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.

Minimally invasive surgery for clinical T4 non-small-cell lung cancer: national trends and outcomes.

OBJECTIVES: Recent randomized data support the perioperative benefits of minimally invasive surgery (MIS) for non-small-cell lung cancer (NSCLC). Its utility for cT4 tumours remains understudied. We, therefore, sought to analyse national trends and outcomes of minimally invasive resections for cT4 cancers. METHODS: Using the 2010-2019 National Cancer Database, we identified patients with cT4N0-1 NSCLC. Patients were stratified by surgical approach. Multivariable logistic analysis was used to identify factors associated with use of a minimally invasive approach. Groups were matched using propensity score analysis to evaluate perioperative and survival end points. RESULTS: The study identified 3715 patients, among whom 64.1% (n = 2381) underwent open resection and 35.9% (n = 1334) minimally invasive resection [robotic-assisted in 31.5% (n = 420); and video-assisted in 68.5% (n = 914)]. Increased MIS use was noted among patients with higher income [≥$40 227, odds ratio (OR) 1.24; 95% confidence interval (CI) 1.01-1.51] and those treated at academic hospitals (OR 1.25; 95% CI 1.07-1.45). Clinically node-positive patients (OR 0.68; 95% CI 0.55-0.83) and those who underwent neoadjuvant therapy (OR 0.78; 95% CI 0.65-0.93) were less likely to have minimally invasive resection. In matched groups, patients undergoing MIS had a shorter median length of stay (5 vs 6 days, P < 0.001) and no significant differences between 30-day readmissions or 30/90-day mortality. MIS did not compromise overall survival (log-rank P = 0.487). CONCLUSIONS: Nationally, the use of minimally invasive approaches for patients with cT4N0-1M0 NSCLC has increased substantially. In these patients, MIS is safe and does not compromise perioperative outcomes or survival.

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.

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.

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.

Tumour immune escape via P2X7 receptor signalling.

While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.

Building a Lung Cancer Screening Program.

Lung cancer screening improves lung-cancer specific and potentially overall survival; however, uptake rates are concerningly low. Several barriers to screening exist and require a systemic approach to address. The authors describe their approach toward building a centralized lung cancer screening program at an urban academic center along with lessons learned. To this end, the identification of involved stakeholders, evaluation of community barriers and needs, optimization of the electronic health system, and implementation of system of standardized follow-up for patients are processes for consideration. Perhaps most important to undertaking this endeavor is the need to customize each program and maintain adaptability.

TIMP1 is an early biomarker for detection and prognosis of lung cancer.

BACKGROUND: Lung cancer remains the major cause of cancer-related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up. METHODS: Using bead-based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single-cell RNA-seq and bulk RNA-seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases. RESULTS: We found that TIMP1 is a tumour-secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients. CONCLUSION: TIMP1 is a suitable biomarker for lung cancer detection.

Underutilization of Systemic Therapy in Patients With NSCLC Undergoing Pneumonectomy: A Missed Opportunity for Survival.

Introduction: Recent trials have reported promising results with the addition of immunotherapy to chemotherapy for patients with locally advanced NSCLC, but in practice, the proportion of patients who receive systemic therapy (ST) has historically been low. Underutilization of ST may be particularly apparent in patients undergoing pneumonectomy, in whom the physiologic insult and surgical complications may preclude adjuvant therapy (ADJ). We, therefore, evaluated the use of ST for patients with NSCLC undergoing pneumonectomy. Methods: We queried the National Cancer Database, including all patients with NSCLC who underwent pneumonectomy between 2006 and 2018. Logistic regression was used to identify associations with ST and neo-ADJ (NEO). Overall survival was compared after propensity score matching (1:1) patients undergoing ST to those undergoing surgery alone using Kaplan-Meier and Cox regression methods. Results: A total of 2619 patients were identified. Among these, 12% received NEO, 43% received ADJ, and 45% surgery alone. Age younger than 65 years (adjusted odds ratio [aOR] = 1.53, 95% confidence interval; [CI]: 1.10-2.11), Asian ethnicity (aOR = 2.68, 95% CI: 1.37-5.23), treatment at a high-volume center (aOR = 1.39, 95% CI: 1.06-1.81), and private insurance (aOR = 1.42, 95% CI: 1.05-1.94) were associated with NEO, whereas age younger than 65 years (aOR = 1.95, 95% CI: 1.61-2.38), comorbidity index less than or equal to 1 (aOR = 1.66, 95% CI: 1.29-2.16), and private insurance (aOR = 1.47, 95% CI: 1.20-1.80) were associated with any ST. In the matched cohort, ST was associated with better survival than surgery (adjusted hazard ratio = 0.67, 95% CI: 0.58-0.78). Conclusions: A high proportion of patients who undergo pneumonectomy do not receive ST. Patient and socioeconomic factors are associated with the receipt of ST. Given its survival benefit, emphasis should be placed on multimodal treatment strategies, perhaps with greater consideration given to neoadjuvant approaches.

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.

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.

The ART of tumor immune escape.

We recently identified the adenosine-5'-diphosphate (ADP)-ribosyltransferase-1 (ART1) as a novel immune checkpoint expressed by cancer cells. ART1 utilizes free nicotinamide adenine dinucleotide (NAD+) in the tumor microenvironment (TME) to mono-ADP-ribosylate (MARylate) the P2X7 receptor (P2X7R) on CD8 T cells, resulting in NAD-induced cell death (NICD) and tumor immune resistance. This process is blocked by therapeutic antibody targeting of ART1.

Safety of lung cancer surgery during COVID-19 in a pandemic epicenter.

BACKGROUND: The influence of SARS-CoV-2 on surgery for non-small cell lung cancer needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. OBJECTIVE: This study reports on the 90-day rate of infection as well as the morbidity and mortality of lung surgery for cancer in a tertiary care hospital located in a pandemic epicenter. METHODS: We conducted a retrospective review of a prospective database to identify consecutive patients who underwent lung cancer resection before (January 1, 2020-March 10, 2020, group 1; 57 patients) and during the COVID-19 pandemic (March 11, 2020-June 10, 2020, group 2; 41 patients). The primary end point was the occurrence of SARS-CoV-2 infection during the first 90-days after surgery. The secondary outcome measure was 90-day perioperative morbidity and mortality. RESULTS: Patient characteristics were not significantly different between the groups. Ninety-day COVID-19 infection rates was 7.3% (3 out of 41) for patients undergoing an operation during the pandemic and 3.5% (2 out of 57) in patients operated on immediately before the pandemic. All patients tested positive 10 to 62 days after the index surgical procedure following hospital discharge. Four COVID-19-positive patients were symptomatic and 4 out of 5 patients required hospitalization, were men, previous or current smokers with hyperlipidemia, and underwent a sublobar resection. Univariate analysis did not identify any differences in postoperative complications before or during the COVID-19 pandemic. Ninety-day mortality was 5% (2 out of 41) for lung cancer surgery performed during the pandemic, with all deaths occurring due to COVID-19, compared with 0% (0 out of 57) mortality in patients who underwent an operation before the pandemic. CONCLUSIONS: During the COVID-19 pandemic, COVID-19 infections occurred in 7.3% of patients who underwent surgery for non-small cell lung cancer. In this series all infections occurred after hospital discharge. Our results suggest that COVID-19 infections occurring within 90 days of surgery portend a 40% mortality, warranting close postoperative surveillance.

Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.

Most patients with non-small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)-induced cell death (NICD) of P2X7 receptor (P2X7R)-expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono-adenosine 5'-diphosphate (ADP)-ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R+ CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD+-degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell-dependent manner. This was associated with increased infiltration of activated P2X7R+CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies.

Minimally Invasive Surgery for Lung Cancer Following Neoadjuvant Therapy in the United States.

Introduction: Pulmonary resections following neoadjuvant therapy (NT) can be technically demanding. There is a paucity of data regarding the use of minimally invasive surgery (MIS) approaches in that setting on the National level. In this study, we explored the trends of using MIS approaches following NT and its associated outcomes. Methods: The study included all adult patients with non-small cell lung cancer who underwent pulmonary resection following NT between 2010 and 2016. Propensity score (PS) matching (MIS versus open) was performed and the perioperative outcomes were compared. Results: The study included 11,287 patients who underwent pulomonary resection after NT. The percentage of patients undergoing MIS lung resection and the number of hospitals performing one or more MIS increased from 19% and 166 (2010) to 41% and 305 (2016), respectively. When compared with thoracotomy, MIS lung resections were more frequently performed in academic centers in patients with higher income (P < .001). In PS matched groups, the use of MIS was associated with shorter hospital length of stay (5 days versus 6 days; P < .001), compared with open approach. However, there were no differences between the two groups in readmission rate (P = .513), or 30-/90-day mortality (P = .145/.685). In multivariable regression analysis, MIS approach was not associated with worse long-term, all-cause, survival (confidence interval: 0.91-1.09). Conclusion: The use of MIS approaches after NT increased significantly over the study period and was associated with perioperative outcomes and long-term survival comparable to those noted with the open approach.