Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Clinical Outcomes of Resected Pure Ground-Glass, Heterogeneous Ground-Glass, and Part-Solid Pulmonary Nodules.

BACKGROUND. Increased (but not definitively solid) attenuation within pure ground-glass nodules (pGGNs) may indicate invasive adenocarcinoma and the need for resection rather than surveillance. OBJECTIVE. The purpose of this study was to compare the clinical outcomes among resected pGGNs, heterogeneous ground-glass nodules (GGNs), and part-solid nodules (PSNs). METHODS. This retrospective study included 469 patients (335 female patients and 134 male patients; median age, 68 years [IQR, 62.5-73.5 years]) who, between January 2012 and December 2020, underwent resection of lung adenocarcinoma that appeared as a subsolid nodule on CT. Two radiologists, using lung windows, independently classified each nodule as a pGGN, a heterogeneous GGN, or a PSN, resolving discrepancies through discussion. A heterogeneous GGN was defined as a GGN with internal increased attenuation not quite as dense as that of pulmonary vessels, and a PSN was defined as having an internal solid component with the same attenuation as that of the pulmonary vessels. Outcomes included pathologic diagnosis of invasive adenocarcinoma, 5-year recurrence rates (locoregional or distant), and recurrence-free survival (RFS) and overall survival (OS) over 7 years, as analyzed by Kaplan-Meier and Cox proportional hazards regression analyses, with censoring of patients with incomplete follow-up. RESULTS. Interobserver agreement for nodule type, expressed as a kappa coefficient, was 0.69. Using consensus assessments, 59 nodules were pGGNs, 109 were heterogeneous GGNs, and 301 were PSNs. The frequency of invasive adenocarcinoma was 39.0% in pGGNs, 67.9% in heterogeneous GGNs, and 75.7% in PSNs (for pGGNs vs heterogeneous GGNs, p < .001; for pGGNs vs PSNs, p < .001; and for heterogeneous GGNs vs PSNs, p = .28). The 5-year recurrence rate was 0.0% in patients with pGGNs, 6.3% in those with heterogeneous GGNs, and 10.8% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .06; for pGGNs vs PSNs, p = .02; and for heterogeneous GGNs vs PSNs, p = .18). At 7 years, RFS was 97.7% in patients with pGGNs, 82.0% in those with heterogeneous GGNs, and 79.4% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .02; for pGGNs vs PSNs, p = .006; and for heterogeneous GGNs vs PSNs, p = .40); OS was 98.0% in patients with pGGNs, 84.6% in those with heterogeneous GGNs, and 82.9% in those with PSNs (for pGGNs vs heterogeneous GGNs, p = .04; for pGGNs vs PSNs, p = .01; and for heterogeneous GGNs vs PSNs, p = .50). CONCLUSION. Resected pGGNs had excellent clinical outcomes. Heterogeneous GGNs had relatively worse outcomes, more closely resembling outcomes for PSNs. CLINICAL IMPACT. The findings support surveillance for truly homogeneous pGGNs versus resection for GGNs showing internal increased attenuation even if not having a true solid component.

Sublobar resections for lung cancer: Finally, some answers and some more questions?

The Lung Cancer Study Group Trial, published in 1995, set the tone for lobectomy as the standard of care for early-stage nonsmall cell lung cancer. Twenty-seven years and two randomized trials later, does the thoracic oncology community have clarity regarding the choice type of resection, or more questions?

Hyperthermic intraoperative chemotherapy (HIOC) for Stage IVa thymic malignancy may improve 5-year disease-free survival.

BACKGROUND AND OBJECTIVES: Stage IVa thymic malignancy has limited treatments. This study evaluated whether hyperthermic intraoperative chemotherapy (HIOC) after radical resection of Stage IVa thymic malignancy improves survival. METHODS: All patients who underwent resection, with or without HIOC, for Stage IVa thymic malignancy at a single center from 1990 to 2021 were reviewed. RESULTS: Thirty-four patients were identified; 22 surgery-only versus 12 surgery and HIOC (60 min cisplatin regimen 175 mg/m2 ). Demographics and comorbidities were similar between groups. Three patients in each group were carcinomas; remainder were thymomas. Thirty-two patients underwent attempted macroscopic complete resection; 22 operations succeeded, 68.8%. Significant complications were similar between groups, 18.2% surgery-only versus 25.0% HIOC, p = 0.68. Median time to recurrence trended longer for HIOC patients (42.9 vs. 32.9 months in surgery-only, p = 0.77). Overall survival, 5-year, was similar (75.8% HIOC vs. 76.2% surgery-only, p = 0.91). On stratified analysis, thymoma patients with macroscopic complete resection and HIOC experienced similar 5-year Overall (80.0% vs. 100.0% surgery-only, p = 0.157) but longer trending 5-year disease-free (85.7% vs. 40.0%, p = 0.18) and 5-year locoregional recurrence-free survival (85.7% vs. 68.6%, p = 0.75). CONCLUSIONS: This retrospective cohort study treating Stage IVa thymic malignancy with radical pleurectomy, with or without HIOC, found addition of HIOC-signaled delayed recurrence and improved disease-free survival.

Plain language summary of the CheckMate 816 study results: nivolumab plus chemotherapy given before surgery for non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). WHAT HAPPENED IN THE STUDY?: Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. WHAT WERE THE RESULTS?: Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 (ClinicalTrials.gov).

Pleurectomy Decortication in the Treatment of Malignant Pleural Mesothelioma: Encouraging Results and Novel Prognostic Implications Based on Experience in 355 Consecutive Patients.

OBJECTIVE: We report a series of 355 consecutive patients treated over 9 years in a single institution with intended PDC. BACKGROUND: Surgery for MPM has shifted from extra-pleural pneumonectomy to PDC with the goal of MCR. METHODS: Clinical and outcome data were reviewed. Kaplan-Meier estimators and log rank test were used to compare the overall survival, and logistic regression models were used. RESULTS: MCR was achieved in 304. There were 223 males, median age was 69 and histology was epithelioid in 184. The 30 and 90-day mortality were 3.0% and 4.6%.Most complications were low grade. Prolonged air leak in 141, deep venous thrombosis in 64, Atrial fibrillation in 42, chylothorax in 24, Empyema in 23, pneumonia in 21, Hemothorax in 12 and pulmonary embolus in 8. Median/5-year survival were 20.7 months/17.9% in the intent-to-treat cohort and 23.2months/21.2% in the MCR group. The survivals were best for patients with Tlstage and epithelioid histology (69.8months/54.1%). In a multivariable analysis, factors that were found to be associated with longer patient overall survival included epithelioid histology, T stage, quantitative clinical stage/tumor volume staging, adjuvant chemotherapy, intraoperative heated chemo, female sex, and length of stay shorter than 14 days. CONCLUSIONS: PDC is feasible with low mortality and is associated with manageable complication rates. 5-year survival of patients undergoing PDC with MCR in multi-modality setting is approaching 25% depending on quantitative and clinical stage, sex and histological subtype and is better than PDC without- MCR.

Pre-COVID-19 National Mortality Trends in Open and Video-Assisted Lobectomy for Non-Small Cell Lung Cancer.

INTRODUCTION: In the current era of episode-based hospital reimbursements, it is important to determine the impact of hospital size on contemporary national trends in surgical technique and outcomes of lobectomy. METHODS: Patients aged >18 y undergoing open and video-assisted thoracoscopic surgery (VATS) lobectomy from 2008 to 2014 were identified using insurance claims data from the National Inpatient Sample. The impact of hospital size on surgical approach and outcomes for both open and VATS lobectomy were analyzed. RESULTS: Over the 7-y period, 202,668 lobectomies were performed nationally, including 71,638 VATS and 131,030 open. Although the overall number of lobectomies decreased (30,058 in 2008 versus 27,340 in 2014, P < 0.01), the proportion of VATS lobectomies increased (24.0% versus 46.9%), and open lobectomies decreased (76.0% versus 53.0%, all P < 0.01). When stratified by hospital size, small hospitals had a significant increase in the proportion of open lobectomies (6.4%-12.2%; P = 0.01) and trend toward increased number of VATS lobectomies (2.7%-12.2%). Annual mortality rates for VATS (range: 1.0%-1.9%) and open (range: 1.9%-2.4%) lobectomy did not significantly differ over time (all P > 0.05) but did decrease among small hospitals (4.1%-1.3% and 5.1%-1.1% for VATS and open, respectively; both P < 0.05). After adjusting for confounders, hospital bed size was not a predictor of in-hospital mortality. CONCLUSIONS: Utilization of VATS lobectomies has increased over time, more so among small hospitals. Mortality rates for open lobectomy remain consistently higher than VATS lobectomy (range 0.4%-1.4%) but did not significantly differ over time. This data can help benchmark hospital performance in the future.

Salvage surgery for local recurrence after sublobar surgery in Stages I and II non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: To examine if patients undergoing salvage surgery for local recurrence following sublobar resection (SLR) have similar perioperative complications and overall survival (OS) compared to lobectomy patients for early stage non-small cell lung cancer (NSCLC). METHODS: Patients undergoing lobectomy and SLR (segmentectomy or wedge resection) for Stages I and II NSCLC from 2010 to 2016 were reviewed. Lobectomy patients and those who underwent salvage surgery for local recurrence after SLR were compared. Salvage surgeries were curative-intent resections for recurrence. RESULTS: Cases included 634 lobectomies and 986 SLR. Fifty-nine SLR patients (6.0%) recurred at a local site compared to 11 lobectomy patients (1.7%; p < 0.001). Twenty-three locally recurrent SLR patients (39.0%) went on to salvage surgery. Peri-operative complications after salvage surgeries were similar to lobectomies (34.8% 8/23 vs. 34.7% 220/634, p = 1.00). OS at 5 years for salvage surgery patients was similar to lobectomy patients (79.6% 13/23 vs. 70.6% 227/634, p = 0.23). OS for patients who underwent salvage surgery was significantly better than those who did not have salvage surgery for recurrence (79.6% vs. 53.0%, p = 0.02). CONCLUSIONS: Patients who undergo salvage surgery for local recurrence after SLR had similar perioperative complications and OS compared to lobectomy patients but less than half underwent salvage surgery.

Adjuvant therapy following induction therapy and surgery improves survival in N2-positive non-small cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate treatment strategies and factors influencing overall survival (OS) and disease-free survival (DFS) in resectable, non-small cell lung cancer (NSCLC) with mediastinal (N2) lymph node metastasis. METHODS: All patients undergoing surgery for NSCLC with N2 disease between 2006 and 2016 were included. Treatment approaches included surgery only, neoadjuvant therapy followed by surgery, surgery followed by adjuvant therapy, and neoadjuvant therapy followed by surgery and adjuvant therapy (triple therapy). Patient clinical and pathologic data were retrospectively collected. RESULTS: A total of 281 patients were included in the study. In total, 209 patients had neoadjuvant therapy, 47.4% of which went on to received additional adjuvant therapy. The pathologic complete response rate was 12.9%. The treatment strategy which included triple therapy was isolated as a significant contributor to improved OS and DFS. Nodal downstaging (N0) after induction therapy conferred an OS benefit (38.3% vs. 15.6%, p = .03). Patients with single-station N2 disease experienced higher DFS. Video-assisted thoracic surgery (VATS) lobectomy completion rates were higher at the end of the study period compared to the beginning (p < .001). CONCLUSIONS: Patients who undergo neoadjuvant therapy for N2-positive NSCLC may benefit from additional adjuvant therapy. Single-station N2 disease confers higher DFS. VATS completion rates for lobectomy increase as experience increases.

Outcomes of superior segmentectomy versus lower lobectomy for superior segment Stage I non-small-cell lung cancer are equivalent: An analysis of 196 patients at a single, high volume institution.

OBJECTIVES: To determine if superior segmentectomy has equivalent overall (OS), disease-free (DFS), and locoregional-recurrence-free survival (LRFS) to lower lobectomy for early-stage non-small-cell lung cancer (NSCLC) in the superior segment. METHODS: We retrospectively reviewed all Stage 1 lower lobectomies for superior segment lesions and superior segmentectomies at our hospital from 2000 to 2018. Comparison statistics and Cox hazard modeling were performed to determine differences between groups and attempt to identify risk factors for OS, DFS, and LRFS. RESULTS: Superior segmentectomy patients, compared with lower lobectomy patients, had more current smokers, worse forced expiratory volume in 1 s percentage, radiologic emphysema scores, clinically and pathologically smaller tumors, and more occurrences of 0 lymph nodes examined. Outcomes for superior segmentectomy compared with lower lobectomy were equivalent for 5-year OS (67.0% vs. 75.1%, p = 0.70), DFS (56.9% vs. 60.4%, p = 0.59), and LRFS (87.9% vs. 91.3%, p = 0.46). Multivariable Cox modeling lacked utility due to no outcome differences. CONCLUSIONS: In well-selected patients, superior segmentectomies can have equivalent OS, DFS, and LRFS compared with lower lobectomies of superior segment tumors for early stage lung cancer. Further data are needed to provide better risk estimates.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

The Impact of Hospital Size on National Trends and Outcomes Following Open Esophagectomy.

Background and Objectives: Previous studies have demonstrated superior patient outcomes for thoracic oncology patients treated at high-volume surgery centers compared to low-volume centers. However, the specific role of overall hospital size in open esophagectomy morbidity and mortality remains unclear. Materials and Methods: Patients aged >18 years who underwent open esophagectomy for primary malignant neoplasia of the esophagus between 2002 and 2014 were identified using the National Inpatient Sample. Minimally invasive procedures were excluded. Discharges were stratified by hospital size (large, medium, and small) and analyzed using trend and multivariable regression analyses. Results: Over a 13-year period, a total of 69,840 open esophagectomy procedures were performed nationally. While the proportion of total esophagectomies performed did not vary by hospital size, in-hospital mortality trends decreased for all hospitals (large (7.2% to 3.7%), medium (12.8% vs. 4.9%), and small (12.8% vs. 4.9%)), although this was only significant for large hospitals (P < 0.01). After controlling for patient demographics, comorbidities, admission, and hospital-level factors, hospital length of stay (LOS), total inflation-adjusted costs, in-hospital mortality, and complications (cardiac, respiratory, vascular, and bleeding) did not vary by hospital size (all P > 0.05). Conclusions: After risk adjustment, patient morbidity and in-hospital mortality appear to be comparable across all institutions, including small hospitals. While there appears to be an increased push for referring patients to large hospitals, our findings suggest that there may be other factors (such as surgeon type, hospital volume, or board status) that are more likely to impact the results; these need to be further explored in the current era of episode-based care.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Response and acquired resistance to everolimus in anaplastic thyroid cancer.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Minimally Invasive Surgery for Early-Stage Lung Cancer: From Innovation to Standard of Care.

The era of minimally invasive surgery for lung cancer follows decades of research; the collection and interpretation of countless qualitative and quantitative data points; and tireless efforts by a few pioneering thoracic surgeons who believed they could deliver a safe and oncologically sound operation with less tissue trauma, an improved physiologic profile, and fewer complications than traditional open surgery. This review highlights those efforts and the role of minimally invasive surgery for early-stage lung cancer in light of evolving technology, the emerging understanding of the biology of early-stage lung cancer, and lung cancer screening.

Non-Small Cell Lung Cancer, Version 6.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.