Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial.

BACKGROUND: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. METHODS: COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. FINDINGS: Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI -0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, -0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93-1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54-5·22). INTERPRETATION: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. FUNDING: Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

The Clinically Actionable Molecular Profile of Early versus Late-Stage Non-Small Cell Lung Cancer, an Individual Age and Sex Propensity-Matched Pair Analysis.

Background: Despite meticulous surgery for non-small cell lung cancer (NSCLC), relapse is as high as 70% at 5 years. Many institutions do not conduct reflexive molecular testing on early stage specimens, although targeted gene therapy may extend life by years in the event of recurrence. This ultimately delays definitive treatment with additional biopsy risking suboptimal tissue acquisition and quality for molecular testing. Objective: To compare molecular profiles of genetic alterations in early and late NSCLC to provide evidence that reflexive molecular testing provides clinically valuable information. Methods: A single-center propensity matched retrospective analysis was conducted using prospectively collected data. Adults with early and late-stage NSCLC had tissue subject to targeted panel-based NGS. Frequencies of putative drivers were compared, with 1:3 matching on the propensity score; p < 0.05 deemed statistically significant. Results: In total, 635 NSCLC patients underwent NGS (59 early, 576 late); 276 (43.5%) females; age 70.9 (±10.2) years; never smokers 140 (22.0%); 527 (83.0%) adenocarcinomas. Unadjusted frequencies of EGFR mutations were higher in the early cohort (30% vs. 18%). Following adjustment for sex and smoking status, similar frequencies for both early and late NSCLC were observed for variants in EGFR, KRAS, ALK, MET, and ROS1. Conclusion: The frequency of clinically actionable variants in early and late-stage NSCLC was found to be similar, providing evidence that molecular profiling should be performed on surgical specimens. This pre-determined profile is essential to avoid treatment delay for patients who will derive clinical benefit from targeted systemic therapy, in the high likelihood of subsequent relapse.

Disparate Time-to-Treatment and Varied Incidence of Actionable Non-Small Cell Lung Cancer Molecular Alterations in British Columbia: A Historical Cohort Study.

Background: non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC. It is crucial to first understand the molecular epidemiology and patterns of time to initiate treatment across its five health authorities (HA) to optimize the delivery of care for NSCLC in BC. In this way, we may harness the benefits of targeted therapy for more people with NSCLC as novel advances in therapy continue to emerge. Objective: to compare (a) the frequency of actionable NSCLC molecular alterations among HAs and (b) the time to treatment initiation. Methods: a retrospective observational study was conducted with prospectively collected data from the BC CGL Database. Adults with late stage NSCLC who underwent targeted NGS were included for the time period from May 2020 to June 2021. Demographics, actionable molecular alterations, PDL-1 expression, and time to treatment across HAs were examined. Using appropriate statistical tests for comparison among HAs, p>0.05 was deemed significant. Results: 582 patients underwent NGS/IHC and analysis during the study period. The mean age was 71 (10.1), and 326 (56%) patients were female. A significantly higher proportion of all EGFRm+ were identified within Vancouver Coastal Health (VCHA) and Fraser Health Authority (FHA) compared to the other health authorities (p < 0.001). This also holds true for common sensitizing EGFRm+ alone (p < 0.001) and for sensitizing EGFRm+ when adjusted for females and smoker status (OR 0.75; 95% CI 0.62, 0.92; p = 0.005). Patients residing within the Northern, Interior, and Island HAs were less likely to receive treatment at the same rate as those in VCHA and FHA HAs. Conclusion: actionable NSCLC driver mutations are present in all regional HAs, with disparity noted in time to initiate treatment between HAs. This provides evidence for the importance of molecular testing for patients in all BC HAs to guide personalized and timely NSCLC treatment.

High-Ambient Air Pollution Exposure Among Never Smokers Versus Ever Smokers With Lung Cancer.

INTRODUCTION: Air pollution may play an important role in the development of lung cancer in people who have never smoked, especially among East Asian women. The aim of this study was to compare cumulative ambient air pollution exposure between ever and never smokers with lung cancer. METHODS: A consecutive case series of never and ever smokers with newly diagnosed lung cancer were compared regarding their sex, race, and outdoor and household air pollution exposure. Using individual residential history, cumulative exposure to outdoor particulate matter (PM2.5) in a period of 20 years was quantified with a high-spatial resolution global exposure model. RESULTS: Of the 1005 patients with lung cancer, 56% were females and 33% were never smokers. Compared with ever smokers with lung cancer, never smokers with lung cancer were significantly younger, more frequently Asian, less likely to have chronic obstructive pulmonary disease or a family history of lung cancer, and had higher exposure to outdoor PM2.5 but lower exposure to secondhand smoke. Multivariable logistic regression analysis revealed a significant association with never-smoking patients with lung cancer and being female (OR = 4.01, 95% confidence interval [CI]: 2.76-5.82, p < 0.001), being Asian (ORAsian versus non-Asian = 6.48, 95% CI: 4.42-9.50, p < 0.001), and having greater exposure to air pollution (ORln_PM2.5 = 1.79, 95% CI: 1.10-7.2.90, p = 0.019). CONCLUSIONS: Compared with ever-smoking patients with lung cancer, never-smoking patients had strong associations with being female, being Asian, and having air pollution exposures. Our results suggest that incorporation of cumulative exposure to ambient air pollutants be considered when assessing lung cancer risk in combination with traditional risk factors.

Thoracic Surgeon Impressions of the Impact of the COVID-19 Pandemic on Lung Cancer Care-Lessons from the First Wave in Canada.

BACKGROUND: COVID-19 has invariably changed the way lung cancer surgical care is provided in Canada. Despite relevant management guidelines, the way in which cancer care has been affected has yet to be described for thoracic surgical populations. Routine lung cancer physiologic and staging assessments are unique in that they are droplet producing and aerosolizing procedures. Our objective was to quantify the effect of the COVID-19 pandemic on surgical lung cancer care as perceived by practicing thoracic surgeons during the first wave of the pandemic in Canada. METHODS: An electronic survey was distributed to members of the Canadian Association of Thoracic Surgeons. The survey was designed to determine surgeon perception of lung cancer preoperative care during the Canadian pandemic-instilled period of resource reallocation compared to standard care. Planned analyses were exploratory in nature; with count and frequency distributions of responses quantified. RESULTS: Fifty-three thoracic surgeons completed the survey. Responses were collected from all Canadian provinces. Little change in access to preoperative imaging was noted. However, a significant decrease in access to lung function and bronchoscopy testing occurred. Pulmonary surgery was perceived to be lengthier with reduced operating theater availability. Despite decreased OR access, only 40% of surgeons were aware of respective institutional mitigation strategies. SUMMARY: The COVID-19 pandemic has had an impact on standard lung cancer care preoperative workup. Further inquiry using institutional data is warranted to quantify its impact on cancer patient outcomes. Assessing the extent and effects of newly present barriers to standard lung cancer care is essential in forming appropriate mitigation strategies and planning for future pandemic waves.

The Diagnostic Accuracy and Sensitivity for Malignancy of Radial-Endobronchial Ultrasound and Electromagnetic Navigation Bronchoscopy for Sampling of Peripheral Pulmonary Lesions: Systematic Review and Meta-analysis.

BACKGROUND: Lung cancer screening with computed tomography chest is identifying peripheral pulmonary lesions (PPLs) suspicious for early-stage lung cancer at increasing rates. Radial-endobronchial ultrasound (R-EBUS) and electromagnetic navigation bronchoscopy (ENB) are 2 methods to sample PPLs to diagnose and treat early lung cancer. ENB has a higher operating financial cost, however, the rationale for its use is possible higher diagnostic accuracy versus R-EBUS. OBJECTIVE: The objective of this study was to determine the comparative diagnostic accuracy, sensitivity, and negative predictive value for R-EBUS and ENB in sampling PPLs. METHODS: A systematic review and meta-analysis were conducted. The Ovid Medline database was queried for original research reporting a diagnostic yield of R-EBUS or ENB for PPLs identified on computed tomography chest suspicious for malignancy. The I statistic assessed study heterogeneity. Random effects models produced pooled estimates of diagnostic accuracy and sensitivity for malignancy. Reasons for heterogeneity were explored with meta-regression. Publication bias and small study effects were assessed. RESULTS: A total of 41 studies involved 2988 lung nodules (R-EBUS 2102, ENB 886) in 3204 patients (R-EBUS 2097, ENB 1107). Overall sensitivity to detect cancer was 70.7% [95% confidence interval (CI): 67.2-74.0]; R-EBUS 70.5% (95% CI: 66.1-74.8), ENB 70.7% (95% CI: 64.7-76.8). Pooled overall diagnostic accuracy was 74.2% (95% CI: 71.0-77.3); R-EBUS 72.4% (95% CI: 68.7-76.1), ENB 76.4% (95% CI: 70.8-82.0). The localization modalities had comparative safety profiles of <2% complications. CONCLUSION: Both technologies have a high proportion of successful PPL localization with similar sensitivity for malignancy and accuracy. As such, both reasonable options for health care authorities to employ diagnostic algorithms.

Computed tomography-guided platinum microcoil lung surgery: A cross-sectional study.

OBJECTIVE: The study objective was to provide a 5-year update on our tertiary-level institutional experience with computed tomography-guided platinum microcoil lung surgery. METHODS: A retrospective cross-sectional study was conducted. All patients admitted to the Thoracic Service at Vancouver General Hospital to undergo computed tomography-guided microcoil lung surgery were included. Key primary outcome variables were successful nodule localization and severity of adverse events associated with placement. Secondary outcomes included nodule characteristics on preoperative computed tomography chest and nodule surgical pathology. Continuous variables were reported as mean (± standard deviation), and counts were reported as proportions n (%). RESULTS: A total of 97 lung nodules were resected in 92 patients. Mean age was 65.3 (±10.6) years, and 59 (61%) were female. All 97 nodules (100%) were successfully localized using video-assisted thoracic surgery wedge resection. There were 59 cases (60.8%) of placement-related events noted on computed tomography of the chest. All were minor and self-limited in nature and did not require treatment: pneumothorax 45 (46.4%), lung hematoma 18 (18.6%), dislodgement 4 (4.1%), and hemoptysis 2 (2.1%). Mean nodule diameter was 13.2 mm (±6.7). Density was nonsolid in 27 (27.8%) and semi-solid in 27 (27.8%). There was a single case of positive surgical margin, and 4 (4.1%) went on to completion lobectomy. Non-small lung cancer was identified in 66 nodules. CONCLUSIONS: Computed tomography-guided platinum microcoil lung surgery is safe with a favorable clinical adverse event profile and is suitable for poor-risk patients. The method is efficient, yielding 100% diagnostic localization in our 5-year update. It eliminates the need for thoracotomy and palpation to localize worrisome subpleural tiny nodules. It is ideal for the management of changing nodules concerning for early lung cancer and diagnosis of small indeterminate lung nodules or metastases.

Clinical outcomes of polymeric sealant use in pulmonary resection: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Prolonged alveolar air leak (PAL) is the most common adverse event following pulmonary resection. It carries morbidity for patients by increasing empyema risk, and for hospital administration with the cost of prolonged length of hospital stay (LOS). Intra-operative sealant technology is available to surgeons, and may decrease PAL. Our aim was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of intraoperative polymeric sealant use on PAL, empyema, and LOS. METHODS: Standard PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis and methods) protocol was adhered to. For qualitative review the search strategy yielded 21 RCTs reporting polymeric sealant use in lung resection, 19 of which were included in meta-analyses. The control arm in the two excluded RCTs was not "standard care." Random-effects meta-analyses were conducted. Inter-trial heterogeneity was assessed with the I2 statistic. Publication bias was assessed with a funnel plot and Egger statistic for small study effects. RESULTS: Pooled analysis was derived from 2,537 randomized participants. They were allocated to the intervention arm of lung resection with intra-operative application of a polymeric sealant (n=1,292), or the control arm of standard care involving pulmonary resection with pneumostasis by sutures and/or stapler (n=1,245). Participants came from 10 different countries, with mean (SD) age of 62.5 (4.2) years, and 31.6% (95% CI: 30.0-33.5) female. Pooled estimates revealed polymeric sealant decreased odds of PAL (OR 0.55, 95% CI: 0.35-0.87), and decreased LOS by one day (mean difference -0.96, 95% CI: -1.74 to -0.18), without increasing odds of pleural sepsis (OR 1.134, 95% CI: 0.343-3.748). There was evidence of publication bias in the LOS meta-analysis. CONCLUSIONS: Pooled analysis revealed decreased odds of PAL, and decreased LOS by one day with intraoperative use of polymeric sealants. There was no associated increase in odds of adverse events, including empyema.

Ectopic thymoma managed by neck dissection & video-assisted thoracoscopic thymectomy.

Ectopic thymoma in the neck is a rare phenomenon, with fewer than 20 cases reported worldwide. Evidence for management of ectopic thymoma comes from literature for mediastinal thymoma despite clinical features that distinguish the two. Here we present a case of a 31-year-old female with an asymptomatic neck mass who was found to have an ectopic cervical thymoma with concomitant mediastinal thymic hyperplasia. The decision was made to perform a left-sided neck dissection and a video-assisted thoracoscopic surgery (VATS) thymectomy. We suggest that this approach be considered for a minimally invasive management of this rare but important condition.

Randomized trial of digital versus analog pleural drainage in patients with or without a pulmonary air leak after lung resection.

OBJECTIVE: An unclear aspect of digital pleural drainage technology is whether it can benefit all lung resection patients or only those who have a postoperative air leak. The aim of this study was to evaluate the impact of digital pleural drainage on time to chest tube removal and length of hospitalization, taking into consideration postoperative air leak status. METHODS: A single-center, randomized, controlled, open-label, parallel-group trial was conducted. On postoperative day 1, stratification according to air leak status was performed by 2 independent, blinded observers. Patients were randomized to a water-sealed, pleural drainage device (analog) or to a digital device (digital). RESULTS: In both air leak groups (no air leak = 87; air leak = 85), patient factors and operative details were comparable. In the no air leak group, the difference in median chest tube drainage between analog and digital randomization arms was not statistically significant (3 days vs 2.9 days; P = .05). Median length of stay was also comparable in that group (analog = 4.3 days; digital = 4 days; P = .09). In patients with an air leak, similar findings were observed for chest tube duration (analog = 5.6 days; digital = 4.9 days; P = .11) and length of stay (analog = 6.2 days; digital = 6.2 days; P = .36). Chest tube clamping trials were significantly reduced in the digital arm of the air leak absent (0% vs 16%; P = .01) and air leak present groups (23% vs 50%; P = .01). CONCLUSIONS: Although digital devices decreased tube clamping trials, the impact on duration of chest tube drainage and hospital stay was not statistically significant, even after stratifying by postoperative air leak status.

Transthoracic Extracorporeal Gastric Conduit Preparation for Minimally Invasive Ivor-Lewis Esophagectomy.

OBJECTIVE: During totally minimally invasive esophagectomy (MIE), the gastric conduit is typically constructed via laparoscopy. Trauma from laparoscopic instruments, inability to palpate the gastroepiploic arcade, and challenges in optimal positioning of the stomach for intra-abdominal stapling have led to the widespread use of laparotomy as part of hybrid MIE procedures. Our objective was to evaluate the safety of transthoracic extracorporeal gastric conduit preparation. We hypothesize that this alternative technique is equivalent in safety to the laparoscopic approach. METHODS: This is a retrospective comparison of laparoscopic and transthoracic extracorporeal gastric conduit preparation with regard to anastomotic and respiratory outcomes. RESULTS: During a 3-year period, 30 patients underwent MIE with a right intrathoracic anastomosis (extracorporeal conduit, 15; laparoscopic conduit, 15). Mean age (58.6 vs 67 years, P = 0.59), tumor location (gastroesophageal junction vs middle and lower esophageal, P = 0.27), and histology (adenocarcinoma vs other 26.7%, P = 0.68) were similar between groups. Anastomotic technique and operating surgeon were the same for all patients. Patients in the laparoscopic gastric conduit group were more likely to have undergone induction chemoradiotherapy (40% vs 80%, P = 0.030). There was no significant difference between groups with respect to anastomotic complications, including anastomotic leak and anastomotic stricture (20% vs 13.3%, P = 0.70). Transthoracic gastric conduit preparation was not associated with increased respiratory complications (8% vs 12%, P = 0.09). CONCLUSIONS: Transthoracic gastric conduit preparation is a simple, minimally invasive alternative laparotomy for gastric conduit preparation during MIE. No additional incision is required. The technique may help surgeons overcome shortcomings of the laparoscopic approach without impacting perioperative risk.

Digital versus analogue pleural drainage phase 1: prospective evaluation of interobserver reliability in the assessment of pulmonary air leaks.

OBJECTIVES: The ability to accurately characterize a pulmonary air leak is an essential skill in chest medicine and surgery. The objective was to evaluate interobserver variability in air leak assessments using analogue and digital pleural drainage systems. METHODS: Air leak severity in lung resection patients with a pulmonary air leak was prospectively evaluated by at least one thoracic surgeon, one surgical resident and one to two nurses using a standardized questionnaire. The first assessment was performed with pleural drains connected to an analogue system. Subsequently, patients were re-assessed after changing from the analogue to a digital drainage system. The thoracic surgeon's evaluation was considered the reference standard for comparison. Agreement between observers was quantified using the kappa (κ) statistic. RESULTS: A total of 128 air leak evaluations were completed in 30 patients (thoracic surgeon = 30; nurses = 56; resident = 30; physiotherapists = 12). The mean time between analogue and digital assessment was 2.16 (±1.66) h. The level of observer agreement regarding air leak severity significantly increased from very slight to substantial when using the digital drainage system [analogue κ = 0.03; confidence interval (CI): 0.04-0.11; P = 0.40) (digital κ = 0.61; CI: 0.49-0.73; P < 0.01]. Similar improvements were observed in subgroups of health-care professionals using digital technology. CONCLUSIONS: Digital pleural drainage technology improves the agreement level between members of the health-care team when assessing the severity of a pulmonary air leak after lung resection.