The American Cancer Society National Lung Cancer Roundtable strategic plan: Advancing comprehensive biomarker testing in non-small cell lung cancer.

Comprehensive biomarker testing is a crucial requirement for the optimal treatment of advanced-stage non-small cell lung cancer (NSCLC), with emerging relevance in the adjuvant treatment setting. To advance its goal of ensuring optimal therapy for persons diagnosed with lung cancer, the American Cancer Society National Lung Cancer Roundtable (ACS NLCRT) held The Summit on Optimizing Lung Cancer Biomarkers in Practice in September 2020 to align its partners toward the goal of ensuring comprehensive biomarker testing for all eligible patients with NSCLC. The ACS NLCRT's Strategic Plan for Advancing Comprehensive Biomarker Testing in NSCLC, a product of the summit, comprises actions to promote comprehensive biomarker testing for all eligible patients. The approach is multifaceted, including policy-level advocacy and the development and dissemination of targeted educational materials, clinical decision tools, and guides to patients, physicians, and payers aimed at ameliorating barriers to testing experienced by each of these groups. PLAIN LANGUAGE SUMMARY: The ACS NLCRT works to improve care for patients with lung cancer. The ACS NLCRT supports comprehensive biomarker testing as essential to determine treatment options for all eligible patients with non-small cell lung cancer. Many factors lead to some patients not receiving optimal biomarker testing. The ACS NLCRT held a collaborative summit and developed a strategic plan to achieve and promote comprehensive biomarker testing for all patients. These plans include developing educational materials and physician tools and advocating for national policies in support of biomarker testing.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Promoting guideline-concordant lung cancer staging.

Accurate staging improves lung cancer survival by increasing the chances of delivering stage-appropriate therapy. However, there is underutilization of, and variability in, the use of guideline-recommended diagnostic tests used to stage lung cancer. Consequently, the American Cancer Society National Lung Cancer Roundtable (ACS NLCRT) convened the Triage for Appropriate Treatment Task Group-a multidisciplinary expert and stakeholder panel-to identify knowledge and/or resource gaps contributing to guideline-discordant staging and make recommendations to overcome these gaps. The task group determined the following: Gap 1: facilitators of and barriers to guideline-concordant staging are incompletely understood; Recommendation 1: identify facilitators of and barriers to guideline-concordant lung cancer staging; Gap 2: the level of evidence supporting staging algorithms is low-to-moderate; Recommendation 2: prioritize comparative-effectiveness studies evaluating lung cancer staging; Gap 3: guideline recommendations vary across professional societies; Recommendation 3: harmonize guideline recommendations across professional societies; Gap 4: existing databases do not contain sufficient information to measure guideline-concordant staging; Recommendation 4: augment existing databases with the information required to measure guideline-concordant staging; Gap 5: health systems do not have a performance feedback mechanism for lung cancer staging; Recommendation 5: develop and implement a performance feedback mechanism for lung cancer staging; Gap 6: patients rarely self-advocate for guideline-concordant staging; Recommendation 6: increase opportunities for patient self-advocacy for guideline-concordant staging; and Gap 7: current health policies do not motivate guideline-concordant lung cancer staging; Recommendation 7: organize a representative working group under the ACS NLCRT that promotes policies that motivate guideline-concordant lung cancer staging. PLAIN LANGUAGE SUMMARY: Staging-determining the degree of cancer spread-is important because it helps clinicians choose the best cancer treatment. Receiving the best cancer treatment leads to the best possible patient outcomes. Practice guidelines are intended to help clinicians stage patients with lung cancer. However, lung cancer staging in the United States often varies from practice guideline recommendations. This report identifies seven opportunities to improve lung cancer staging.

Acquisition and Handling of Endobronchial Ultrasound Transbronchial Needle Samples - An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: Endobronchial Ultrasound-Guided Transbronchial Aspiration (EBUS-TBNA) has become the standard for initial lung cancer diagnosis and staging. Previous guidelines have generally focused on the "when" and "how" of EBUS-TBNA; however, little guidance is available on handling and processing specimens during and after acquisition to help optimize both diagnostic yield and tissue integrity for ancillary studies. This document examines the available literature on EBUS-TBNA specimen processing and handling. METHODS: Rigorous methodology was applied to provide a trustworthy evidence-based guideline and expert panel report. Panelists developed key clinical questions utilizing the PICO (population, intervention, comparator, and outcome) format, addressing specific topics in EBUS-TBNA specimen processing. MEDLINE (via PubMed) and the Cochrane Library were systematically searched to identify relevant literature, supplemented by manual searches. References were screened for inclusion with document evaluation tools to assess the quality of included studies, extract meaningful data, and grade the level of evidence to support each recommendation or suggestion. RESULTS: Our systematic review and critical analysis of the literature of the 9 PICO questions related to handling and processing EBUS-TBNA specimens resulted in nine evidence-based statements. CONCLUSIONS: Evidence of the handling and processing of EBUS-TBNA specimens varies in strength but is satisfactory in some areas to guide clinicians in certain aspects of specimen handling. Additional research in many aspects of specimen handling and processing is needed to help improve our knowledge base.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Optimizing strategies for lung nodule evaluation and management.

Lung nodules are frequently detected on low-dose computed tomography scans performed for lung cancer screening and incidentally detected on imaging performed for other reasons. There is wide variability in how lung nodules are managed by general practitioners and subspecialists, with high rates of guideline-discordant care. This may be due in part to the level of evidence underlying current practice guideline recommendations (primarily based on findings from uncontrolled studies of diagnostic accuracy). The primary aims of lung nodule management are to minimize harms of diagnostic evaluations while expediting the evaluation, diagnosis, and treatment of lung cancer. Potentially useful tools such as lung cancer probability calculators, automated methods to identify patients with nodules in the electronic health record, and multidisciplinary team evaluation are often underused due to limited availability, accessibility, and/or provider knowledge. Finally, relatively little attention has been paid to identifying and reducing disparities among individuals with screening-detected or incidentally detected lung nodules. This contribution to the American Cancer Society National Lung Cancer Roundtable Strategic Plan aims to identify and describe these knowledge gaps in lung nodule management and propose recommendations to advance clinical practice and research. Major themes that are addressed include improving the quality of evidence supporting lung nodule evaluation guidelines, strategically leveraging information technology, and placing emphasis on equitable approaches to nodule management. The recommendations outlined in this strategic plan, when carried out through interdisciplinary efforts with a focus on health equity, ultimately aim to improve early detection and reduce the morbidity and mortality of lung cancer. PLAIN LANGUAGE SUMMARY: Lung nodules may be identified on chest scans of individuals who undergo lung cancer screening (screening-detected nodules) or among patients for whom a scan was performed for another reason (incidental nodules). Although the vast majority of lung nodules are not lung cancer, it is important to have evidence-based, standardized approaches to the evaluation and management of a lung nodule. The primary aims of lung nodule management are to diagnose lung cancer while it is still in an early stage and to avoid unnecessary procedures and other harms.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Methods for improving turnaround time of comprehensive biomarker testing in non-small cell lung cancer.

Comprehensive biomarker testing for patients with non-small cell lung cancer is critical for selecting appropriate targeted therapy or immunotherapy. Ensuring timely ordering, processing, and reporting is key to optimizing patient outcomes. However, various factors can prevent or delay patients from being offered the option of treatment selection based on comprehensive biomarker testing. These factors include problems with access to testing, tissue adequacy, turnaround time, and health insurance coverage and billing practices. Turnaround time depends on several logistical and tissue handling factors, which involve institutional policies, processes, resources, testing methodology, and testing algorithms that vary across different practices. In this article, the authors identify key factors that prolong biomarker testing turnaround time, propose strategies to reduce it, and present a process map to aid physicians and key organizational stakeholders in improving testing efficiency.

Screening Low-Risk Individuals for Lung Cancer: The Need May Be Present, but the Evidence of Benefit Is Not.

Worldwide, lung cancer is the most common killer among cancers, advanced disease has worse outcomes, earlier stage detection leads to better outcomes, and high-quality screening has a favorable net benefit. With the mortality reduction recognized from annual low-radiation dose computed tomography by screening those at high risk, there has been consideration that this benefit could translate to those who have never smoked. There have been several large-scale, single-arm, observational trials in Asia in persons with light to no smoking histories, with or without a family history of lung cancer, which have revealed high or higher lung cancer detection rates than previously reported in high-risk persons who currently or formerly smoked. The Early Detection Program for Lung Cancer in Taiwan, of nearly 50,000 persons, revealed that the cancer detection rate for those screened with low-radiation dose computed tomography was more than twofold higher in light- or never-smokers with a family history of lung cancer compared with high-risk persons with more than 30 or more pack-years exposure and meeting U.S. Preventative Services Task Force criteria for screening. In addition, more than 90% of the cancers detected in those with a family history were in early stage. On the basis of those findings, the researchers concluded that screening first-degree relatives of those with a family history of lung cancer, irrespective of smoking history, would lead to a decrease in lung cancer mortality. We believe that the findings in this cohort and others like it represent substantial overdiagnosis and that the harms associated with screening a population that has a low likelihood of developing lethal cancers have not been thoroughly considered. Here, we provide our perspective and consider the potential benefits and harms of screening populations outside those currently eligible using the U.S. Preventative Services Task Force criteria.

Biomarker Testing for Guiding Precision Medicine for Patients with Non-Small Cell Lung Cancer.

The initial management of patients with lung cancer is growing more complex in the context of an expanding number of precision medicine treatments. These challenges are accompanied by opportunities to deliver more efficacious and less toxic treatments to patients. Indications for these treatments are also expanding, and patients with lung cancer across multiple stages now require biomarker testing. Given their role in the initial management of patients being diagnosed with lung cancer, pulmonologists must have fundamental knowledge regarding the importance, indications, and implications of biomarker testing across the spectrum of histology and stage. The purpose of this review is to provide fundamental knowledge regarding biomarker testing, its incorporation into the initial diagnostic and staging evaluation, and guidance for working within a multidisciplinary team to achieve timely and comprehensive biomarker testing to direct the use of precision medicine treatments.

Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

Pulmonologists' Attitudes and Role in Precision Medicine Biomarker Testing for Non-Small Cell Lung Cancer.

BACKGROUND: Despite advances in precision medicine for non-small cell lung cancer (NSCLC), biomarker testing for these therapies remain frequently underused, delayed, and inequitable. Pulmonologists often play a critical role in the initial diagnostic steps for patients with lung cancer, and previous data show variability in their knowledge and practices regarding biomarker testing. The purpose of this study is to better understand how pulmonologists view their role in lung cancer care. RESEARCH QUESTION: With the increasing importance of biomarker testing and precision medicine, how do pulmonologists view their role in lung cancer care? STUDY DESIGN: An electronic survey consisting of 31 items focused on attitudes and practices regarding diagnostic steps for NSCLC was randomly distributed to a sample of practicing pulmonologists in the American College of Chest Physicians (CHEST) analytics database. Inferential statistics were performed using χ2 tests and multivariable logistic regression models. RESULTS: A total of 401 pulmonologists responded to the survey. Most (92%) were general pulmonologists, and more than half (62%) indicate they order biomarker testing. Longer practice tenure, higher case volumes, and participation in a multidisciplinary tumor board were associated with ordering biomarkers (P < .05). Pulmonology was identified to have the leading responsibility for the initial diagnostic biopsy by most respondents (83%) and less often for staging (45%), leading discussions about biomarker testing with patients (28%), and for ordering biomarkers (22%). The most common reasons for not ordering biomarkers included the following: oncology was responsible (84%), it was not within their scope of practice (46%), or lack of the necessary knowledge (51%). INTERPRETATION: Pulmonologists vary in their practices for ordering biomarkers, and many defer this responsibility to oncology. Despite the role of bronchoscopy and pulmonology societal guidelines for staging, many defer leadership of this process. Many pulmonologists lack the necessary resources and multidisciplinary infrastructure likely required to efficiently accomplish biomarker testing.

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.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Navigational Bronchoscopy versus Computed Tomography-guided Transthoracic Needle Biopsy for the Diagnosis of Indeterminate Lung Nodules: protocol and rationale for the VERITAS multicenter randomized trial.

Background: Lung nodule incidence is increasing. Many nodules require biopsy to discriminate between benign and malignant etiologies. The gold-standard for minimally invasive biopsy, computed tomography-guided transthoracic needle biopsy (CT-TTNB), has never been directly compared to navigational bronchoscopy, a modality which has recently seen rapid technological innovation and is associated with improving diagnostic yield and lower complication rate. Current estimates of the diagnostic utility of both modalities are based largely on non-comparative data with significant risk for selection, referral, and publication biases. Methods: The VERITAS trial (na V igation E ndoscopy to R each Indeterminate lung nodules versus T ransthoracic needle A spiration, a randomized controlled S tudy) is a multicenter, 1:1 randomized, parallel-group trial designed to ascertain whether electromagnetic navigational bronchoscopy with integrated digital tomosynthesis is noninferior to CT-TTNB for the diagnosis of peripheral lung nodules 10-30 mm in diameter with pre-test probability of malignancy of at least 10%. The primary endpoint is diagnostic accuracy through 12 months follow-up. Secondary endpoints include diagnostic yield, complication rate, procedure duration, need for additional invasive diagnostic procedures, and radiation exposure. Discussion: The results of this rigorously designed trial will provide high-quality data regarding the management of lung nodules, a common clinical entity which often represents the earliest and most treatable stage of lung cancer. Several design challenges are described. Notably, all nodules are centrally reviewed by an independent interventional pulmonology and radiology adjudication panel relying on pre-specified exclusions to ensure enrolled nodules are amenable to sampling by both modalities while simultaneously protecting against selection bias favoring either modality. Conservative diagnostic yield and accuracy definitions with pre-specified criteria for what non-malignant findings may be considered diagnostic were chosen to avoid inflation of estimates of diagnostic utility. Trial registration: ClinicalTrials.gov NCT04250194.

A Multicenter, Single-Arm, Prospective Trial Assessing the Diagnostic Yield of Electromagnetic Bronchoscopic and Transthoracic Navigation for Peripheral Pulmonary Nodules.

Rationale: Strict adherence to procedural protocols and diagnostic definitions is critical to understand the efficacy of new technologies. Electromagnetic navigational bronchoscopy (ENB) for lung nodule biopsy has been used for decades without a solid understanding of its efficacy, but offers the opportunity for simultaneous tissue acquisition via electromagnetic navigational transthoracic biopsy (EMN-TTNA) and staging via endobronchial ultrasound (EBUS). Objective: To evaluate the diagnostic yield of EBUS, ENB, and EMN-TTNA during a single procedure using a strict a priori definition of diagnostic yield with central pathology adjudication. Methods: A prospective, single-arm trial was conducted at eight centers enrolling participants with pulmonary nodules (<3 cm; without computed tomography [CT]- and/or positron emission tomography-positive mediastinal lymph nodes) who underwent a staged procedure with same-day CT, EBUS, ENB, and EMN-TTNA. The procedure was staged such that, when a diagnosis had been achieved via rapid on-site pathologic evaluation, the procedure was ended and subsequent biopsy modalities were not attempted. A study finding was diagnostic if an independent pathology core laboratory confirmed malignancy or a definitive benign finding. The primary endpoint was the diagnostic yield of the combination of CT, EBUS, ENB, and EMN-TTNA. Measurements and Main Results: A total of 160 participants at 8 centers with a mean nodule size of 18 ± 6 mm were enrolled. The diagnostic yield of the combined procedure was 59% (94 of 160; 95% confidence interval [CI], 51-66%). Nodule regression was found on same-day CT in 2.5% of cases (4 of 160; 95% CI, 0.69-6.3%), and EBUS confirmed malignancy in 7.1% of cases (11 of 156; 95% CI, 3.6-12%). The yield of ENB alone was 49% (74 of 150; 95% CI, 41-58%), that of EMN-TTNA alone was 27% (8 of 30; 95% CI, 12-46%), and that of ENB plus EMN-TTNA was 53% (79 of 150; 95% CI, 44-61%). Complications included a pneumothorax rate of 10% and a 2% bleeding rate. When EMN-TTNA was performed, the pneumothorax rate was 30%. Conclusions: The diagnostic yield for ENB is 49%, which increases to 59% with the addition of same-day CT, EBUS, and EMN-TTNA, lower than in prior reports in the literature. The high complication rate and low diagnostic yield of EMN-TTNA does not support its routine use. Clinical trial registered with www.clinicaltrials.gov (NCT03338049).

ACR Appropriateness Criteria® Lung Cancer Screening: 2022 Update.

Lung cancer remains the leading cause of cancer-related mortality for men and women in the United States. Screening for lung cancer with annual low-dose CT is saving lives, and the continued implementation of lung screening can save many more. In 2015, the CMS began covering annual lung screening for those who qualified based on the original United States Preventive Services Task Force (USPSTF) lung screening criteria, which included patients 55 to 77 year of age with a 30 pack-year history of smoking, who were either currently using tobacco or who had smoked within the previous 15 years. In 2021, the USPSTF issued new screening guidelines, decreasing the age of eligibility to 80 years of age and pack-years to 20. Lung screening remains controversial for those who do not meet the updated USPSTF criteria, but who have additional risk factors for the development of lung cancer. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: A National Lung Cancer Roundtable best-practice guide.

Advances in biomarker-driven therapies for patients with nonsmall cell lung cancer (NSCLC) both provide opportunities to improve the treatment (and thus outcomes) for patients and pose new challenges for equitable care delivery. Over the last decade, the continuing development of new biomarker-driven therapies and evolving indications for their use have intensified the importance of interdisciplinary communication and coordination for patients with or suspected to have lung cancer. Multidisciplinary teams are challenged with completing comprehensive and timely biomarker testing and navigating the constantly evolving evidence base for a complex and time-sensitive disease. This guide provides context for the current state of comprehensive biomarker testing for NSCLC, reviews how biomarker testing integrates within the diagnostic continuum for patients, and illustrates best practices and common pitfalls that influence the success and timeliness of biomarker testing using a series of case scenarios.