Resectable N2 Research Articles

Prophylactic cranial irradiation in patients with resected small-cell lung cancer: A systematic review and meta-analysis.

Prophylactic cranial irradiation (PCI) was recommended for limited-stage small-cell lung cancer (SCLC) patients with complete or partial response to primary chemoradiotherapy. But it is still controversial regarding its role in SCLC patients who have had radical resection. This meta-analysis aims to evaluate the efficacy of PCI in resected SCLC patients. We searched PubMed, EMBASE, Web of Science, CENTRAl, and ClinicalTrials for controlled trials and cohort studies regarding PCI in postoperative SCLC patients. The correlation between PCI and post-operative outcomes in SCLC patients, including survival and brain metastasis rate (BMR), was examined using hazard ratios (HRs) and risk ratios with corresponding 95% confidence intervals. Quality of studies was assessed by the Newcastle-Ottawa Scale (NOS), and publication bias was assessed by Begg's test. Meta-analysis of eight studies with 2688 patients in total showed PCI was associated with improved overall survival (OS) for resected SCLC (HR: 0.65, 95% CI: 0.57-0.75, p < 0.01). In addition, subgroup analysis on three studies including 923 patients confirmed the protective role of postoperative PCI in N0 SCLC patients (HR: 0.79, 95% CI: 0.61-0.97, p < 0.05). There was also a significant reduction in BMR in the PCI group pooled from six studies (HR: 0.58, 95% CI: 0.40-0.85, p < 0.01). The use of PCI delayed brain recurrence and improved OS in patients with resected, stage I-III SCLC. Importantly, patients with N0 SCLC can also benefit from postoperative PCI. In future studies, PCI's role in patients with resected N0 SCLC at different T stage may need to be explored.

Surgeon experience influence lymphadenectomy during VATS lobectomy: National VATS database results

ObjectivesAim of this study is to identify the factors that may influence the lymphadenectomy during VATS anatomical lung resection with particular interest on operator experience. Materials and methodsClinical and pathological data from the prospective VATS Italian nationwide registry were reviewed and analysed. Patients with incomplete data regarding tumor and surgical characteristics, GGO, or with distant metastases were excluded. Patients clinical data, tumor characteristics, operation information and surgeon experience were collected and compared to resected lymph nodes number (#RN), resected N2 nodes number (#N2RN) and resected N2 stations number. A multivariable model was built using logistic regression analysis. Surgeon experience was categorized considering the number of VATS major anatomical resection and years after residency. ResultsThe final analysis was conducted on 3727 patients. The median #RN and #N2RN were 11 (1–51) and 5 (0–41). Regarding the analysed outcomes, #N2RN > 6 resulted in 1812 (48.8%)cases, #RN > 10 in 2124 (57.0%)cases and more than 3 N2 stations were harvested in 1447 (38.8%)patients.First operator experience with number of VATS lobectomies>50 (p < 0.001), operator seniority after residency5-10years (p < 0.001), cTNM II/III(p = 0.017), lobectomy/bilobectomy vs segmentectomy (p < 0.001), and upper/middle lobe tumor location (p < 0.005)resulted significantly associated to #N2RN > 6 at the multivariable analysis. First operator experience with number of VATS lobectomies>50 (p < 0.001), operator seniority after residency5-10years (p < 0.001) and lobectomy/bilobectomy (p < 0.001) resulted significantly associated to #RN > 10 at the multivariable analysis. ConclusionsOur study showed that lymphadenectomy during VATS lobectomy is influenced by tumor factors such as cTstage and tumor location but also by operator experience, with a higher number of resected lymph nodes in surgeons with a high number of VATS procedures and years after residency compared to surgeons with less experience.

Prognostic factors for recurrence-free survival in resected pathologic N2-stage III non-small cell lung cancer treated with upfront surgery.

The standard treatment for pathological N2 (pN2) non-small-cell lung cancer (NSCLC) patients is definitive chemoradiation. Surgery might be beneficial for resectable pN2 disease, so we investigated the recurrence-free interval of upfront surgery for selected patients with resectable pN2 disease. The clinicopathologic characteristics of patients with pN2 NSCLC who underwent upfront anatomical resection at Taipei Veterans General Hospital from 2011 January to 2019 December were retrospectively reviewed. A Cox regression model was used to identify prognostic factors of recurrence-free survival (RFS). In total, 84 patients after curative lung anatomic resection were analyzed, with a 44-month median survival. The 1-, 3-, and 5-year RFS rates were 63.1%, 31.3%, and 19.9%, respectively, with a median RFS of 18.9 months. Multivariable cox regression analysis identified that the significant predictor for RFS was a tumor size of more than 3 cm (hazard ratio [HR] = 1.74, 95% CI, 1.07-2.83, p = 0.027). Visceral pleural invasion, LN harvest number, tumor stage, and N2 status including single zone (N2a) or multiple zones (N2b) were not prognostic factors in this study. Upfront surgery for resectable N2 disease achieved favorable outcomes in selected patients, especially better recurrence control with limited tumor size. Therapeutic advances might encourage surgeons to aggressive intervention.

Development and validation of a nomogram for predicting overall survival of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy.

Currently, the prognosis of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy is poor. The goal of this research was to develop and validate a novel nomogram for exactly predicting the overall survival (OS) of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. The data applied in our research were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. We divided selected data into a training cohort and a validation cohort using R software, with a ratio of 7:3. Univariate Cox regression and multivariate Cox regression were utilized to select significant variables to build the nomogram. To validate our nomogram, calibration curves, receiver operating characteristic curves (ROC), decision curve analysis (DCA), and Kaplan-Meier survival curves were employed. The nomogram model was also compared with the tumor-node-metastasis (TNM) staging system by utilizing net reclassification index (NRI) and integrated discrimination improvement (IDI). Eight variables-age, sex, operative type, LN removed number, chemotherapy, AJCC stage, M stage, histology-were statistically significant in the multivariate Cox regression analysis and were selected to develop our nomogram. Based on ROC curves, calibration curves, and DCA analysis, our novel nomogram demonstrated good predictive accuracy and clinical utility. Using Kaplan-Meier (KM) survival curves and log-rank tests, the risk stratification system was able to stratify patients based on their estimated mortality risk. The nomogram performed better than the TNM staging system based on the NRI and IDI indexes. We developed and validated a nomogram to predict prognosis of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. Using this nomogram, clinicians may find this nomogram useful in predicting OS of targeted patients and making more appropriate treatment decisions.

ASTRO Radiation Therapy Summary of the ASCO Guideline on Management of Stage III Non-Small Cell Lung Cancer

To develop a radiation therapy summary of recommendations on the management of locally advanced non-small cell lung cancer (NSCLC) based on the Management of Stage III Non-Small Cell Lung Cancer: American Society of Clinical Oncology Guideline, which was endorsed by the American Society for Radiation Oncology (ASTRO). The American Society of Clinical Oncology, ASTRO, and the American College of Chest Physicians convened a multidisciplinary panel to develop a guideline based on a systematic review of the literature and a formal consensus process, that has been separately published. A new panel consisting of radiation oncologists from the original guideline as well as additional ASTRO members was formed to provide further guidance to the radiation oncology community. A total of 127 articles met the eligibility criteria to answer 5 clinical questions. This summary focuses on the 3 radiation therapy questions (neoadjuvant, adjuvant, and unresectable settings). Radiation-specific recommendations are summarized with additional relevant commentary on specific questions regarding the management of preoperative radiation, postoperative radiation, and combined chemoradiation. Patients with stage III NSCLC who are planned for surgical resection, should receive either neoadjuvant chemotherapy or chemoradiation. The addition of neoadjuvant treatment is particularly important in patients planned for surgery in the N2 or superior sulcus settings. Postoperatively, patients who did not receive neoadjuvant chemotherapy should be offered adjuvant chemotherapy. The use of postoperative radiation for completely resected N2 disease is not routinely recommended. Unresectable patients with stage III NSCLC should ideally be managed with combined concurrent chemoradiation using a platinum-based doublet with a standard radiation dose of 60 Gy followed by consolidation durvalumab in patients without progression after initial therapy. Patients who cannot tolerate a concurrent chemoradiation approach can be managed either by sequential chemotherapy followed by radiation or by dose-escalated or hypofractionated radiation alone.

The association of postoperative radiotherapy with survival in resected N2 non-small cell lung cancer.

The current staging system for completely resected pathologic N2 non-small cell lung cancer (NSCLC) treated with chemotherapy is not suitable for distinguishing those patients most likely to benefit from postoperative radiotherapy (PORT). This study aimed to construct a survival prediction model that will enable individualized prediction of the net survival benefit of PORT in patients with completely resected N2 NSCLC treated with chemotherapy. A total of 3,094 cases from between 2002 and 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patient characteristics were included as covariates, and their association with overall survival (OS) with and without PORT was assessed. Data from 602 patients from China were included for external validation. Age, sex, the number of examined/positive lymph nodes, tumor size, the extent of surgery, and visceral pleural invasion (VPI) were significantly associated with OS (P<0.05). Two nomograms were developed based on clinical variables to estimate individuals' net survival difference attributable to PORT. The calibration curve showed excellent agreement between the OS predicted by the prediction model and that actually observed. In the training cohort, the C-index for OS was 0.619 [95% confidence interval (CI): 0.598-0.641] in the PORT group and 0.627 (95% CI: 0.605-0.648) in the non-PORT group. Results showed that PORT could improve OS [hazard ratio (HR): 0.861; P=0.044] for patients with a positive PORT net survival difference. Our practical survival prediction model can be used to make an individualized estimate of the net survival benefit of PORT for patients with completely resected N2 NSCLC who have been treated with chemotherapy.

Effect of postoperative radiotherapy on survival in patients with completely resected and pathologically confirmed stage N2 non-small-cell lung cancer: a systematic review and meta-analysis.

The role of postoperative radiotherapy (PORT) for patients with completely resected stage N2 non-small-cell lung cancer (NSCLC) has been controversial. This study aimed to investigate the efficacy of PORT and prognosis in these patients. An updated meta-analysis was conducted in this study to investigate the efficacy of PORT and prognosis in patients with completely resected and pathologically confirmed stage N2 NSCLC. This study is a systematic review and meta-analysis. Databases were searched up to 2 March 2022. All trials on patients with completely resected and pathologically confirmed stage N2 NSCLC undergoing PORT were screened, and data indicators in the PORT and non-PORT groups were extracted, respectively. The effect of PORT on overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) was estimated. Subgroup and sensitivity analyses were performed. In all, 20 studies involving 6340 patients were finally included. The PORT significantly increased OS [hazard ratio (HR) = 0.77, 95% CI: 0.71-0.84, p < 0.001), LRFS (HR = 0.63, 95% CI: 0.52-0.76, p < 0.001), and DFS (HR = 0.72, 95% CI: 0.63-0.82, p < 0.001) while it showed no significant difference in improving DMFS (HR = 0.86, 95% CI: 0.71-1.05, p = 0.14). Our results suggest that in the postoperative treatment of patients with completely resected and pathologically confirmed stage N2 NSCLC, the addition of PORT provides better local recurrence control and survival benefit, but no benefit for distant metastases. The PORT may be incorporated into the postoperative treatment options for some patients with high-risk factors. However, it needs to be validated by more prospective studies in the future. CRD42022314095.

124P Phase II study of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgery and adjuvant immunotherapy for resectable stage IIIA-B N2 non-small cell lung cancer: SQUAT trial (WJOG 12119L)

Neoadjuvant chemo-immunotherapy (CheckMate 816 regimen) has become a standard of care in treatment of resectable non-small cell lung cancer (NSCLC) patients in some countries. Addition of radiation therapy (RT) may further improve local control in locally advanced NSCLC patients. Here, we report the primary endpoint, major pathologic response (MPR), of the SQUAT trial (WJOG 12119L, JapicCTI- 195069)-a multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B 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.

Exploration of the optimal number of regional lymph nodes removed for resected N0 NSCLC patients: A population-based study.

BackgroundThe aim of our study was to explore the optimal number of regional lymph nodes removed (LNRs) in resected N0 non-small cell lung cancer (NSCLC) patients and identify potential risk factors.MethodsIncluded in this study were 55,024 N0 NSCLC patients between 2004 and 2015 based on the Surveillance, Epidemiology, and End Results database (SEER). All the patients were divided into No LNR group (57.8%), 1-3 LNRs group (8.1%) and ≥4 LNRs group (31.4%). Relevant clinical and patient parameters including overall survival (OS), lung cancer-specific survival (LCSS), gender, race, year of diagnosis, primary site, T stage, AJCC stage, laterality, histological type, lymphadenectomy, radiation, chemotherapy, age at diagnosis, insurance status, marital status, family income.ResultsKaplan-Meier analysis demonstrated LNRs had significantly better OS and LCSS than No LNRs in all the N0 NSCLC patients with different T stages (Logrank p<.001). Univariate and multivariate analysis showed that both OS and LCSS in ≥ 4 LNRs group were better than those in <1-3 LNRs group (OS: ≥4 LNRs group: HR, 0.583; 95%CI, 0.556-0.610; P<.001 vs.1-3 LNRs group: HR, 0.726; 95%CI, 0.687-0.769; P<.001; LCSS: ≥4 LNRs group: HR, 0.514; 95%CI, 0.480-0.550; P<.001 vs.1-3 LNRs group: HR, 0.647; 95%CI, 0.597-0.702; P<.001). In addition, whites, males, not upper lobe, large cell carcinoma and others, advance T stage or AJCC stage, no surgery, no LNR, no radiation, no chemotherapy, elder age at diagnosis, singled marital status and low family income had negative impact on prognosis of N0 NSCLC patients.ConclusionsOur study suggests that ≥ 4 LNRs can yield better survival outcomes compared with 1-3 LNRs in N0 NSCLC patients.

EP05.03-004 Risk Prediction of Multiple-station N2 Metastasis in Patients with Clinical Single-station N2 Non-small Cell Lung Cancer

Although the standard treatment for patients with N2 non-small-cell lung cancer (NSCLC) is definitive chemoradiation, several studies have demonstrated that minimal N2 disease, such as single-station N2 disease (N2 disease limited to a single mediastinal station), is a favorable prognostic indicator of resected N2 NSCLC. The objective of this study is to investigate long-term survival outcomes and develop a risk model for multiple-station N2 metastasis in patients with clinical single-station N2 NSCLC.

Long-term clinical outcomes and prognostic factors of upfront surgery as a first-line therapy in biopsy-proven clinical N2 non-small cell lung cancer.

BackgroundMultimodality therapy offers the best opportunity to improve pathological N2 non-small cell lung cancer (NSCLC) prognosis. This paper aimed to evaluate the long-term clinical outcomes and the prognostic factors of upfront surgery as first-line therapy in biopsy-proven clinical N2.MethodsRetrospective review of biopsy-proven cN2 NSCLC patients operated between 2007 and 2017. Upfront surgery was considered if the primary tumour was deemed completely resectable, with mediastinal nodal involvement confined to a single station and no preoperative evidence of extranodal tumour invasion.ResultsTwo hundred eighty-five patients who underwent radical resections were included. One hundred fifty-nine patients (55.8%) received induction chemotherapy. At follow-up completion, 127 (44.6%) patients had died. For the induction chemotherapy group, the median overall survival (OS) was 49 months [95% confidence interval (CI): 38–70 months], and the 5-year OS was 44.4%. The median and 5-year OS for the up front surgery group was 66 months (95% CI: 40–119 months) and 66.3%, respectively. There were no statistically significant differences between treatment approaches (p = 0.48). One hundred thirty-four patients (47.0%) developed recurrence. The recurrence-free survival (RFS) at 5 years was 17% (95% CI: 11–25%) for induction chemotherapy and 22% (95% CI: 9–32%) for upfront surgery; there were no statistically significant differences between groups (p = 0.93). No significant differences were observed based on the clinical N status (OS, p = 0.36; RFS, p = 0.65).ConclusionsUpfront surgery as first-line therapy for biopsy-proven cN2 NSCLC showed favourable clinical outcomes, similar to those obtained after induction chemotherapy followed by surgery. Therefore, it should be considered one of the multimodality treatment options in resectable N2 NSCLC.

Prognostic factors in completely resected lymph-node-negative pulmonary adenocarcinoma.

BackgroundLymph node involvement is one of the important prognostic factors for early-stage lung cancer. However, in lymph node-negative (N0) lung cancer the recurrent rate may be as high as 30%. We aimed to study potential prognostic factors including clinicopathological factors and epidermal growth factor receptor (EGFR) mutation status in this lung cancer population.MethodsWe retrospectively reviewed the medical records and pathological examinations of patients with completely resected N0 pulmonary adenocarcinoma treated in our institute between 2009 and 2016. We used Cobas® test to determine EGFR mutation status. Recurrence-free survival (RFS) was analyzed by univariable and multivariable Cox regression analyses.ResultsWe recruited 220 patients with median duration of follow up 5 years. Majority of these patients were in stage I (80%) and did not receive adjuvant therapy (86%). There were 53% with EGFR mutations which comprised of exon 19 deletion 51% and L858R 43%. Recurrence occurred in 64 out of 220 patients (29%). The median time to recurrence was 2.1 years. Statistically significant prognostic factors in both univariate and multivariate analyses included tumor size ≥4 centimeter (cm) (HR: 1.94; 95% CI: 1.03–3.67), visceral pleural invasion (HR: 2.53; 95% CI: 1.34–4.79), tumor necrosis (HR: 2.45; 95% CI: 1.13–5.31) and bronchial resection margin <2 cm (HR: 1.96; 95% CI: 1.10–3.51). However, presence of sensitizing EGFR mutation was not found to be a significant prognostic factor (HR: 1.20; 95% CI: 0.66–2.18; P=0.56).ConclusionsIn N0 surgically resected lung adenocarcinoma, there were significant pathological prognostic factors including tumor 4 cm or more, visceral pleural invasion, tumor necrosis and bronchial resection margin less than 2 cm. Mutation of EGFR is not a significant prognostic factor to determine the risk of recurrence in this population and their risks shall be determined by the other poor prognostic factors.

Meta-analysis of rates and causes of local recurrence in surgically-resected NSCLC and differences in recurrence and survival between Asian and non-Asian populations.

e20579 Background: Recently, the PORT-C (China) and Lung ART (Europe) trials have been reported for non-small cell lung cancer patients (NSCLC) with surgically resected N2 nodal disease subsequently randomized to post-operative radiation (PORT). The two studies noted widely different locoregional relapse (LR) rates in the control arms, 18.3% in PORT-C and 28.1%(46% of recurrences) in Lung ART. We performed a meta-analysis of patients with N0-N2 disease to better understand risk factors for LR, and the possible differences in risk and rates between Asian (AP) vs. non-Asian populations (NAP). Methods: The present systematic review and meta-analysis identified all original studies of curative NSCLC surgical resections which reported risk and rates of LR between January 1st, 2000 and January 10th, 2021. Studies were excluded if patient number was less than 10, if metastatic disease was present, or if any neo-adjuvant chemotherapy and/or radiation was given. Eighty-seven studies were included; of these, 56 were of high quality (HQ) based on the Newcastle-Ottawa Scale (ratings 7-9). For each risk factor, we derived pooled relative risk (RR) and rate estimates using random-effects models. Results: Overall, the three highest pooled RRs for LR were N2 vs. N0 (RR 3.01), lymphovascular invasion (LVI; 1.92), and advanced T stage (T3-T4) vs. T1 (1.86). For HQ studies, the highest RRs for LR were LVI (1.94), sublobar vs. lobar resection (1.86), and N1 vs. N0 (1.84), but N2 vs N0 was no longer significant (RR 3.0 (95% confidence interval 0.57 -15.61) based on only 2 studies. The RRs for LR were consistent for most factors across geographic areas, although the RRs for male vs. female sex were higher in AP (1.44) than in NAP (1.09). The pooled rate of LR at 5-years was lower in the AP 12.00% (6.92-17.09) vs. NAP 22.66% (17.06 - 28.26), despite similar overall recurrence rates (both LR and distal) at 5 years in both populations: 38.03% (25.15-50.90) in AP and 37.30% (32.44-42.17) in NAP. However, a lower 5-year mortality rate was noted in AP (24.30%, 15.56 -33.03) than in NAP (45.87%, 41.23-50.50). Conclusions: Our meta-analysis found that N2 nodal disease is not a risk factor for LR when considering HQ studies based upon scant data, and confirmed that LR is lower in AP. We propose that prospective evaluation of LR risk factors and rates should be undertaken prior to any other prospective evaluation of PORT because LR may not be dependent upon N2 node status and because LR rates may differ in AP.

UPFRONT SURGERY AS FIRST-LINE TREATMENT IN PATHOLOGICAL N2 NON-SMALL CELL LUNG CANCER

TYPE: Abstract TOPIC: Lung Cancer PURPOSE: Multimodality therapy offers highest chance of improving prognosis in pN2 NSCLC. PURPOSE: to determine the long-term clinical outcomes and prognostic variables associated with upfront surgery as first-line therapy in pN2. METHODS: Retrospective evaluation of pN2 NSCLC underwent surgery (2007-2017). Patients with concurrent malignancies, neoadjuvant therapy; partial surgical resection; and insufficient data were excluded. Multidisciplinary team devised treatment methods for biopsy-confirmed N2 disease. Upfront surgery was considered if initial tumour was resectable, mediastinal nodal metastases were limited to single station, and there was no evidence of extra-nodal tumour invasion. RESULTS: Cox proportional hazards analysis revealed that older age and number of comorbidities were substantially linked with poorer OS. Mean duration of follow-up was 39.6 24.7 months. At conclusion of follow-up , 127 (44.6%) patients had died. Median overall survival (OS) for induction chemotherapy group was 49 months [95%CI: 38–70 months], and 5-year OS rate was 44.4%. Median and 5-year OS for patients who underwent upfront surgery were 66 months (95%CI: 40–119) and 66.3%, respectively. No statistically significant differences in treatment techniques were observed (p=0.48). At 5-years, DFS for induction chemotherapy was 17% (95%CI: 11–25) and upfront surgery was 22% (95%CI: 9–32%); there were no statistically significant differences between groups (p = 0.93). No significant variations in survival were identified according to clinical N status (OS, p=0.36; DFS, p=0.65). CONCLUSIONS: In patients with pN2 NSCLC, upfront surgery as first-line therapy resulted in favourable clinical results. CLINICAL IMPLICATIONS: In resectable N2 NSCLC, upfront surgery should be considered as one of the multimodality treatment choices. DISCLOSURE: Nothing to declare. KEYWORD: lung cancer

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.

18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma.

Positron emission tomography is a useful technique for diagnosing lymph node (LN) metastasis. This study aimed to elucidate the association between fluorodeoxyglucose accumulation and the microenvironment in metastatic LNs in lung adenocarcinoma. We retrospectively analyzed 62 patients with surgically resected pathological N2 lung adenocarcinoma who underwent preoperative PET. The maximum standardized uptake value (SUVmax) in the metastatic LNs was measured. Lymph node specimens were immunohistochemically analyzed for CD8+, FoxP3+, and CD79a+ lymphocytes, CD204+ tumor‐associated macrophages (TAMs), and alpha‐smooth muscle actin‐positive cancer‐associated fibroblasts (αSMA+ CAFs). We compared the clinicopathologic and immunohistochemical characteristics between two groups with high and low LN SUVmax. Using novel 3D hybrid spheroid models, we investigated the change in invasiveness of cancer cells in the presence of CAFs. In the multivariate analyses, LN SUVmax was an independent prognostic factor. The overall survival in the LN SUVmax high group was significantly worse than in the low group (P = .034). In the LN SUVmax high group, metastatic cancer cell invasion of extranodal tissue was more frequent (P = .005) and the number of CD204+ TAMs and αSMA+ CAFs in metastatic LNs was significantly higher than in the low group (P < .001 and P = .002, respectively). Hybrid spheroid models revealed that cancer cells coexisting with CAFs were more invasive than those without CAFs. Our results indicated a strong association between LN SUVmax and poor prognosis in patients with N2 lung adenocarcinoma. Moreover, LN SUVmax was suggested to be associated with the presence of tumor‐promoting stromal cells in metastatic LNs.

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

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

Postoperative radiotherapy in resected N2 non-small-cell lung cancer: Lung ART.

For more than 20 years, the role of postoperative radiotherapy (PORT) has been controversial in patients with completely resected (R0) N2 non-small-cell lung cancer (NSCLC), because no contemporary clinical trials with adequate staging and treatment were available. Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART, IFCT 0503): an open-label, randomised, phase 3 trialLung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (18F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC. Full-Text PDF

Analysis of the relationship between the anatomical location of intrapulmonary metastatic lymph nodes and relapse risk and survival in patients with N1 non-small cell lung cancer

Objective: To evaluate the relationship between the anatomical location of intrapulmonary metastatic lymph nodes and relapse risk and survival in patients with N1 non-small cell lung cancer(NSCLC). Methods: A retrospective analysis of the clinical and pathological data of 138 patients with completely resected N1 NSCLC was conducted. There were 79 males and 59 females, aged from 26 to 81 years with an average of (59±10) years. All of them were treated in the Department of Thoracic Surgery Ⅱ of Peking University Cancer Hospital between January 2007 and December 2015. Patients were stratified based on the 8th edition of the American Joint Committee on Cancer (AJCC) N1 classification and the modified pathological N1 classification strategy, respectively. According to modified pathological N1 classification strategy, which was defined based on the anatomical location of intrapulmonary metastatic lymph nodes, N1 nodes were subcategorized into the hilar (stations 10-11, mN1b) (n=36) and peripheral (stations 12-14, mN1a) (n=102) zones. The Kaplan-Meier curves were plotted to compare the relapse risk and survival analysis, disease-free survival (DFS), and overall survival (OS) were compared between the two staging methods through univariate and multivariate analysis to evaluate the effectiveness of the two classifications in stratifying patients with distinct risks of disease relapse and survival. Results: According to the modified N1 classification, the differences in 5-year DFS and OS between the subgroups (mN1a vs mN1b) were statistically significant(59.5% vs 35.7%; 81.2% vs 56.0%; both P<0.05). However, following the 8th edition of the AJCC N1 classification, no significant differences were found in DFS and OS between the subgroups (both P>0.05). Multivariate analysis showed that the modified N1 classification was an independent prognostic factor to DFS (HR=1.814, 95%CI: 1.005-3.275) and OS (HR=3.919, 95%CI: 1.918-8.009) (all P<0.05). However, the 8th edition of the AJCC N1 classification was not an independent prognostic factor to DFS (HR=1.360, 95%CI:0.767-2.412) or OS (HR=1.620, 95%CI:0.839-3.131) (both P>0.05) as revealed by multivariate analysis. Conclusions: The relapse risk and survival could be assessed effectively using the modified pathological N1 classification, which was defined and subcategorized based on the anatomical location of intrapulmonary metastatic lymph nodes for N1 NSCLC patients. The modified pathological N1 classification is superior to the 8th edition of the AJCC classification.