pN2 Non-small Cell Lung Cancer Research Articles

NUF2 Expression in Cancer Tissues and Lymph Nodes Suggests Post-Surgery Recurrence of Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection.

Frequency and predictive factors of nodal micro-metastasis (NMM) in resectable non-small cell lung cancer.

The frequency of lymph nodal micrometastasis (NMM) in resectable non-small cell lung cancer (NSCLC) is frequently underestimated when relying solely on standard hematoxylin and eosin staining during pathological examination. This is a retrospective cross-sectional diagnostic research. Medical records of resectable pN0 NSCLC patients who underwent curative resection in Maharaj Nakorn Chiang Mai Hospital between January 2006 to December 2017 were retrospectively reviewed. Immunohistochemistry (IHC) staining using cytokeratin AE1/AE3, p53 and BerEP4 markers was employed to detect NMM. Primary objective of this study was to determine frequency of NMM in pN0 resectable NSCLC. This study included 98 patients with pN0 NSCLC, of which 47 were male and 51 were female. NMM was detected in 21 of 98 patients (21.43%). Lymph node station 10 and 7 were the most common site of micrometastasis among patients with N1 and N2 micrometastasis, respectively. Cytokeratin AE1/AE3 was the most sensitive antibody in detecting micrometastasis in lymph nodes, identifying 25 out of 27 positive lymph nodes. Tumor size greater than 4 cm was a statistically significant predictive factor for NMM with risk ratio 6.69 [95% confidence interval (CI): 2.38-18.85, P<0.001]. NMM was identified in 21.43% of pN0 resectable NSCLC patients and tumor size greater than 4 cm is predictive factor for NMM.

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.

Adjuvant chemotherapy in pathological node-negative non-small cell lung cancer

Non–small cell lung cancer (NSCLC) is associated with a poor survival rate, even for patients with early-stage cancer. Identifying patients with pathological N0 NSCLC who may benefit from adjuvant chemotherapy treatment after surgery is essential. We conducted a retrospective cohort study used data from the Surveillance, Epidemiology, and End Results database and included 26,380 patients with pathological N0 NSCLC after surgery between January 2018, and December 2019. Among 26,380 patients, 24,273 patients received surgery alone and the other 2107 patients received surgery plus adjuvant chemotherapy. After 1:1 propensity score matching, both groups contained 2107 patients. Adjuvant chemotherapy did not show significantly better 24-month survival in T2aN0 NSCLC patients (83.41% vs. 82.91%, p = 0.067), although it did for T2bN0 patients (86.36% vs. 81.70%, p = 0.028). Poorly-differentiated NSCLC remained a high-risk factor for pT2N0, and adjuvant chemotherapy provided better 24-month survival after matching (86.36% vs. 81.70%, p = 0.029). In conclusion, when treating pN0 NSCLC, adjuvant chemotherapy had a beneficial effect when the tumor size was larger than 4 cm. The effect when the tumor size was between 3 and 4 cm was not remarkable. Poorly-differentiated NSCLC was a high-risk factor in the pT2N0 stage.

The additional radiotherapy to adjuvant chemotherapy improves the prognosis of stage III-N2 with highest mediastinal lymph node metastasis in non-small cell lung cancer.

The benefits of adjuvant chemoradiation therapy (CRT) for heterogeneous pathological N2 (pN2) diseases remain unclear in non-small cell lung cancer (NSCLC). This study aimed to investigate suitable pN2 patients for adjuvant CRT. This study retrospectively reviewed the data of patients with pN2 NSCLC in Shanghai Pulmonary Hospital from January 2012 to December 2016. Included cases were subdivided as highest mediastinal lymph node (HM) (n = 732) metastasis and non-HM metastasis (n = 677) groups according to the International Association for the Study of Lung Cancer (IASLC). Furthermore, the Kaplan-Meier and Cox models were used to evaluate the prognostic benefits of adjuvant CRT in heterogeneous pN2 subgroups. A total of 1409 patients were enrolled in this study, with a median follow-up time of 63.8months. Patients with HM involvement had worse prognoses (p < 0.001 for recurrence-free survival (RFS) and overall survival (OS)). Furthermore, the survival improvement of adjuvant CRT was significant for these patients (p < 0.001 for RFS and p = 0.032 for OS), regardless of whether it was single (p < 0.001 for RFS and p = 0.029 for OS) or multiple pN2 (p < 0.001 for RFS and p = 0.026 for OS) diseases. According to multivariable cox analysis, the long-term RFS and OS in the cancerous HM group were independently predicted by pathological N stage (p = 0.002 for RFS and p < 0.001 for OS) and adjuvant CRT (p < 0.001 for RFS and p = 0.011 for OS). Metastatic HM was associated with a worse prognosis in pN2 disease. Our analysis supported that adjuvant CRT significantly improved both RFS and OS for these patients.

Prognostic Impact of the Immune-Cell Infiltrate in N1-Positive Non–Small-Cell Lung Cancer

IntroductionThe tumoral immune milieu plays a crucial role for the development of non–small-cell lung cancer (NSCLC) and may influence individual prognosis. We analyzed the predictive role of immune cell infiltrates after curative lung cancer surgery. Materials and MethodsThe tumoral immune-cell infiltrate from 174 patients with pN1 NSCLC and adjuvant chemotherapy was characterized using immunofluorescence staining. The density and distribution of specific immune cells in tumor center (TU), invasive front (IF) and normal tissue (NORM) were correlated with clinical parameters and survival data. ResultsTumor specific survival (TSS) of all patients was 69.9% at 5 years. The density of tumor infiltrating lymphocytes (TIL) was higher in TU and IF than in NORM. High TIL density in TU (low vs. high: 62.0% vs. 86.7%; p = .011) and the presence of cytotoxic T-Lymphocytes (CTLs) in TU and IF were associated with improved TSS (positive vs. negative: 90.6% vs. 64.7% p = .024). High TIL-density correlated with programmed death-ligand 1 expression levels ≥50% (p < .001). Multivariate analysis identified accumulation of TIL (p = .016) and low Treg density (p = .003) in TU as negative prognostic predictors in squamous cell carcinoma (p = .025), whereas M1-like tumor- associated macrophages (p = .019) and high programmed death-ligand 1 status (p = .038) were associated with better survival in adenocarcinoma. ConclusionThe assessment of specific intratumoral immune cells may serve as a prognostic predictor in pN1 NSCLC. However differences were observed related to adenocarcinoma or squamous cell carcinoma histology. Prospective assessment of the immune-cell infiltrate and further clarification of its prognostic relevance could assist patient selection for upcoming perioperative immunotherapies.

Prognostic significance of extranodal extension in patients with pathologic N1 non-small cell lung cancer undergoing complete resection.

The prognostic significance of extranodal extension (ENE) remains unclear in patients with pathologic N1 (pN1) non-small-cell lung cancer (NSCLC) undergoing surgery. We evaluated the prognostic impact of ENE in patients with pN1 NSCLC. From 2004 to 2018, we retrospectively analyzed the data of 862 patients with pN1 NSCLC who underwent lobectomy and more (lobectomy, bilobectomy, pneumonectomy, sleeve lobectomy). According to their resection status and the presence of ENE, patients were classified into R0 without ENE (pure R0) (n=645), R0 with ENE (R0-ENE) (n=130), and incomplete resection (R1/R2) groups (n=87). The primary and secondary endpoints were 5-year overall survival (OS) and recurrence-free survival (RFS), respectively. The prognosis of the R0-ENE group was significantly worse than the pure R0 group for both OS (5-year rate: 51.6% vs. 65.4%, P=0.008) and RFS (44.4% vs. 53.0%, P=0.04). According to the recurrence pattern, a difference of RFS was found only for distant metastasis (55.2% vs. 65.0%, P=0.02). The multivariable Cox analysis revealed that the presence of ENE was a negative prognostic factor in patients who did not undergo adjuvant chemotherapy [hazard ratio (HR) =1.58; 95% confidence interval (CI): 1.06-2.36; P=0.03], but it was not in those with adjuvant chemotherapy (HR =1.20; 95% CI: 0.80-1.81; P=0.38). For patients with pN1 NSCLC, the presence of ENE was a negative prognostic factor for both OS and RFS, regardless of resection status. The negative prognostic effect of ENE was significantly associated with an increase in distant metastasis and was not observed in patients who underwent adjuvant chemotherapy.

Survival outcome of upfront surgery for clinical single-station N2 non-small cell lung cancer.

Pathological N2 (pN2) non-small cell lung cancer (NSCLC) is diverse; its treatment depends on the clinical N (cN) status. We aimed to determine the efficacy of upfront surgery for cN2pN2 NSCLC. The study included 43 cN2pN2 NSCLC patients who underwent upfront surgery at the Shizuoka Cancer Center between 2002 and 2017. Survival outcome, focusing on cN2 status, was retrospectively investigated. Mediastinal lymph nodes were pre-operatively evaluated using computed tomography and positron emission tomography. Surgical eligibility criteria included single-station cN2. N2 with N1 and skip N2 were defined as N2 with and without ipsilateral hilar lymph node metastasis, respectively. A platinum-doublet regimen was used for adjuvant chemotherapy. Survival curves were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model. Clinical-skip N2 and cN2 with N1 cases included 22 and 21 patients, respectively. Twenty-three patients received adjuvant chemotherapy. The median follow-up duration was 73months. Clinical-skip N2 had a significantly better 5-year recurrence-free survival (RFS) than cN2 with N1 (58.3 vs 28.6%, P = 0.038) and was an independent favorable RFS predictor. Recurrence within 18 months occurred in 71% of cN2 with N1 cases. Five-year overall survival and RFS rates in patients receiving adjuvant chemotherapy vs those without adjuvant chemotherapy were 82.2 vs 41.9% (P = 0.019) and 56.5 vs 28.0% (P = 0.049), respectively. Clinical-skip N2 had an excellent prognosis, and upfront surgery was acceptable. Conversely, upfront surgery followed by chemotherapy is not recommended for cN2 with N1 patients because of early recurrence.

Uncertain resection of highest mediastinal lymph node positive among pN2 non-small cell lung cancer patients: survival analysis of postoperative radiotherapy and driver gene mutations.

The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients. 140 selected patients were grouped according to whether they received PORT and their DGMS. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of each group were evaluated by Kaplan-Meier analyses. COX regression was used to evaluate the effects of various factors on DFS and OS. Of 140 patients, thirty-four patients (24.3%) received PORT, and forty (28.6%) had positive driver gene mutation status (DGp). PORT significantly prolonged LRFS (p = 0.002), DFS (p = 0.019) and OS (p = 0.02), but not DMFS (p = 0.062). By subgroup analysis, in patients with negative driver gene mutation status (DGn), those receiving PORT had notably longer LRFS (p = 0.022) and DFS (p = 0.033), but not DMFS (p = 0.060) or OS (p = 0.215), compared to those not receiving PORT. Cox analysis showed that the number of positive lymph nodes (PLNs) and administration of PORT were independent prognostic factors of DFS, and pathology, PLNs, and DGMS may be prognostic factors of OS (all p < 0.05). Postoperative radiotherapy may improve locoregional recurrence-free and disease-free survival in patients with pN2 NSCLC with positive highest mediastinal lymph nodes, while driver gene mutation status impacted OS significantly. Only patients with positive driver gene mutations experienced significant overall survival benefits from postoperative radiotherapy.

Postoperative Radiotherapy can Improve the Disease-Free Survival of EGFR Wild Type Patients with pN2 NSCLC after Complete Resection and Adjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> Recently published phase III trials showed that postoperative radiotherapy (PORT) did not improve the survival of patients with pN2 non-small-cell lung cancer (NSCLC) after complete resection. However, the effect of PORT for pN2 NSCLC with different EGFR status remains unclear. <h3>Materials/Methods</h3> From 2010 to 2019, consecutive patients with pN2 NSCLC after complete resection and adjuvant chemotherapy who had detection of EGFR status were retrospectively analyzed. PORT was administered using IMRT at 2 Gy per fraction up to 50 Gy over 5 weeks. Patients were categorized into 4 groups according to EGFR status and treatment: Group 1 (EGFR wild type with PORT), Group 2 (EGFR wild type without PORT), Group3 (EGFR-mutated with PORT), Group 4 (EGFR-mutated without PORT). The Kaplan-Meier method and log-rank test were used to evaluate the disease-free survival (DFS), overall survival (OS), locoregional relapse free survival (LRFS), and distant metastasis free survival (DMFS). <h3>Results</h3> Totally 575 patients were enrolled. 264 patients (45.9%) were EGFR wild type, including 96 with PORT and 168 without PORT. 311 patients (54.1%) were EGFR-mutated, including 109 with PORT and 202 without PORT. The median DFS was 28.4 months in Group 1 and 17.3 months in Group 2 (HR 0.70, 95% CI 0.52-0.96, p=0.032). The median OS was not reached in Group 1 and Group 2 (HR 0.75, 95%CI 0.46-1.21, p=0.263). LRFS was statistically higher in Group 1 than Group 2 (HR 0.64, 95%CI 0.43-0.96, p=0.041). However, no significant difference was shown in DMFS (HR 0.75, 95%CI 0.54-1.04, P=0.097). Group 3 and Group 4 showed median DFS of 20.2 months and 25.7 months (HR 1.113, 95% CI 0.84-1.53, p=0.402), respectively. The median OS was not reached in either Group 3 or Group 4 (HR 0.64, 95% CI 0.33-1.21, p=0.201). LRFS was not significantly different (HR 0.83, 95% CI 0.53-1.31, p=0.45) in Group3 vs Group4, neither was DMFS (HR 1.15, 95%CI 0.85-1.57, p=0.73). <h3>Conclusion</h3> For completely resected pN2 NSCLC, PORT can improve DFS and LRFS in EGFR wild type patients. However, PORT may not prolong survival in EGFR-mutated patients. Prospective randomized clinical trials are needed for validation.

Validation of the Role of Postoperative Radiotherapy in Improving Disease-Free Survival of Patients with Stage III ypN2 Non-Small Cell Lung Cancer after Neoadjuvant Therapy Followed by Complete Resection – A Propensity-Score Matching Study

<h3>Purpose/Objective(s)</h3> Although the Lung ART study, a phase III trial, showed that postoperative radiotherapy (PORT) could not significantly improve the disease-free survival (DFS) of patients with pN2 non-small cell lung cancer (NSCLC) after complete resection. However, its subgroup analysis showed that PORT did significantly improve the DFS of those with ypN2 NSCLC after neoadjuvant therapy and surgery. Our study aimed to validate the effect of PORT on the survival of patients with ypN2 NSCLC. <h3>Materials/Methods</h3> Patients was filtrated from our center from 2004 to 2021. The inclusion criteria of patients were as follows: 1) diagnosed with NSCLC; 2) accepted neoadjuvant systematic treatments including chemotherapy, tyrosine kinase inhibitors (EGFR, ALK), or immune checkpoint inhibitors; 3) received complete resection (R0 resection); 4) with stage III ypN2 disease (AJCC 8^th). We excluded patients with multiple primary malignant tumors and those who died within four months after surgery. The primary endpoint was DFS. The second endpoints were overall survival (OS) and locoregional recurrence-free survival (LRFS). Propensity-score matching (PSM) was used to match the baseline characteristics between the PORT group and the non-PORT group. Kaplan-Meier method was used to estimate the endpoints. All data were analyzed using R 4.1.2. <h3>Results</h3> Totally 185 patients were included in the final analysis. There were 49 patients (26.5%) with PORT. After 1:1 PSM between the PORT group and the non-PORT group, 82 patients remained with 41 in each group. The baseline characteristics of majority in the matched cohort were as follows: male (75.6%), smoking history (79.3%), performances scores 0-1 (100%), adenocarcinoma (47.6%), grade 3-4 (58.5%), receiving neoadjuvant chemotherapy (91.5%), lobectomy (82.9%), ypT1-2 (78.9%), and ypN2b (51.2%). The median age of patients was 58. The median numbers of examined and positive lymph nodes were 20.5 and 6. The median follow-up time was 49.5 months. The median DFS of the PORT group and the non-PORT group were 25.5 months vs. 18.6 months, with the 5-year DFS rates of 43.4% vs. 24.8%, respectively (P=0.044). The median LRFS of the two groups were not reached vs. 56.8 months, with the 5-year LRFS rates of 89.1% vs. 39.8% (P<0.001). The median OS of the two groups were not reached vs. 67.7 months, with the 5-year OS rates of 76.7% vs. 34.8% (P=0.092). <h3>Conclusion</h3> For patients with stage III ypN2 NSCLC after neoadjuvant systematic therapy followed by complete resection, PORT can significantly improve the DFS and LRFS, but failed to improve OS. However, the results need to be clarified by prospective randomized clinical trials.

EP05.01-027 Uncertain Resection of pN2 NSCLC Patients-survival Analysis of Postoperative Radiotherapy and Driver Gene Mutations

The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients.

A decision support framework for postoperative radiotherapy in patients with pathological N2 non-small cell lung cancer

IntroductionPostoperative radiotherapy (PORT) plays a highly controversial role in pathological N2 (pN2) non-small cell lung cancer (NSCLC) disease. Recent studies reveal that not all patients can benefit from PORT. Further research is needed to identify predictors of PORT. MethodsA total of 1044 pathologic stage T1-3N2M0 NSCLC patients were analyzed. Risk factors of distant metastasis were identified by the log-rank tests and the multivariable Cox models. We integrated risk factors of distant metastasis and our previously published loco-regional recurrence (LRR) related prognostic index into a decision support framework (DSF) to predict the outcomes of PORT. An independent cohort was used to validate the DSF. ResultsWe defined patients with more than two of three identified LRR-related features (heavy cigarette smoking history, clinical N2 status, and more than four positive lymph nodes) as a high LRR risk group. We found the high-intermediate-risk histological type (with micropapillary and/or solid components) was associated with a higher risk of distant metastasis (HR = 1.207, 95 % CI 1.062 to 1.371, P = 0.0038), but not LRR. We built the DSF by combining these two types of features. Patients were stratified into four groups by using the DSF. PORT significantly improved OS only in the subgroup without high-risk histological features (without micropapillary or solid components) and with a high risk for LRR (three-year OS: 66.7 % in the PORT group vs 50.2 % in the non-PORT group; P = 0.023). ConclusionsA particular pN2 subgroup with a high risk of LRR and without micropapillary or solid components could benefit from PORT.

Role of Adjuvant Radiotherapy in Non-Small Cell Lung Cancer-A Review.

Simple SummaryThe role of postoperative radiotherapy (PORT) in completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2) is controversial. The aim of our review was to study the literature relating to PORT for completely resected NSCLC patients with pN2 involvement. The Lung ART and PORT-C trials indicate better locoregional control with PORT, but this has not yet translated into survival benefits. Given the conflicting results, guidelines do not recommend the use of PORT routinely. Future research should focus on identifying subgroups of patients who might benefit from PORT.Background: For patients with completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2), the administration of adjuvant chemotherapy is the standard of care. The role of postoperative radiation therapy (PORT) is controversial. Methods: We describe the current literature focusing on the role of PORT in completely resected NSCLC patients with pN2 involvement and reflect on its role in current guidelines. Results: Based on the results of the recent Lung ART and PORT-C trials, the authors conclude that PORT cannot be generally recommended for all resected pN2 NSCLC patients. A substantial decrease in the locoregional relapse rate without translating into a survival benefit suggests that some patients with risk factors might benefit from PORT. This must be balanced against the risk of cardiopulmonary toxicity with potentially associated mortality. Lung ART has already changed the decision making for the use of PORT in daily practice for many European lung cancer experts, with lower rates of recommendations for PORT overall. Conclusions: PORT is still used, albeit decreasingly, for completely resected NSCLC with pN2 involvement. High-level evidence for its routine use is lacking. Further analyses are required to identify patients who would potentially benefit from PORT.

Optimal positive lymph node ratio showing the benefit of postoperative radiotherapy in pathologic N2 non-small cell lung cancer: an exploratory study using the Surveillance, Epidemiology, and End Results data.

PurposeThis study aimed to identify the clinical parameters having the beneficial effect of postoperative radiotherapy (PORT) in pathologic N2 (pN2) non-small cell lung cancer (NSCLC) using the Surveillance, Epidemiology, and End Results (SEER) data.Materials and methodsAmong non-metastatic NSCLC patients in the SEER data, we included patients who diagnosed after 2002, who confirmed as pN2 after lobectomy or pneumonectomy, and who coded as underwent PORT or observation. Patients who survived less than 4 months of diagnosis were excluded in consideration of the perioperative mortality. After performing propensity score matching (PSM) on the selected patients, we compared PORT group with surgery alone group. We also performed exploratory subgroup analysis to find patients who could benefit from PORT.ResultsAmong the selected 4,456 patients, 1,729 patients received PORT, and 2,727 patients did not. There was no survival benefit of PORT in all patients with pN2 disease (hazard ratio [HR] = 1.03, p = 0.5). In subgroup analyses, the patients with a positive lymph node (LN) ratio of 60%–80% showed the significant benefit of PORT (HR = 0.71, p = 0.002).ConclusionPORT did not show the significant survival benefit in patients with pN2 disease after correcting the confoundedness in the SEER data. However, a specific range of LN ratios can be a potential indicator maximizing the survival benefit of PORT.

A narrative review of postoperative adjuvant radiotherapy for non-small cell lung cancer.

To summarize the principal studies investigating the role of postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC) and to discuss the recent major breakthroughs deriving from the Lung ART trial, in order to provide a real-world scenario of the management of resected NSCLC patients. Surgery followed by platinum-based chemotherapy remains the mainstay of adjuvant treatments for completely resected stage II and IIIA NSCLC. Less consistent is the employment of PORT, as no significant benefit was clearly identified from the previous published meta-analysis. Furthermore, the recent results of Lung ART trial questioned for the first time the efficacy of PORT for pathological N2 (pN2) NSCLC patients. Hence, the need to define if PORT still has a role for resected NSCLC and which subgroup of patients could benefit most from this treatment. A literature search of PubMed was performed to identify publications, including prospective and retrospective clinical studies, meta-analysis and systematic review of PORT for NSCLC. No limit concerning years of publication or publication status were applied. Only papers using the English language were selected. The ESMO 2020 and ESMO 2021 online resources were used to analyze the Lung ART trial results. The authors provide a narrative summary of the findings and implications of these studies and how they improve the clinical practice. PORT was considered the standard of care for patients with completely resected pN2 NSCLC based on the results of an old meta-analysis that did not demonstrate a detrimental effect. The more recent randomized phase III Lung ART trial concluded that PORT could not anymore be recommended for pN2 NSCLC as a significant benefit in terms of 3 years disease-free survival (DFS) was not reached and an increased rate of radiotherapy related toxicity was observed. Retrospective studies suggest a possible role of PORT for incompletely resected NSCLC patients and those with an extranodal extension (ENE), but this issue needs to be reinforced from randomized prospective trials. The extensive publication of Lung ART trial is largely awaited to define if there is a role of PORT for resected NSCLC patients.

Impact of Postoperative Radiotherapy on Overall Survival in Patients with pN1 Non-Small Cell Lung Cancer

Objective: to comparatively analyze overall survival (OS) in patients with non-small cell lung cancer (NSCLC) with affected lymph nodes (pN1) of the lung root after surgical and combination treatment with postoperative radiotherapy (PORT). Subjects and methods. OS was studied in 310 patients with grade 2-3 NSCLC. (pT1a-4N1M0): in 101 patients after lobectomy/bilobectomy, pulmonectomy with ipsilateral mediastinal lymphadenectomy and in 209 patients after combination treatment with the similar surgical volume and hypofractionated PORT (a single focal dose (SFD) of 3 Gy; 5 fractions per week, a cumulative focal dose (CFD) of 36-39 Gy (43.2-46.8 Gy-eq)) or classical fractionation (SFD2 Gy, 5 fractions per week, CFD44 Gy). An analysis was carried out in the groups of patients younger and older than 60 years with central or peripheral cancer, squamous cell carcinoma or adenocarcinoma, with different tumor grading according to the T criterion (T1-4). Results. PORT in radically operated patients with NSCLC increased 5- and 10-year OS rates only in central squamous cell lung cancer (56.1% and 39.5% vs.25.4% and 4.3%, p = 0.002). This group receiving combination therapy showed a statistically significant increasing trend in 5-year OS rates for both pT1-2 tumors (57.5% vs. 21.3%, respectively, p = 0.013) and pT3-4 tumors (53.9% versus 26.0%; p = 0.044), so did patients younger than 61 years (65.5% vs.29.4%, p = 0.008) and those over 60 years old (47.5% vs.21.3%, p = 0.047). Patients with peripheral squamous cell carcinoma or lung adenocarcinoma at any site exhibited no statistically significant increase in OS after PORT. In general, the 5- and 10-year OS rates in the compared groups were statistically significantly higher in the PORT group (47.9% and 28.9% vs. 27.1% and 11.4, p = 0.006). None of the analyzed subgroups showed a decrease in OS after PORT. Conclusion. In patients with pN1 NSCLC who had radical surgery via lobectomy/bilobectomy or pulmonectomy with ipsilateral mediastinal lymphadenectomy, PORT can be recommended only for those with central squamous cell carcinoma, regardless of tumor size and age group. In other subgroups of patients with pN1 NSCLC, PORT can only be performed within the scientific protocols. The expediency of PORT after bilateral mediastinal lymph node dissection needs to be investigated.

Lymph Node Metastasis Location and Postoperative Adjuvant Chemotherapy in Patients With pN1 Stage IIB Non-small Cell Lung Cancer.

The benefit of adjuvant chemotherapy for patients with pN1 non-small cell lung cancer (NSCLC) according to the location of lymph node (LN) metastases remains unclear. In this study, we examined the location of LN metastasis and prognosis to identify the significance of adjuvant chemotherapy. Thirty-five patients with pathological T1a-2bN1M0 NSCLC who underwent curative resection between 2010 and 2016 were enrolled in the study. We defined patients with LN metastasis extending in stations 10-12 as the hilar group (n=22), and only in stations 13-14 as the intralobar group (n=13). There was a significant difference in the overall survival (OS) (p=0.042) and disease-free survival (DFS) rates (p=0.021) between the intralobar and hilar groups. In the intralobar group, there were no significant differences in the OS and DFS rates according to adjuvant chemotherapy. However, patients without adjuvant chemotherapy had a poorer OS (p<0.001) and DFS rates (p<0.001) in the hilar group. Prognosis significantly differed according to adjuvant chemotherapy in the hilar group.

Role of Adjuvant Radiation in pN2 Non-Small Cell Lung Cancer (NSCLC) Patients

Past studies have shown mixed results of postoperative radiation (PORT) for pN2 NSCLC patients and the recent LungART trial has shown no disease free survival or overall survival (OS) benefits with PORT for pN2 NSCLC patients. High lymph node ratio (LNR = number of positive lymph nodes in the resected specimen/number of total lymph nodes resected) has been shown to correlate with worse outcomes. We hypothesize that PORT can improve survival outcomes in pN2 NSCLC patients with high LNR.The National Cancer Database was queried for cases of NSCLC from 2004-2016. Patients without neoadjuvant treatment, with at least a lobectomy with resection of at least 10 lymph nodes, with pN2 disease, with histology of squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma and large cell carcinoma were included. Exclusion criteria were neoadjuvant therapy, lack of pathological confirmation or lack of information about chemotherapy and metastatic disease. For patients with PORT, RT was directed to thorax with dose≥30Gy. Log-rank test and Cox proportional hazards models were used to compare survival adjusted for age, sex, CCI, pT, grade, chemotherapy, LNR, and PORT. Predictors for overall survival (OS) were identified.Among 10272 patients, 6266 (61%) did not have PORT, and 4006 (39%) had PORT. Median follow up was over 5 years. PORT was given to 51.3% and 37.7% patients with non-R0 and R0 resection, respectively (P < 0.001). PORT was given to 48.4% and 9.91% of patients with and without adjuvant chemotherapy, respectively (P < 0.001). The average LNR for patients with and without PORT were 0.33 and 0.29 (P < 0.001), respectively. In multivariate analysis (MVA) of patients with R0 resection, predictors of OS were listed in Table 1. PORT was not associated with better OS (HR, 1.04, P = 0.63) for patients with LNR of 1-15%. However, PORT was associated with better survival in patients with higher LNRs (HR, 0.90, P = 0.23 for LNR of 15-29% and HR, 0.82, P = 0.01 for LNR ≥ 30%). In MVA of patients with non-R0 resection, PORT was associated with better survival (HR, 0.56, P = 0.01).High LNR after R0 surgery in pN2 NSCLC patients portends worse survival. PORT is associated with better survival for pN2 NSCLC patients after R0 resection with high LNR after accounting for multiple confounders including adjuvant chemotherapy. PORT is also associated with better survival in pN2 NSCLC patients after R1 or R2 surgery.

Role of Adjuvant Radiation in pN1 Non-Small Cell Lung Cancer (NSCLC) Patients

Previous studies have shown a detrimental effect of postoperative radiation (PORT) in pN1 NSCLC patients after R0 surgery. High lymph node ratio (LNR = number of positive lymph nodes in the resected specimen/number of total lymph nodes resected) has been shown to correlate with worse outcomes. We hypothesize that PORT can improve survival outcomes in pN1 NSCLC patients with high LNR after R0 surgery.The National Cancer Database was queried for cases of lung cancer from 2004-2016. Patients without neoadjuvant treatment, with at least a lobectomy with resection of at least 10 lymph nodes, with pN1 disease, with histology of squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma and large cell carcinoma were included. Exclusion criteria were neoadjuvant therapy, lack of pathological confirmation or lack of information about chemotherapy and metastatic disease. For patients with PORT, RT was directed to thorax with dose≥30Gy. Log-rank test and Cox proportional hazards models were used to compare survival adjusted for age, sex, CCI, pT, grade, chemotherapy, LNR, and PORT. Predictors for overall survival (OS) were identified.Among 13742 patients, 12542 (91.3%) did not have PORT, and 1200 (8.7%) had PORT. Median follow up was over 5 years. For years of 2004-2010 and 2011-2016, PORT was given to 8% (413 out of 5132) and 5.5% (423 out of 7622) of patients after R0 resection, respectively. PORT was given to 36.8% and 6.55% patients with non-R0 and R0 resection, respectively (P < 0.001). PORT was given to 11.6% and 3.37% of patients with and without adjuvant chemotherapy, respectively (P < 0.001). The average LNR for patients with and without PORT were 0.2 and 0.14 (P < 0.001), respectively. In multivariate analysis (MVA) of patients with R0 resection, predictors of OS were listed in Table 1. In patients with intermediate LNR (15-29%), PORT was marginally correlated with better OS (HR, 0.80, P = 0.07). In patients with high LNR (≥30%), PORT was correlated with better OS (HR, 0.80, P = 0.047). In MVA of patients with non-R0 resection, high LNR was associated with worse OS (HR, 1.35 and 1.66 for LNR of 15-29% and ≥30%, respectively). In patients with intermediate (15-29%) and high (≥30%) LNR, PORT was numerically correlated with better OS (HR, 0.89 and 0.77 respectively, P non-significant).For pN1 NSCLC patients after R0 resection, use of PORT is decreasing. High LNR after R0 surgery in pN1 NSCLC patients portends worse survival. PORT does not benefit pN1 NSCLC patients with low LNR after R0 surgery, but it is associated with better survival for patients with high LNR after accounting for multiple confounders including adjuvant chemotherapy.