Proceedings of the 1st biannual bridging the gaps in lung cancer conference.

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such scenarios relate to biomarkers and testing in lung cancer, small cell lung cancer, EGFR mutations and targeted therapy in non-small cell lung cancer (NSCLC), early-stage NSCLC, KRAS/BRAF/MET and other genomic alterations in NSCLC, and immunotherapy in advanced NSCLC.

The Effect of Neoadjuvant Therapy on Esophagectomy for cT2N0M0 Esophageal Adenocarcinoma.

BACKGROUND: For cT2N0M0 esophageal adenocarcinomas, the effects of neoadjuvant chemoradiotherapy (NT) on surgical outcomes and the oncological benefits to the patients are debatable. In this study, we investigated the optimal management for cT2N0M0 adenocarcinoma (1) assessing the perioperative impact of NT on esophagectomy and (2) evaluating the oncologic effect of NT in a homogeneous group of patients with clinical stage IIA. We hypothesized that NT does not negatively affect perioperative outcomes and provides an oncologic benefit to selected patients with cT2N0M0 disease. METHODS: The National Cancer Database was queried (2010-2019) for patients with cT2N0M0 esophageal adenocarcinoma undergoing esophagectomy. After propensity-matching to adjust for differences in patient and tumor characteristics, we compared postoperative outcomes (logistic regression) and survival (Kaplan-Meier and Cox regression) among those who underwent NT vs upfront surgery (S). RESULTS: This study included 3413 patients, of whom 2359 (69%) received NT, and 1054 (31%) S. In contrast to those who underwent S, in the matched cohort, patients treated with NT had comparable conversion rates (8% vs11.1%, p = 0.06), length of stay (9 vs 10 days, p = 0.078), unplanned readmission (5.4% vs 8.8%, p = 0.109), and 30- (3.9% vs 3.7%, p = 0.90) and 90-day mortality (5.7% vs 4.7%, p = 0.599). In addition, NT associated with improved survival in patients with cT2N0M0 tumors > 5 cm (HR 0.30, 95% CI 0.17-0.36). CONCLUSIONS: NT does not appear to increase technical complexity or to adversely affect postoperative outcomes after esophagectomy. Furthermore, minimally invasive esophagectomy is feasible following NT, with comparable conversion rates to those who had upfront surgery. Lastly, NT was selectively associated with improved survival in patients with cT2N0M0 esophageal cancer.

Trends and Disparities in Robotic Surgery Utilization for Non-Small Cell Lung Cancer.

INTRODUCTION: Robotic surgery has become an increasingly utilized approach for resectable lung cancer. However, availability may be limited for certain patient populations, underscoring inequity in access to innovative surgical techniques. We hypothesize that there is an association between social determinants of health and robotic surgery utilization for resectable non-small cell lung cancer (NSCLC). METHODS: We queried the National Cancer Database (2010-2019) for patients with clinical stage I-III NSCLC who underwent resection, stratifying the cohort based on surgical technique. Multivariable logistic regression analysis was performed to identify associations between sociodemographic and clinicopathologic factors and the robotic approach. RESULTS: Among the 226,455 clinical stage I-III NSCLC patients identified, 34,059 (15%) received robotic resections, 78,039 (34.5%) underwent thoracoscopic resections, and 114,357 (50.5%) had open resections. Robotic surgery utilization increased from 3.1% in 2010 to 34% in 2019 (P < 0.001). Despite this, after adjusting by clinical stage, extent of resection, site of tumor, and receipt of neoadjuvant therapy, multivariable analysis revealed various sociodemographic and treatment facility factors that were associated with underutilization of this approach: lack of insurance (adjusted odds ratio [aOR] 0.83, 95% confidence interval [CI] 0.73-0.93), lower income brackets (aOR 0.93, 95% CI 0.91-0.96), provincial settings (urban aOR 0.79, 95% CI 0.76-0.82; rural aOR 0.57, 95% CI 0.51-0.64), and treatment at community centers (comprehensive community cancer programs aOR 0.73, 95% CI 0.70-0.75; community cancer programs aOR 0.51, 95% CI 0.47-0.55). CONCLUSIONS: This study suggests that disparities in determinants of health influence accessibility to robotic surgery for resectable NSCLC. Identification of these gaps is crucial to target vulnerable sectors of the population in promoting equality and uniformity in surgical treatment.

Extended Lymphadenectomy Improves Survival After Induction Chemoradiation for Esophageal Cancer: A Propensity-Matched Analysis of the National Cancer Database.

OBJECTIVES: The aim of this study was to explore the potential value of extended nodal-dissection following neoadjuvant chemoradiation (CRT), by analyzing data from the National Cancer Database (NCDB). BACKGROUND: A CROSS-trial post-hoc analysis showed that the number of dissected lymph nodes was associated with improved survival in patients undergoing upfront surgery but not in those treated with neoadjuvant CRT. METHODS: The NCDB was queried (2004-2014) for patients who underwent esophagectomy following induction CRT. Predictors of overall survival (OS) were assessed. The optimal number of dissected LNs associated with highest survival benefit was determined by multiple regression analyses and receiveroperating characteristic curve analysis. The whole cohort was divided into 2 groups based on the predefined cutoff number. The two groups were propensity-matched (PMs). RESULTS: Esophagectomy following induction-CRT was performed in 14,503 patients. The number of resected nodes was associated with improved OS in the multivariable analysis (hazard ratio for every 10 nodes: 0.95 (95% confidence interval: 0.93-0.98). The cutoff number of resected LNs that was associated with the highest survival benefit was 20 nodes. In the PM groups, patients in the "≥20 LNs" group had a 14% relative-increase in OS ( P = 0.002), despite having more advanced pathological stages (stage II-IV: 76% vs 72%, P < 0.001), and higher number of positive nodes (0-2 vs 0-1, P < 0.001). CONCLUSIONS: The total number of resected nodes is a significant determinant of improved survival following induction CRT in patients with either node negative or node positive disease. In the matched groups, patients with higher number of resected lymph nodes had higher OS rate, despite having more advanced pathological disease and higher number of resected positive lymph nodes.

Surgical Treatment at an Academic Medical Center is Associated with Statistically Insignificant Lung Cancer Survival Outcome Differences Related to ZIP Code.

BACKGROUND: Low socioeconomic status is a well-characterized adverse prognostic factor in large lung cancer databases. However, such characterizations may be confounded as patients of lower socioeconomic status are more often treated at low-volume, non-academic centers. We evaluated whether socioeconomic status, as defined by ZIP code median income, was associated with differences in lung cancer resection outcomes within a high-volume academic medical center. METHODS: Consecutive patients undergoing resection for non-small cell lung cancer were identified from a prospectively maintained database (2011-18). Patients were assigned an income value based on the median income of their ZIP code as determined by census-based geographic data. We stratified the population into income quintiles representative of SES and compared demographics (chi-square), surgical outcomes, and survival (Kaplan-Meier). RESULTS: We identified 1,693 patients, representing 516 ZIP codes. Income quintiles were Q1: $24,421-53,151; Q2:$53,152-73,982; Q3:$73,983-99,063; Q4:$99,064-123,842; and Q5:$123,843-250,001. Compared to Q5 patients, Q1 patients were younger (median 69 vs. 73, p < 0.001), more likely male (44 vs. 36%, p = 0.035), and more likely Asian, Black, or self-identified as other than white, Asian, or Black. (67 vs. 11%, p = < 0.001). We found minor differences in surgical outcomes and no significant difference in 5-year survival between Q1 and Q5 patients (5-year: 86 vs. 85%, p = 0.886). CONCLUSIONS: Surgical care patterns at a high-volume academic medical center are similar among patients from varying ZIP codes. Surgical treatment at such a center is associated with no survival differences based upon socioeconomic status as determined by ZIP code. Centralization of lung cancer surgical care to high-volume centers may reduce socioeconomic outcome disparities.

CUL4high Lung Adenocarcinomas Are Dependent on the CUL4-p21 Ubiquitin Signaling for Proliferation and Survival.

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non-small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4Ak/d) or CUL4B (CUL4Bk/d) leads to cell cycle arrest at G1 and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G1 arrest of CUL4Ak/d or CUL4Bk/d NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4Ahigh/CUL4Bhigh may serve as a prognostic marker and therapeutic target for patients with NSCLC.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING: AstraZeneca.

Percutaneous and Open Tracheostomy in Patients with COVID-19: Comparison and Outcomes of an Institutional Series in New York City.

OBJECTIVE: The aim of this study was to report the safety, efficacy, and early results of tracheostomy in patients with COVID-19 and determine whether differences exist between percutaneous and open methods. SUMMARY BACKGROUND DATA: Prolonged respiratory failure is common in symptomatic patients with COVID-19, the disease process caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tracheostomy, although posing potential risk to the operative team and other healthcare workers, may be beneficial for safe weaning of sedation and ventilator support. However, short- and long-term outcomes remain largely unknown. METHODS: A prospectively collected database of patients with COVID-19 undergoing tracheostomy at a major medical center in New York City between April 4 and April 30, 2020 was reviewed. The primary endpoint was need for continued mechanical ventilation. Secondary outcomes included complication rates, sedation weaning, and need for intensive care unit (ICU) level of care. Patient characteristics, perioperative conditions, and outcomes between percutaneous and open groups were analyzed. RESULTS: During the study period, 67 consecutive patients underwent tracheostomy, including 48 males and 19 females with a median age of 66 years [interquartile range (IQR) 52-72]. Two surgeons alternated techniques, with 35 tracheostomies performed percutaneously and 32 via an open approach. The median time from intubation to tracheostomy was 23 days (IQR 20-26). At a median follow-up of 26 days, 52 patients (78%) no longer required mechanical ventilation and 58 patients (87%) were off continuous sedation. Five patients (7.5%) died of systemic causes. There were 11 total complications (16%) in 10 patients, most of which involved minor bleeding. There were no significant differences in outcomes between percutaneous and open methods. CONCLUSIONS: Tracheostomy under apneic conditions by either percutaneous or open technique can be safely performed in patients with respiratory failure due to COVID-19. Tracheostomy facilitated weaning from continuous intravenous sedation and mechanical ventilation. Continued follow-up of these patients to ascertain long-term outcome data is ongoing.

Sensitivity and specificity of fine needle aspiration for the diagnosis of mediastinal lesions.

Fine needle aspiration cytology (FNAC) of mediastinal masses allows for rapid on-site evaluation and the triaging of material for ancillary studies. However, surgical pathology is often considered to be the gold standard for diagnosis. This study examines the sensitivity and specificity of FNAC compared to a concurrent or subsequent surgical pathology specimen in 77 mediastinal lesions. The overall sensitivity for mediastinal mass FNAC was 78% and the overall specificity was 98%. For individual categories the sensitivity and specificity of FNAC was respectively as follows: inflammatory/infectious (33%, 99%), metastatic carcinoma (93%, 100%), lymphoma (84%, 97%), cysts (25%, 100%), soft tissue tumors (100%, 100%), paraganglioma (50%, 100%), germ cell tumor (100%, 99%), thymoma (87%, 94%), thymic carcinoma (60%, 100%), benign thymus (0%, 100%), and indeterminate (100%, 90%). For different locations within the mediastinum the sensitivity and specificity of FNAC was respectively as follows: anterosuperior mediastinum (80%, 98%), posterior mediastinum (33%, 95%), middle mediastinum (100%, 100%), and mediastinum, NOS (79%, 99%). Thus, mediastinal FNAC is fairly sensitive, very specific, and is a valuable technique in the diagnosis of mediastinal masses.

p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.

Predictors of Disease-free Survival and Recurrence in Patients with Resected Bronchial Carcinoid Tumors.

BACKGROUND: Bronchial carcinoids are characterized by neuroendocrine differentiation and have distinct biological behavior, recurrence patterns, and prognosis compared with adenocarcinomas or squamous cell carcinomas. Because of their often indolent nature, it has been suggested that routine postoperative imaging surveillance may not be warranted in the majority of patients. This study aims to define the factors that predict disease-free survival (DFS) and recurrence after resection of these tumors, with the goal of identifying high-risk patients for whom image surveillance may be warranted. METHODS: We conducted a retrospective review of a prospective database to identify patients with completely resected bronchial carcinoid tumors. Surgical procedure, histology, pathological stage, follow-up, tumor recurrence, and survival were assessed. RESULTS: One hundred and forty-two patients were identified. Median age was 62 years and the majority was women (106). Surgical procedures included 20 wedge resections, 10 segmentectomies, 99 lobectomies, 3 bilobectomies, 2 pneumonectomies, 6 sleeve resections, and 2 bronchectomies. Pathologic stages included I (81%), II (10%), III (8%), and IV (1%). With a median follow-up of 31 months, there were seven recurrences. The 5- and 10-year overall survival rates were 92% and 75% and DFS rates were 88% and 72%, respectively. There were 34 patients with atypical carcinoids, and 6 (18%) developed recurrence, compared with 1 recurrence (1%) in the group of 108 patients with typical carcinoids (p = 0.0008). For atypical carcinoid tumors, the 5- and 10-year DFS rates were 72% and 32% versus 92% and 85% in typical carcinoid tumors (p = 0.001). Patients with more advanced tumor stage pT2-4 and pathologic N1/N2 nodal metastases had a significantly decreased 5- and 10-year DFS compared with those with early pT1 stage (p = 0.029) or those without nodal disease (p = 0.043). Multivariate Cox regression analyses showed advancing age (p = 0.001), atypical histology (p = 0.021), and advanced tumor stage (p = 0.047) were significant negative predictors for DFS. CONCLUSION: Long-term survival after resection of bronchial carcinoids is common, especially for patients with typical carcinoid tumors. DFS can be negatively influenced by atypical histology, advanced tumor, and nodal statuses. Efforts at postoperative image surveillance should target those patients with such high-risk factors.

Clinical Issues in the Surgical Management of Screen-Identified Lung Cancers.

The National Lung Screening Trial reported a 20% reduction in lung cancer-specific mortality in patients screened with low-dose computed tomography (CT) compared with those screened by plain chest radiography. This led to the endorsement of CT screening for lung cancer by the US Preventive Services Task Force and the subsequent approval of screening as a preventive health service reimbursable by the Centers for Medicare and Medicaid Services. This review outlines the diagnostic and therapeutic challenges associated with the increased number of screen-identified indeterminate lung nodules, highlighting currently recommended follow-up and management algorithms, as well as the various methods of nodule localization, tissue diagnosis, and definitive local therapeutic modalities.

Perioperative Outcomes after Lung Resection in Obese Patients.

BACKGROUND: Obesity is a growing epidemic in the developed world. However, little is known about the impact of obesity on the perioperative morbidity and mortality after lung resection. PATIENTS AND METHODS: We analyzed the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2010 to determine whether obesity is a risk factor for perioperative morbidity and mortality after pulmonary resection. Demographic, clinical, intraoperative, and morbidity and mortality data were collected. Multivariable predictors of morbidity and mortality were determined using regression analysis. RESULTS: A total of 5,216 lung resections were identified (1,372 wedges, 3,713 lobectomies, and 131 pneumonectomies). The median age was 66 years and 2,587 (49.6%) were females. The body mass index (BMI, kg/m(2)) of the patients was as follows: 192 (3.7%) < 18.5; 1,727 (33.1%) 18.5 to 24.9; 1,754 (33.6%) 25 to 29.9; and 1,488 (28.5%) > 30. In-hospital mortality and all-cause morbidity was 2.4% (n = 127) and 14.5% (n = 757) for the entire cohort of patients, respectively. BMI was not found to be a predictor of increased mortality or morbidity, even in the morbidly obese (BMI > 35). Rather, age, approach (video-assisted thoracoscopic surgery vs. open), parameters assessing performance status, operative time, and preoperative radiation therapy were the predictors of morbidity and mortality. Conversely, being overweight (BMI 25-30) approached significance as a multivariate predictor for decreased pulmonary complications (odds ratio, 0.77 [0.592-1.004]; p = 0.054) consistent with the "obesity paradox" observed after nonbariatric general surgery. CONCLUSION: Our large national study shows that obesity does not negatively impact perioperative mortality and morbidity in patients undergoing lung resection. Surgical resections should not be denied to obese (BMI > 30) patients.

Untapping the Prognostic Value of Patient-Generated Health Data in Locally Advanced Non-small Cell Lung Cancer.

BACKGROUND: Patient-generated health data (PGHD), which includes patient-reported outcomes (PROs) and wearable device data, may have prognostic value for cancer patients. We tested that hypothesis using data from several prospective trials where patients with locally advanced non-small cell lung cancer (LA-NSCLC) were treated with definitive chemoradiotherapy. METHODS: Cox proportional hazards models were utilized to identify the baseline patient-reported symptom that best predicted progression-free survival (PFS) duration in a trial that involved PRO-CTCAE collection (Cohort 1). Using data from trials that included EORTC QLQ-C30 questionnaires and wearable devices (Cohort 2), the same symptom was tested as a predictor of PFS. Baseline physical inactivity was also tested as a predictor of PFS. A simple risk stratification tool utilizing PROs and physical activity was proposed. RESULTS: In Cohort 1 (n = 50), anorexia was the only pretreatment PRO that was significantly associated with PFS after Bonferroni correction (HR = 3.94, P = .002). In Cohort 2 (n = 58), baseline anorexia was also significantly associated with PFS (HR = 2.48, P = .018), as was physical inactivity (HR = 3.11, P < .001). Median PFS duration for patients in Cohort 2 with anorexia or physical inactivity was 6 months, compared to 18 months for other patients (HR = 3.08, P < .001). Median overall survival duration for patients with anorexia or physical inactivity was 19 months, compared to 65 months for other patients (HR = 2.44, P = .021). CONCLUSION: PGHD, including PROs and wearable device data, can provide valuable prognostic information for LA-NSCLC patients treated with definitive chemoradiotherapy. These findings should be validated using larger datasets.

Advancing neoadjuvant therapies in resectable non-small cell lung cancer: implications for novel treatment strategies and biomarker discovery.

The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of targeted therapies as well as immune checkpoint inhibitors alone or alongside conventional chemotherapy. This evolution has been particularly notable in the incorporation of immunotherapy and targeted therapy into the treatment of resectable NSCLC, where recent FDA approvals of drugs such as nivolumab and pembrolizumab, in combination with platinum doublet chemotherapy, have led to considerable improvements in pathological complete response rates and the potential for enhanced long-term survival outcomes. This review emphasizes the growing importance of biomarkers in optimizing treatment selection and explores the impact of emerging studies that challenge existing treatment paradigms and investigate novel therapeutic combinations poised to redefine standard of care practices. Furthermore, the discussion extends to the unmet needs within perioperative treatment assessment and prognostication, highlighting the prospective value of biomarkers in evaluating treatment responses and prognosis.

Perioperative Immunotherapy for Non-Small Cell Lung Cancer: Practical Application of Emerging Data and New Challenges.

Immune checkpoint inhibition, with or without chemotherapy, is an established standard of care for metastatic non-small cell lung cancer (NSCLC). For locally advanced NSCLC treated with chemoradiotherapy, consolidation immunotherapy has dramatically improved outcomes. Recently, immunotherapy has also been established as a valuable component of treatment for resectable NSCLC with pembrolizumab, atezolizumab, and nivolumab all approved for use in this setting. As more results read out from ongoing perioperative clinical trials, navigating treatment options will likely become increasingly complex for the practicing oncologist. In this paper, we distill key outcomes from major perioperative trials and highlight current knowledge gaps. In addition, we provide practical considerations for incorporating perioperative immunotherapy into the clinical management of operable NSCLC.

Sublobar resection is associated with less lymph nodes examined and lower delivery of adjuvant therapy in patients with 1.5- to 2.0-cm clinical IA2 non-small-cell lung cancer: a retrospective cohort study.

OBJECTIVES: CALGB140503, in which nodal sampling was mandated, reported non-inferior disease-free survival for patients undergoing sublobar resection (SLR) compared to lobectomy (L). Outside of trial settings, the adequacy of lymphadenectomy during SLR has been questioned. We sought to evaluate whether SLR is associated with suboptimal lymphadenectomy, differences in pathologic upstaging and survival in patients with 1.5- to 2.0-cm tumours using real-world data. MATERIALS AND METHODS: Using the National Cancer Database(2018-2019), we evaluated patients with 1.5- to 2.0-cm non-small-cell lung cancer who underwent resection (sublobar versus lobectomy). We studied factors associated with nodal upstaging (logistic regression) and survival (Cox regression and Kaplan-Meier method) after propensity matching to adjust for differences among groups. RESULTS: Among 3196 patients included, SLR was performed in 839 (26.3%) (of which 588 were wedge resections) and L was performed in 2357 (73.7%) patients. More patients undergoing SLR (21.7%) compared to L (2.1%) had no lymph nodes sampled (P < 0.001). Those undergoing SLR had fewer total lymph nodes examined (4 vs 11, P < 0.001) and were less likely to have pathologic nodal metastases (4.7% vs 9%, P < 0.001) compared to L. Multivariable analysis identified L [adjusted odds ratio (aOR) 2.21, 95% confidence interval, 1.47-3.35] to be independently associated with pathologic N+ disease. Overall survival was not associated with the type of procedure but was significantly decreased in those with N+ disease. CONCLUSIONS: Despite comparable overall survival to L, SLR is associated with suboptimal lymphadenectomy in patients with 1.5-2.0 cm non-small-cell lung cancer. Surgeons should be careful to perform adequate lymphadenectomy when performing SLR to mitigate nodal under-staging and to identify appropriate patients for systemic therapy.

Association of socioeconomic factors with the receipt of neoadjuvant therapy for patients with non-small cell lung cancer.

BACKGROUND: Neoadjuvant therapy (NT) will be increasingly used for patients with non-small cell lung cancer (NSCLC), particularly given the recent approval of neoadjuvant chemoimmunotherapy. Several barriers may prevent the uptake of NT and should be identified and addressed. We queried the National Cancer Database (NCDB) to determine predictors of the use of NT. METHODS: Using the NCDB (2006-2019), we identified 80,707 patients who underwent surgery for clinical stage II and III NSCLC. Sociodemographic and clinical factors were reviewed, and univariable and multivariable analyses were performed to identify associations with the uptake of NT. In propensity score-matched groups, survival was determined using the Kaplan-Meier method. RESULTS: Among 80,707 eligible patients, 17,262 (21.4%) received NT. Clinical stage and node positivity were associated with receipt of NT. On multivariable analysis, factors associated with lower rates of NT included black race (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.67-0.90), Charlson Comorbidity Index ≥2 (OR, 0.75; 95% CI, 0.67-0.85), Medicaid/Medicare insurance (OR, 0.82; 95% CI, 0.75-0.90), lower income level (OR, 0.79; 95% CI, 0.71-0.87), and treatment at a community center (OR, 0.81; 95% CI, 0.67-0.96). In an exploratory analysis, those patients who received NT had longer 5-year overall survival compared with those who did not (48.3% vs 46.0%; P < .001). CONCLUSIONS: Rates of NT are relatively low for patients with clinical stage II/III NSCLC treated prior to recent chemoimmunotherapy trials. Socioeconomic barriers to the uptake of NT include race, insurance status, income, and area of residence. As NT becomes more widely offered, accessibility for vulnerable populations must be assured.

Resection of the Primary Tumor and Survival in Patients with Single-Site Synchronous Oligometastatic Non-Small Cell Lung Cancer: Propensity-Matched Analysis of the National Cancer Database.

BACKGROUND: Local therapy for the primary tumor is postulated to remove resistant cancer cells as well as immunosuppressive cells from the tumor microenvironment, potentially improving response to systemic therapy (ST). We sought to determine whether resection of the primary tumor was associated with overall survival (OS) in a multicentric cohort of patients with single-site synchronous oligometastatic non-small cell lung cancer. STUDY DESIGN: Using the National Cancer Database (2018 to 2020), we evaluated patients with clinical stage IVA disease who received ST and stratified the cohort based on receipt of surgery for the primary tumor (S). We used multivariable and propensity score-matched analysis to study factors associated with S (logistic regression) and OS (Cox regression and Kaplan-Meier), respectively. RESULTS: Among 12,215 patients identified, 2.9% (N = 349) underwent S and 97.1% (N = 11,886) ST (chemotherapy or immunotherapy) without surgery. Patients who underwent S were younger, more often White, had higher income levels, were more likely to have private insurance, and were more often treated at an academic facility. Among those who received S, 22.9% (N = 80) also underwent resection of the distant metastatic site. On multivariable analysis, metastasis to bone, N+ disease, and higher T-stages were independently associated with less S. On Cox regression, S and resection of the metastatic site were associated with improved survival (hazard ratio 0.67, 95% CI 0.56 to 0.80 and hazard ratio 0.80, 95% CI 0.72 to 0.88, respectively). After propensity matching, OS was improved in patients undergoing S (median 36.8 vs 20.8 months, log-rank p < 0.001). CONCLUSIONS: Advances in ST for non-small cell lung cancer may change the paradigm of eligibility for surgery. This study demonstrates that surgical resection of the primary tumor is associated with improved OS in selected patients with single-site oligometastatic disease.