The Proposed 9th Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The 9th edition TNM classification of lung cancer, which is scheduled to take effect in January of 2025, addresses this need. It is based on a large international database, multidisciplinary input and extensive statistical analyses. Key features of the 9th edition include validation of the significant changes in the T component introduced in the 8th edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA and IIIB. This paper summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the 9th edition system.

Trends and predictors of Quality of Life in lung cancer survivors.

INTRODUCTION: Health-related quality of life (HR-QoL) is often impaired in lung cancer survivors. To inform personalized survivorship care, we identified associations between HR-QoL scores and patient-, tumor-, and treatment-factors over time. MATERIALS AND METHODS: We evaluated HR-QoL scores provided at diagnosis, 6 months, 1 year, and 2 years from the Yale Lung Cancer Biorepository. HR-QoL was measured via the Functional Assessment of Cancer Therapy - Lung (FACT-L) instrument and available for a subset of patients (n = 513). Analyses were stratified by early-stage (I-II; n = 355) non-small cell lung cancer (NSCLC), advanced stage NSCLC (III-IV; n = 158), and small cell lung cancer (SCLC, n = 21). We used mixed effects modeling and multivariable analysis with covariate adjustment to examine changes in FACT-L from diagnosis to follow-up. Sensitivity analysis was performed including patients with early-stage disease and complete FACT-L scores at both baseline and year 2 (n = 91). RESULTS: The average FACT-L scores at diagnosis in early-stage NSCLC, advanced stage NSCLC, and SCLC were 121.0 (standard deviation (SD) 11.4), 109.2 (18.7), and 98.7 (20.2) respectively. At all timepoints, HR-QoL was higher in patients with early-stage NSCLC (vs advanced-stage disease). In patients with early- and advanced-stage NSCLC, HR-QoL was higher at years 1 and 2 than at diagnosis, though the changes did not meet clinical significance. At NSCLC diagnosis, higher HR-QoL was associated with older age, better performance status, participating in physical activity, adenocarcinoma histology, and (in advanced stage NSCLC) anticipated treatment with chemotherapy. At NSCLC follow-up, HR-QoL was higher in patients with higher BMI and better performance status. DISCUSSION: In patients with newly diagnosed NSCLC, HR-QoL scores are impacted by patient factors, tumor factors, and treatment factors. HR-QoL is higher in patients with early-stage disease. In patients surviving 2 years, HR-QoL was higher at follow-up, though the change did not meet clinical significance. To optimize HR-QoL, lung cancer survivorship teams should prioritize comorbidity management, physical activity, healthy weight maintenance, and treatment-related side effects.

Impact of the COVID-19 Pandemic on Lung Cancer Screening Processes in a Northeast Tertiary Health Care Network.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic disrupted health care systems, including implementation of lung cancer screening programs. The impact and recovery from this disruption on screening processes is not well appreciated. Herein, the radiology database of a Northeast tertiary health care network was reviewed before and during the pandemic (2013-2022). In the 3 months before the pandemic, an average of 77.3 lung cancer screening with computed tomography scans (LCS-CT) were performed per month. The average dropped to 23.3 between April and June of 2020, whereas COVID-19 hospitalizations peaked at 1604. By July, average hospitalizations dropped to 50, and LCS-CTs rose to >110 per month for the remaining year. LCS-CTs did not decline during COVID-19 surges in December of 2021 and 2022. The LCS-CT performance grew by 4.5% in 2020, 69.6% in 2021, and 27.0% in 2022, exceeding projected growth by 722 examinations. This resiliency indicates a potentially smaller impact of COVID-19 on lung cancer diagnoses than initially feared.

Lung cancer with air lucency: a systematic review and clinical management guide.

Background: Lung cancers with air lucency are poorly understood, often recognized only after substantial progression. Methods: From a systematic review (PubMed and EMBASE, 2000-2022, terms related to cystic, cavitary, bulla, pseudocavitary, bubble-like, date 10-30-2022) 49 studies were selected using broad inclusion criteria (case series of ≥10 cases up to trials and reviews). There was no source of funding. Primary evidence relevant to clinical management issues was assembled. Because data was available only from heterogeneous retrospective case series, meta-analysis and formal risk-of-bias assessment was omitted. A framework was developed to guide clinical management based on the available data. Results: Demographic, smoking and histologic differences suggest that cystic, cavitary and bullous lung cancers with air lucency may be distinct entities; insufficient data leaves it unclear whether this also applies to pseudocavitary (solid) or bubble-like (ground glass) cancers. Annual observation of irregular thin-walled cysts is warranted; a surgical diagnosis (and resection) is justified once a solid component appears because subsequent progression is often rapid with markedly worse outcomes. Bubble-like ground glass lesions should be managed similarly. Cavitary lesions must be distinguished from infection or vasculitis, but generally require needle or surgical biopsy. Pseudocavitary lesions are less well studied; positron emission tomography may be useful in this setting to differentiate scar from malignancy. Further research is needed because these conclusions are based on interpretation of retrospective case series. Conclusions: The aggregate of available evidence suggests a framework for management of suspected lung cancers with air lucency. Greater awareness, earlier detection, and aggressive management once a solid component appears are needed. This review and framework should facilitate further research; questions include whether the suggested entities and proposed management are borne out and should involve clearly defined terms and outcomes related to progression and treatment. In summary, a conceptual understanding is emerging from interpretation of available data about a previously poorly understood topic; this should improve patient outcomes.

Evidence of Racial Disparities in the Lung Cancer Screening Process: a Systematic Review and Meta-Analysis.

BACKGROUND: Annual lung cancer screening (LCS) with low-dose chest computed tomography for high-risk individuals reduces lung cancer mortality, with greater reduction observed in Black participants in clinical trials. While racial disparities in lung cancer mortality exist, less is known about disparities in LCS participation. We conducted a systematic review to explore LCS participation in Black compared with White patients in the USA. METHODS: A systematic review was conducted through a search of published studies in MEDLINE, PubMed, EMBASE, Web of Science, and Cumulative Index to Nursing and Allied-Health Literature Database, from database inception through October 2020. We included studies that examined rates of LCS participation and compared rates by race. Studies were pooled using random-effects meta-analysis. RESULTS: We screened 18,300 titles/abstracts; 229 studies were selected for full-text review, of which nine studies met inclusion criteria. Studies were categorized into 2 groups: studies that reported the screening rate among an LCS-eligible patient population, and studies that reported the screening rate among a patient population referred for LCS. Median LCS participation rates were 14.4% (range 1.7 to 62.6%) for eligible patient studies and 68.5% (range 62.6 to 88.8%) for referred patient studies. The meta-analyses showed screening rates were lower in the Black compared to White population among the LCS-eligible patient studies ([OR]=0.43, [95% CI: 0.25, 0.74]). However, screening rates were the same between Black and White patients in the referred patient studies (OR=0.94, [95% CI: 0.74, 1.19]). DISCUSSION: Black LCS-eligible patients are being screened at a lower rate than White patients but have similar rates of participation once referred. Differences in referrals by providers may contribute to the racial disparity in LCS participation. More studies are needed to identify barriers to LCS referral and develop interventions to increase provider awareness of the importance of LCS in Black patients. Trial Registry PROSPERO; No.: CRD42020214213; URL: http://www.crd.york.ac.uk/PROSPERO.

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition.

PURPOSE: The identification of actionable oncogenic alterations has enabled targeted therapeutic strategies for subsets of patients with advanced malignancies, including lung adenocarcinoma (LUAD). We sought to assess the frequency of known drivers and identify new candidate drivers in a cohort of LUAD from patients with minimal smoking history. EXPERIMENTAL DESIGN: We performed genomic characterization of 103 LUADs from patients with ≤10 pack-year smoking history. Tumors were subjected to targeted molecular profiling and/or whole-exome sequencing and RNA sequencing in search of established and previously uncharacterized candidate drivers. RESULTS: We identified an established oncogenic driver in 98 of 103 tumors (95%). From one tumor lacking a known driver, we identified a novel gene rearrangement between OCLN and RASGRF1. The encoded OCLN-RASGRF1 chimera fuses the membrane-spanning portion of the tight junction protein occludin with the catalytic RAS-GEF domain of the RAS activator RASGRF1. We identified a similar SLC4A4-RASGRF1 fusion in a pancreatic ductal adenocarcinoma cell line lacking an activating KRAS mutation and an IQGAP1-RASGRF1 fusion from a sarcoma in The Cancer Genome Atlas. We demonstrate these fusions increase cellular levels of active GTP-RAS, induce cellular transformation, and promote in vivo tumorigenesis. Cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway in vitro and in vivo. CONCLUSIONS: Our findings credential RASGRF1 fusions as a therapeutic target in multiple malignancies and implicate RAF-MEK-ERK inhibition as a potential treatment strategy for advanced tumors harboring these alterations. See related commentary by Moorthi and Berger, p. 2983.

Standardizing the Reporting of Incidental, Non-Lung Cancer (Category S) Findings Identified on Lung Cancer Screening Low-Dose CT Imaging.

Lung cancer screening is slowly but steadily entering the realm of preventive health maintenance. Standardization of reporting of positive findings identified on screening low-dose CT (LDCT) scans, specifically lung nodules, is a key element of high-quality lung cancer screening. The American College of Radiology developed the Lung CT Screening Reporting and Data System (Lung-RADS) system for this purpose. In addition to detailed categorization of lung nodules, Lung-RADS identifies category S for other incidental findings identified on screening LDCT scans. In contrast to the highly structured reporting for nodules, category S findings are reported at the discretion of individual readers, with the potential for high variability of reporting. Incidental findings on lung cancer screening studies are common, may trigger unwarranted evaluation with potential harm and cost, and may precipitate patient distress. In response to these concerns, our multidisciplinary lung cancer screening program developed a structured system for standardized reporting of category S findings based on recommendations of the American College of Radiology and relevant specialty societies.

Racial Differences in Adherence to Lung Cancer Screening Follow-up: A Systematic Review and Meta-analysis.

BACKGROUND: In 2013, the United States Preventive Services Taskforce instituted recommendations for annual lung cancer screening (LCS) with low-dose chest CT imaging for high-risk individuals. LCS reduces lung cancer mortality, with greater reduction observed in Black participants in clinical trials. Although racial disparities in lung cancer mortality have been well documented, less is known about disparities in LCS participation and adherence to follow-up in clinical practice. RESEARCH QUESTION: What is the association between race and adherence to LCS follow-up? STUDY DESIGN AND METHODS: A systematic review was conducted through a search of published studies in MEDLINE, PubMed, EMBASE, Web of Science, and Cumulative Index to Nursing and Allied Health Literature Database from database inception through October 2020. We included studies that examined rates of adherence to LCS follow-up and compared rates by race. Studies were pooled using random-effects meta-analysis. RESULTS: We screened 18,300 titles and abstracts, and 229 studies were selected for full-text review. Nine studies met inclusion criteria; seven were included in the meta-analysis. Median adherent follow-up rate was 37% (range, 16%-82%). Notable differences among the studies included the proportion of the Black population (range, 4%-47%) and the structure of the LCS programs. The meta-analyses showed lower adherence to LCS follow-up in the Black population (OR, 0.67; 95% CI, 0.55-0.80). This disparity persisted across all malignancy risk levels determined by initial screening results. INTERPRETATION: Lower adherence to LCS follow-up in Black compared with White patients occurs despite the higher potential lung cancer mortality benefit. Literature specifically addressing race-related barriers to LCS adherence remains limited. To ensure equity in LCS benefits, greater outreach to eligible Black patients should be implemented through increased physician education and use of screening program coordinators to focus on this patient population. TRIAL REGISTRY: PROSPERO; No.: CRD42020214213; URL: http://www.crd.york.ac.uk/PROSPERO.

Women and Lung Cancer.

The world is witnessing a global epidemic of lung cancer in women. Cigarette smoking remains the dominant risk factor in both sexes, but multiple observations suggest that important sex-related distinctions in lung cancer exist. These include differences in histologic distribution, prevalence in never-smokers, frequency of activating EGFR mutations, likelihood of DNA adduct accumulation, and survival outcomes. Important questions such as whether women are more susceptible to carcinogenic effects of smoking or derive more benefit from lung cancer screening merit more study. A deeper understanding of sex-related differences in lung cancer may lead to improved outcomes for both women and men.

"Randomized trial of physical activity on quality of life and lung cancer biomarkers in patients with advanced stage lung cancer: a pilot study".

BACKGROUND: Lung cancer survivors need more options to improve quality of life (QoL). It is unclear to what extent patients with advanced stage disease are willing to participate in home-based physical activity (PA) and if these interventions improve QoL. The goal of our study was to determine interest in participating in our 3-month home-based walking regimen in patients with advanced stage lung cancer. We used a randomized design to evaluate for potential benefit in PA and patient-reported outcomes. METHODS: We performed an open-label, 1:1 randomized trial in 40 patients with stage III/IV non-small cell lung cancer (NSCLC) evaluating enrollment rate, PA, QoL, dyspnea, depression, and biomarkers. Compared to usual care (UC), the intervention group (IG) received an accelerometer, in-person teaching session, and gain-framed text messages for 12 weeks. RESULTS: We enrolled 56% (40/71) of eligible patients. Participants were on average 65 years and enrolled 1.9 years from diagnosis. Most patients were women (75%), and receiving treatment (85%) for stage IV (73%) adenocarcinoma (83%). A minority of patients were employed part-time or full time (38%). Both groups reported low baseline PA (IG mean 37 (Standard deviation (SD) 46) vs UC 59 (SD 56) minutes/week; p = 0.25). The IG increased PA more than UC (mean change IG + 123 (SD 212) vs UC + 35 (SD 103) minutes/week; p = 0.051)). Step count in the IG was not statistically different between baseline (4707 step/day), week 6 (5605; p = 0.16), and week 12 (4606 steps/day; p = 0.87). The intervention improved EORTC role functioning domain (17 points; p = 0.022) with borderline improvement in dyspnea (- 13 points; p = 0.051) compared to UC. In patients with two blood samples (25%), we observed a significant increase in soluble PD-1 (219.8 (SD 54.5) pg/mL; p < 0.001). CONCLUSIONS: Our pilot trial using a 3-month, home-based, mobile health intervention enrolled over half of eligible patients with stage III and IV NSCLC. The intervention increased PA, and may improve several aspects of QoL. We also identified potential biomarker changes relevant to lung cancer biology. Future research should use a larger sample to examine the effect of exercise on cancer biomarkers, which may mediate the association between PA and QoL. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03352245 ).

A 62-Year-Old Woman With Lung Cancer, Ulcerating Rash, and Rapidly Progressive Hypoxemia.

CASE PRESENTATION: A 62-year-old nonsmoking woman with no medical history initially presented with a 3-month history of rash. A painful, erythematous exanthem had progressed from her forehead, cheeks, and upper chest to her eyes (heliotrope rash) and hands, primarily involving the extensor surface finger joints with prominent digital ulceration.

Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report.

BACKGROUND: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. METHODS: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. RESULTS: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small-cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small-cell lung cancer. CONCLUSIONS: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care.

Lung Cancer Staging.

Anatomic staging is a critical step in evaluation of patients with lung cancer. Accurate identification of stage based on features of primary tumor (T), regional nodes (N), and metastatic disease (M) is fundamental to determining appropriate care. In this article, the TNM components of the anatomic staging system and a framework for description of lung cancer with multiple pulmonary sites of involvement are discussed. TNM combinations are grouped according to prognosis, with patient-level, tumor-level, and environment-level factors also influencing survival outcomes. Although the staging system does not include molecular and immunologic information, anatomic staging remains the common language for communicating extent of disease.

Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report.

BACKGROUND: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. METHODS: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. RESULTS: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small cell lung cancer. CONCLUSIONS: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care.

Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report.

Background: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. Materials and Methods: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. Results: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small cell lung cancer. Conclusion: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care.© 2020 RSNA; The American College of Chest Physicians, published by Elsevier Inc; and The American College of Radiology, published by Elsevier Inc.

Improved discrimination between benign and malignant LDCT screening-detected lung nodules with dynamic over static 18F-FDG PET as a function of injected dose.

Lung cancer mortality rate can be significantly reduced by up to 20% through routine low-dose computed tomography (LDCT) screening, which, however, has high sensitivity but low specificity, resulting in a high rate of false-positive nodules. Combining PET with CT may provide more accurate diagnosis for indeterminate screening-detected nodules. In this work, we investigated low-dose dynamic 18F-FDG PET in discrimination between benign and malignant nodules using a virtual clinical trial based on patient study with ground truth. Six patients with initial LDCT screening-detected lung nodules received 90 min single-bed PET scans following a 10 mCi FDG injection. Low-dose static and dynamic images were generated from under-sampled list-mode data at various count levels (100%, 50%, 10%, 5%, and 1%). A virtual clinical trial was performed by adding nodule population variability, measurement noise, and static PET acquisition start time variability to the time activity curves (TACs) of the patient data. We used receiver operating characteristic (ROC) analysis to estimate the classification capability of standardized uptake value (SUV) and net uptake constant K i from their simulated benign and malignant distributions. Various scan durations and start times (t *) were investigated in dynamic Patlak analysis to optimize simplified acquisition protocols with a population-based input function (PBIF). The area under curve (AUC) of ROC analysis was higher with increased scan duration and earlier t *. Highly similar results were obtained using PBIF to those using image-derived input function (IDIF). The AUC value for K i using optimized t * and scan duration with 10% dose was higher than that for SUV with 100% dose. Our results suggest that dynamic PET with as little as 1 mCi FDG could provide discrimination between benign and malignant lung nodules with higher than 90% sensitivity and specificity for patients similar to the pilot and simulated population in this study, with LDCT screening-detected indeterminate lung nodules.