persistent ypN2 status, patients received 3D-PORT (n = 53) to a dose of 50-66 Gy in 2 Gy fractions. Patients with a complete resection and with nodal downstaging to ypN0 or ypN1 did not receive PORT. Results: Median follow up time was 46.3 months. For the operated group (n = 103) the 5-year OS was 31.3%, relapse free survival (RFS) 29.8%, and the cumulative local recurrence (LR) rate 51.0%. Multivariate analysis identified as significant co-variables for 5-year OS: PORT (relative risk (RR) = 0.441, p = 0.017), downstaging after chemotherapy (RR = 0.478, p = 0.030) and completeness of resection (RR = 2.051, p = Conclusions: Although patients having received PORT were a group with adverse prognostic factors, PORT could improve survival for patients with stage IIIA NSCLC and ypN0/1 or R1/R2. This needs to be investigated further in a prospective randomized trial. As LR remains high also in the ypN0 and ypN1 groups, PORT is worth to be investigated or considered in these patients as well. Disclosure: All authors have declared no conflicts of interest.

Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy

BackgroundInhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy).MethodsWe have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy.ResultsId1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed.ConclusionsA correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.

Predictors for Locoregional Recurrence for Clinical Stage III-N2 Non-small Cell Lung Cancer with Nodal Downstaging After Induction Chemotherapy and Surgery

PurposePathologic downstaging following chemotherapy for stage III-N2 NSCLC is a well-known positive prognostic indicator. However, the predictive factors for locoregional recurrence (LRR) in these patients are largely unknown.MethodsBetween 1998 and 2008, 153 patients with clinically or pathologically staged III-N2 NSCLC from two cancer centers in the United States were treated with induction chemotherapy and surgery. All had pathologic N0-1 disease, and none received postoperative radiotherapy. LRR were defined as recurrence at the surgical site, lymph nodes (levels 1–14 including supraclavicular), or both.ResultsMedian follow-up was 39.3 months. Pretreatment N2 status was confirmed pathologically (18.2 %) or by PET/CT (81.8 %). Overall, the 5-year LRR rate was 30.8 % (n = 38), with LRR being the first site of failure in 51 % (22/+99877943). Five-year overall survival for patients with LRR compared with those without was 21 versus 60.1 % (p < 0.001). Using multivariate analysis, significant predictors for LRR were pN1 disease at time of surgery (p < 0.001, HR 3.43, 95 % CI 1.80–6.56) and a trend for squamous histology (p = 0.072, HR 1.93, 95 % CI 0.94–3.98). Five-year LRR rate for pN1 versus pN0 disease was 62 versus 20 %. Neither single versus multistation N2 disease (p = 0.291) nor initial staging technique (p = 0.306) were predictors for LRR. N1 status also was predictive for higher distant recurrence (p = 0.021, HR 1.91, 95 % CI 1.1–3.3) but only trended for poorer survival (p = 0.123, HR 1.48, 95 % CI 0.9–2.44).ConclusionsLRR remains high in resected stage III-N2 NSCLC patients after induction chemotherapy and nodal downstaging, particularly in patients with persistent N1 disease.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-012-2800-x) contains supplementary material, which is available to authorized users.