Incorporating Coexisting Chronic Illness into Decisions about Patient Selection for Lung Cancer Screening. An Official American Thoracic Society Research Statement.

BACKGROUND: Lung cancer screening (LCS) has the potential to reduce the risk of lung cancer death in healthy individuals, but the impact of coexisting chronic illnesses on LCS outcomes has not been well defined. Consideration of the complex relationship between baseline risk of lung cancer, treatment-related harms, and risk of death from competing causes is crucial in determining the balance of benefits and harms of LCS. OBJECTIVES: To summarize evidence, identify knowledge and research gaps, prioritize topics, and propose methods for future research on how best to incorporate comorbidities in making decisions regarding LCS. METHODS: A multidisciplinary group of international clinicians and researchers reviewed available data on the effects of comorbidities on LCS outcomes, focusing on the juxtaposition of lung cancer risk and competing risks of death, consideration of benefits and risks in patients with chronic obstructive pulmonary disease, communication of risk, and treatment of screen-detected lung cancer. RESULTS: This statement identifies gaps in knowledge regarding how comorbidities and competing causes of death impact outcomes in LCS, and we have developed questions to help guide future research efforts to better inform patient selection, education, and implementation of LCS. CONCLUSIONS: There is an urgent need for further research that can help guide clinical decision-making with patients who may not benefit from LCS owing to coexisting chronic illness. This statement establishes a research framework to address essential questions regarding how to incorporate and communicate risks of comorbidities into patient selection and decisions regarding LCS.

Lung cancer screening.

PURPOSE OF REVIEW: Lung cancer screening with low-dose chest computed tomography is now recommended for high-risk individuals by the US Preventive Services Task Force. This recommendation was informed by several randomized controlled trials, the largest of which, the National Lung Screening Trial, demonstrated a 20% relative reduction in lung cancer mortality with annual low-dose chest computed tomography compared with chest radiography. RECENT FINDINGS: The benefit of lung cancer screening must be balanced against potential harms, including a high false-positive rate with consequent further evaluative studies and invasive testing. It is critical that harms be minimized as screening generalizes to the broad community. Informed decision making between providers and patients should include individualized risk assessment, a discussion of both potential benefit and harm, and tobacco treatment. Given the multiple components required for high quality, screening should ideally occur in the context of a multidisciplinary program. SUMMARY: We are in the early days of lung cancer screening, still with much to learn. Ongoing studies are necessary to refine the definition of a positive screen and develop better methods of distinguishing between true positive and false-positive results. Novel approaches, including the development of multicomponent lung cancer biomarkers, will likely inform and improve our future screening practice.

Lung cancer screening.

The United States Preventive Services Task Force recommends lung cancer screening with low-dose computed tomography (LDCT) in adults of age 55 to 80 years who have a 30 pack-year smoking history and are currently smoking or have quit within the past 15 years. This recommendation is largely based on the findings of the National Lung Screening Trial. Both policy-level and clinical decision-making about LDCT screening must consider the potential benefits of screening (reduced mortality from lung cancer) and possible harms. Effective screening requires an appreciation that screening should be limited to individuals at high risk of death from lung cancer, and that the risk of harm related to false positive findings, overdiagnosis, and unnecessary invasive testing is real. A comprehensive understanding of these aspects of screening will inform appropriate implementation, with the objective that an evidence-based and systematic approach to screening will help to reduce the enormous mortality burden of lung cancer.

The Proposed Ninth 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 ninth edition TNM classification of lung cancer, which is scheduled to take effect in January 2025, addresses this need. It is based on a large international database, multidisciplinary input, and extensive statistical analyses. Key features of the ninth edition include validation of the significant changes in the T component introduced in the eighth 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 article summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the ninth edition system.

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.

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.

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.

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.

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.

Addressing Gender Inequality in Our Disciplines: Report from the Association of Pulmonary, Critical Care, and Sleep Division Chiefs.

Despite the increasing proportion of women in U.S. medical schools, there are relatively few women in leadership positions, and a number of recent publications have highlighted many factors that could contribute to gender inequity and inequality in medicine. The Association of Pulmonary, Critical Care, and Sleep Division Directors, an organization of Division Directors from across the United States, convened a workshop to review data and obtain input from leaders on the state of gender equity in our field. The workshop identified a number of factors that could contribute to gender inequality and inequity: gender climate (including implicit and perceived biases); disproportionate family responsibilities; lack of women in leadership positions; poor retention of women; and lack of gender equality in compensation. The panel members developed a roadmap of concrete recommendations for societies, leaders, and individuals that should promote gender equity to achieve gender equality and improve retention of women in the field of pulmonary, critical care, and sleep medicine.

Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition).

BACKGROUND: Correctly staging lung cancer is important because the treatment options and the prognosis differ significantly by stage. Several noninvasive imaging studies including chest CT scanning and positron emission tomography (PET) scanning are available. Understanding the test characteristics of these noninvasive staging studies is critical to decision making. METHODS: Test characteristics for the noninvasive staging studies were updated from the first iteration of the lung cancer guidelines using systematic searches of the MEDLINE, HealthStar, and Cochrane Library databases up to May 2006, including selected metaanalyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. RESULTS: The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% confidence interval [CI], 47 to 54%) and 85% (95% CI, 84 to 88%), respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, the pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69 to 79%) and 85% (95% CI, 82 to 88%), respectively. These findings demonstrate that PET scanning is more accurate than CT scanning. If the clinical evaluation in search of metastatic disease is negative, the likelihood of finding metastasis is low. CONCLUSIONS: CT scanning of the chest is useful in providing anatomic detail, but the accuracy of chest CT scanning in differentiating benign from malignant lymph nodes in the mediastinum is poor. PET scanning has much better sensitivity and specificity than chest CT scanning for staging lung cancer in the mediastinum, and distant metastatic disease can be detected by PET scanning. With either test, abnormal findings must be confirmed by tissue biopsy to ensure accurate staging.

Treatment of lung cancer in older patients.

Lung cancer is a disease of older persons. It is the most common cause of cancer death in men and women in the United States. A comprehensive evaluation of medical comorbidities and functional status is important in all patients but perhaps more so in older adults, and it should be included in the assessment of older patients who have lung cancer. Age, per se, should not be a limiting factor to treatment, because a large body of evidence demonstrates that fit older patients who have lung cancer can safely undergo the same treatments as their younger counterparts with equally good results.

The Eighth Edition Lung Cancer Stage Classification.

Stage classification provides a nomenclature about the anatomic extent of a cancer; a consistent language provides the ability to communicate about a specific patient and about cohorts of patients in clinical studies. This paper summarizes the eighth edition of lung cancer stage classification, which is the worldwide standard as of January 1, 2017. This revision is based on a large global database, a sophisticated analysis, extensive internal validation as well as multiple assessments confirming generalizability. Practicing clinicians must be familiar with the stage classification system when managing contemporary patients with lung cancer.

Evaluation and definitive management of medically inoperable early-stage non-small-cell lung cancer. Part 1: Assessment and conventional radiotherapy.

Lung cancer is estimated to be the second most commonly diagnosed cancer in both men and women in 2006, and the leading cause of cancer mortality. Non-small-cell lung cancer represents the majority of such cases. Most of these patients have locally advanced disease at presentation and are not eligible for curative resection. For the minority of patients who are technically resectable at presentation, lobectomy or pneumonectomy and pathologic mediastinal nodal staging offer the best overall survival. The high rate of comorbid medical illness and poor baseline pulmonary function in this population, however, make many such early-stage patients medically inoperable. For these patients, conventional single-modality radiotherapy has been the primary definitive treatment option, as discussed in part 1 of this two-part article. Numerous retrospective reports demonstrate long-term disease-free and overall survival data that are modestly superior to that expected after observation, but both local and distant failure continue to be significant risks. Investigation of radiotherapy dose escalation is ongoing, in an effort to improve local control while maintaining minimal toxicity. Additionally, emerging evidence suggests that new modalities, such as stereotactic radiosurgery and radiofrequency ablation, may also be potentially curative treatment alternatives. These modalities will be addressed in part 2.

Evaluation and definitive management of medically inoperable early stage non-small-cell lung cancer. Part 2: newer treatment modalities.

Lung cancer is estimated to be the second most commonly diagnosed cancer in both men and women in 2006, and the leading causes of cancer mortality. Non-small-cell lung cancer represents the majority of such cases. Most of these patients have locally advanced disease at presentation and are not eligible for curative resection. For the minority of patients who are technically resectable at presentation, lobectomy or pneumonectomy and pathologic mediastinal nodal staging offer the best overall survival. The high rate of comorbid medical illness and poor baseline pulmonary function in this population, however, make many such early-stage patients medically inoperable. For these patients, conventional single-modality radiotherapy has been the primary definitive treatment option, as discussed in part 1 of this article, which appeared in last month's issue. Numerous retrospective reports demonstrate long-term disease-free and overall survival data that are modestly superior to that expected after observation, but both local and distant failure continue to be significant risks. Investigation of radiotherapy dose escalation is ongoing, in an effort to improve local control while maintaining minimal toxicity. Additionally, emerging evidence suggests that new modalities, such as stereotactic radiosurgery and radiofrequency ablation, may also be potentially curative treatment alternatives. These modalities are addressed in part 2.

Surveillance Practice Patterns after Curative Intent Therapy for Stage I Non-Small-Cell Lung Cancer in the Medicare Population.

OBJECTIVES: Recurrence after treatment for non-small cell lung cancer (NSCLC) is common, and routine imaging surveillance is recommended by evidence-based guidelines. Little is known about surveillance patterns after curative intent therapy for early stage NSCLC. We sought to understand recent practice patterns for surveillance of stage I NSCLC in the first two years after curative intent therapy in the Medicare population. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database we selected patients diagnosed with stage I NSCLC between 1998 and 2008. We studied adherence to surveillance guidelines based on specialty society recommendations for chest radiography and computed tomography (CT) scanning. We also tracked the use of Positron Emission Tomography (PET) scans, which are not recommended for surveillance. We calculated the percent of patients who received guideline-adherent surveillance imaging and used logistic regression to determine associations between patient and provider factors and guideline adherence. RESULTS: Overall, 61.4% of patients received guideline-adherent surveillance during the initial 2 years after treatment. Use of CT scans in the first year after treatment increased from 47.4% in 1998-78.5% in 2008, and PET use increased from 5.8% to 28.9%. Adherence with surveillance imaging was associated with younger age, higher income, more comorbidities, access to primary care, and receipt of SBRT as the primary treatment. CONCLUSIONS: Adherence to specialty society guidelines for surveillance after treatment for stage I NSCLC was poor in this population of Medicare beneficiaries, with less than two-thirds of patients receiving recommended imaging, and almost 30% receiving non-recommended PET scans.

The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. METHODS: A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. RESULTS: It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. CONCLUSIONS: Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.