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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., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Targeted therapies for advanced non-small cell lung cancer (NSCLC) with oncogenic drivers have caused a paradigm shift in care. Biomarker testing is needed to assess eligibility for these therapies. Pulmonologists often perform bronchoscopy, providing tissue for both pathologic diagnosis and biomarker analysis. We performed this survey to define the existing knowledge and practices regarding the pulmonologists' role in biomarker testing for advanced NSCLC., Research Question: What is the current knowledge and practice of pulmonologists regarding biomarker testing and targeted therapies in advanced NSCLC?, Study Design and Methods: This cross-sectional study was performed using an electronic survey of a random sample of 7,238 pulmonologists. Questions focused on diagnostic steps and biomarker analyses for NSCLC., Results: A total of 453 pulmonologists responded. Respondents vary by reported lung cancer patient volume, ranging from 51% evaluating one to four new cases per month to 19% evaluating > 10 cases per month. Interventional training, academic practice setting, and higher volume of endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) were associated with increased knowledge of practice guidelines for the number of recommended passes during EBUS-TBNA (P < .05). Academic pulmonologists more commonly performed or referred for EBUS-TBNA than community pulmonologists (96% and 83%, respectively; P < .0005). Higher testing rates were associated with interventional training, academic setting, and the presence of an institutional policy, whereas lower testing rates were associated with general pulmonologists, practice in community settings, and lack of a guiding institutional policy (P < .05)., Interpretation: Substantial differences among pulmonologists' evaluation of advanced NSCLC, variation in knowledge of available biomarkers and the importance of targeted therapies, and differences in institutional coordination likely lead to underutilization of biomarker testing. Interventional training appears to drive improved knowledge and practice for biomarker testing more than practice setting. Improvements are needed in tissue acquisition and interdisciplinary coordination to ensure universal and comprehensive testing for eligible patients., (Copyright © 2021. Published by Elsevier Inc.)

Background: In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor., Methods: We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV., Results: Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively., Conclusions: A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Patients who have incidentally detected pulmonary nodules and an estimated intermediate risk (5-60%) of lung cancer frequently are followed via computed tomography (CT) surveillance to detect nodule growth, despite guidelines for a more aggressive diagnostic strategy. We examined the cost-effectiveness of an autoantibody test (AABT)-Early Cancer Detection Test-Lung (EarlyCDT-LungTM)-as an aid to early diagnosis of lung cancer among such patients., Methods: We developed a decision-analytic model to evaluate use of the AABT versus CT surveillance alone. In the model, patients with a positive AABT-because they are at substantially enhanced risk of lung cancer-are assumed to go directly to biopsy, resulting in diagnosis of lung cancer in earlier stages than under current guidelines (a beneficial stage shift). Patients with a negative AABT, and those scheduled for CT surveillance alone, are assumed to have periodic CT screenings to detect rapid growth and thus to have their lung cancers diagnosed-on average-at more advanced stages., Results: Among 1,000 patients who have incidentally detected nodules 8-30 mm, have an intermediate-risk of lung cancer, and are evaluated by CT surveillance alone, 95 (9.5%) are assumed to have lung cancer (local, 73.6%; regional, 22.0%; distant, 4.4%). With use of the AABT set at a sensitivity/specificity of 41%/93% (stage shift = 10.8%), although expected costs would be higher by $949,442 ($949 per person), life years would be higher by 53 (0.05 per person), resulting in a cost per life-year gained of $18,029 and a cost per quality-adjusted life year (QALY) gained of $24,330. With use of the AABT set at a sensitivity/specificity of 28%/98% (stage shift = 7.4%), corresponding cost-effectiveness ratios would be $18,454 and $24,833., Conclusions: Under our base-case assumptions, and reasonable variations thereof, using AABT as an aid in the early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules who are estimated to be at intermediate risk of lung cancer and are scheduled for CT surveillance alone is likely to be a cost-effective use of healthcare resources., Competing Interests: Mark Atwood, John Edelsberg, and Derek Weycker are employees of Policy Analysis Inc. (PAI), which received financial support from Oncimmune Inc. for this study. Geoffrey Hamilton-Fairley and James R. Jett are employed by, and own stock in, Oncimmune Inc. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials (as detailed online in the guide for authors http://journals.plos.org/plosone/s/competing-interests).

Background: The optimal extent of lung resection and lymph node (LN) assessment for surgical treatment of clinical stage T1aN0M0 typical carcinoid tumors is unclear. Using a cohort including only these patients, we aimed to determine the impact of extent of lung resection and LN assessment on overall survival., Methods: Patients undergoing lobectomy or sublobar resection for clinical stage T1aN0M0 intraparenchymal typical carcinoid tumor were identified in the National Cancer Data Base from 1998 to 2012. Kaplan-Meier analysis was used to determine overall survival. A multivariable Cox proportional hazards model was used to determine independent predictors of mortality., Results: Of 1,495 patients, 536 (35.9%) had sublobar resection (wedge resection, n = 429; segmentectomy, n = 91) and 959 (64.2%) had lobectomy. There were 366 patients (24.5%) with no LN assessment. As tumor size increased, sublobar resection decreased and LN assessment increased. Overall, 60 patients (4.0%) were upstaged. Fifty-two patients were upstaged because of LN metastases (40 pN1, 11 pN2, and 1 pN3). The 5-year overall survival rate was 87%. It was 88% for lobectomy versus 87% for sublobar resection (p = 0.3), 65% for LN upstaging versus 89% for patients without LN upstaging, and 86% for patients with no LN assessment (p = 0.002). Independent predictors of mortality included LN upstaging, age, male sex, and Charlson comorbidity index., Conclusions: For patients with clinical stage T1aN0M0 typical carcinoid, sublobar resection results in similar overall survival compared with lobectomy. However, regardless of resection type, LN assessment is important to identify LN upstaging, the strongest independent predictor of overall mortality., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded., Methods: In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease., Results: Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease., Conclusions: The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary nodules are frequently detected during diagnostic chest imaging and as a result of lung cancer screening. Current guidelines for their evaluation are largely based on low-quality evidence, and patients and clinicians could benefit from more research in this area., Methods: In this research statement from the American Thoracic Society, a multidisciplinary group of clinicians, researchers, and patient advocates reviewed available evidence for pulmonary nodule evaluation, characterized six focus areas to direct future research efforts, and identified fundamental gaps in knowledge and strategies to address them. We did not use formal mechanisms to prioritize one research area over another or to achieve consensus., Results: There was widespread agreement that novel tests (including novel imaging tests and biopsy techniques, biomarkers, and prognostic models) may improve diagnostic accuracy for identifying cancerous nodules. Before they are used in clinical practice, however, better evidence is needed to show that they improve more distal outcomes of importance to patients. In addition, the pace of research and the quality of clinical care would be improved by the development of registries that link demographic and nodule characteristics with patient-level outcomes. Methods to share data from registries are also necessary., Conclusions: This statement may help researchers to develop impactful and innovative research projects and enable funders to better judge research proposals. We hope that it will accelerate the pace and increase the efficiency of discovery to improve the quality of care for patients with pulmonary nodules.

Background: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging., Results: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775)., Conclusions: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.

Introduction: We investigated the expression of microRNAs and mRNAs in pleural tissues from patients with either malignant pleural mesothelioma or benign asbestos-related pleural effusion., Methods: Fresh frozen tissues from a total of 18 malignant pleural mesothelioma and 6 benign asbestos-related pleural effusion patients were studied. Expression profiling of mRNA and microRNA was performed using standard protocols., Results: We discovered significant upregulation of multiple microRNAs in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Hsa-miR-484, hsa-miR-320, hsa-let-7a, and hsa-miR-125a-5p were able to discriminate malignant from benign disease. Dynamically regulated mRNAs were also identified. MET was the most highly overexpressed gene in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Integrated analyses examining microRNA-mRNA interactions suggested multiple altered targets within the Notch signaling pathway., Conclusions: Specific microRNAs and mRNAs may have diagnostic utility in differentiating patients with malignant pleural mesothelioma from benign asbestos-related pleural effusion. These studies may be particularly helpful in patients who reside in a region with a high incidence of mesothelioma.

Background: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy., Methods: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility., Results: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%., Conclusions: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Accurate staging of lung cancer is crucial to ensure the validity of lung cancer clinical research efforts and constitutes the cornerstone of the management of affected patients. The last decade has witnessed unprecedented technological advances allowing for more accurate and less invasive staging. In general, these techniques should be viewed as complementary rather than competitive, and indications, contraindications, and limitations of all staging techniques should be fully understood by providers involved with lung cancer patients. Noninvasive imaging techniques include chest computed tomography (CT) and positron emission tomography (PET). Invasive techniques can be nonsurgical such as needle-based techniques (endobronchial or endoscopic ultrasound) or surgical (mediastinoscopy and variants). The necessary multidisciplinary approach to lung cancer patients dictates that all stakeholders be familiar with the benefits and limitations of these newer techniques., (Published by Elsevier Inc.)

Studies have shown that fluorescence in situ hybridization (FISH) testing increases lung cancer detection on cytology specimens in peripheral nodules. The goal of this study was to determine whether a predictive model using clinical features and routine cytology with FISH results could predict lung malignancy after a nondiagnostic bronchoscopic evaluation. Patients with an indeterminate peripheral lung nodule that had a nondiagnostic bronchoscopic evaluation were included in this study (N = 220). FISH was performed on residual bronchial brushing cytology specimens diagnosed as negative (n = 195), atypical (n = 16), or suspicious (n = 9). FISH results included hypertetrasomy (n = 30) and negative (n = 190). Primary study end points included lung cancer status along with time to diagnosis of lung cancer or date of last clinical follow-up. Hazard ratios (HRs) were calculated using Cox proportional hazards regression model analyses, and P values < .05 were considered statistically significant. The mean age of the 220 patients was 66.7 years (range, 35-91), and most (58%) were men. Most patients (79%) were current or former smokers with a mean pack year history of 43.2 years (median, 40; range, 1-200). After multivariate analysis, hypertetrasomy FISH (HR = 2.96, P < .001), pack years (HR = 1.03 per pack year up to 50, P = .001), age (HR = 1.04 per year, P = .02), atypical or suspicious cytology (HR = 2.02, P = .04), and nodule spiculation (HR = 2.36, P = .003) were independent predictors of malignancy over time and were used to create a prediction model (C-statistic = 0.78). These results suggest that this multivariate model including test results and clinical features may be useful following a nondiagnostic bronchoscopic examination., (© 2013.)

Objectives: EarlyCDT(®)-Lung may enhance detection of early stage lung cancer by aiding physicians in assessing high-risk patients through measurement of biological markers (i.e., autoantibodies). The test's performance characteristics in routine clinical practice were evaluated by auditing clinical outcomes of 1613 US patients deemed at high risk for lung cancer by their physician, who ordered the EarlyCDT-Lung test for their patient., Methods: Clinical outcomes for all 1613 patients who provided HIPAA authorization are reported. Clinical data were collected from each patient's treating physician. Pathology reports when available were reviewed for diagnostic classification. Staging was assessed on histology, otherwise on imaging., Results: Six month follow-up for the positives/negatives was 99%/93%. Sixty-one patients (4%) were identified with lung cancer, 25 of whom tested positive by EarlyCDT-Lung (sensitivity=41%). A positive EarlyCDT-Lung test on the current panel was associated with a 5.4-fold increase in lung cancer incidence versus a negative. Importantly, 57% (8/14) of non-small cell lung cancers detected as positive (where stage was known) were stage I or II., Conclusions: EarlyCDT-Lung has been extensively tested and validated in case-control settings and has now been shown in this audit to perform in routine clinical practice as predicted. EarlyCDT-Lung may be a complementary tool to CT for detection of early lung cancer., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The treatment of advanced non-small cell lung cancer has been with systemic chemotherapy and usually consists of a platinum doublet chemotherapy. The identification of somatic driver mutations has resulted in new drugs that target these mutations. This report discusses the two most important new targeted therapy drugs for the treatment of advanced non-small cell lung cancer that have these driver mutations.

Efforts in lung cancer screening with chest X-ray (CXR) and sputum cytology in the 1970s and 1980s were negative. In the ensuing decade, the early lung cancer action project (ELCAP), and the Mayo screening study showed the promise of low-dose CT. These and other studies led to the National lung screening study (NLST), which showed definitively that low-dose spiral computed tomography had a measurable impact on mortality and could be justified as a tool for lung cancer screening. This review examines the results of past and recent studies of lung cancer screening., (© 2013 Wiley Periodicals, Inc.)

Background: Small cell lung cancer (SCLC) is a lethal disease for which there have been only small advances in diagnosis and treatment in the past decade. Our goal was to revise the evidence-based guidelines on staging and best available treatment options., Methods: A comprehensive literature search covering 2004 to 2011 was conducted in MEDLINE, Embase, and five Cochrane databases using SCLC terms. This was cross-checked with the authors' own literature searches and knowledge of the literature. Results were limited to research in humans and articles written in English., Results: The staging classification should include both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the new seventh edition American Joint Committee on Cancer/International Union Against Cancer staging by TNM. The use of PET scanning is likely to improve the accuracy of staging. Surgery is indicated for carefully selected stage I SCLC. LS disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle 1 or 2 of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. ES disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in those individuals with both LS and ES disease who achieve a complete or partial response to initial therapy. To date, no molecularly targeted therapy agent has demonstrated proven efficacy against SCLC., Conclusion: Evidence-based guidelines are provided for the staging and treatment of SCLC. LS-SCLC is treated with curative intent with 20% to 25% 5-year survival. ES-SCLC is initially responsive to standard treatment, but almost always relapses, with virtually no patients surviving for 5 years. Targeted therapies have no proven efficacy against SCLC.

Objective: The study objective was to establish The American Association for Thoracic Surgery (AATS) lung cancer screening guidelines for clinical practice., Methods: The AATS established the Lung Cancer Screening and Surveillance Task Force with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 4 medical oncologists, 1 pulmonologist, 1 pathologist, and 1 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with, and at risk for, lung cancer. The task force reviewed the literature, including screening trials in the United States and Europe, and discussed local best clinical practices in the United States and Canada on 4 conference calls. A reference library supported the discussions and increased individual study across disciplines. The task force met to review the literature, state of clinical practice, and recommend consensus-based guidelines., Results: Nine of 14 task force members were present at the meeting, and 3 participated by telephone. Two absent task force members were polled afterward. Six unanimous recommendations and supporting work-up algorithms were presented to the Council of the AATS at the 2012 annual meeting in San Francisco, California., Conclusions: Annual lung cancer screening and surveillance with low-dose computed tomography is recommended for smokers and former smokers with a 30 pack-year history of smoking and long-term lung cancer survivors aged 55 to 79 years. Screening may begin at age 50 years with a 20 pack-year history of smoking and additional comorbidity that produces a cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Screening should be undertaken with a subspecialty qualified interdisciplinary team. Patient risk calculator application and intersociety engagement will provide data needed to refine future lung cancer screening guidelines., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer-specific mortality by 20%., Method: The American Association for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer., Results: The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines., Conclusions: The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America., (Copyright © 2012. Published by Mosby, Inc.)

Context: Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer., Objective: To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline., Data Sources: MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012)., Study Selection: Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation., Data Extraction: Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus., Results: Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare., Conclusion: Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.

Background: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data., Methods: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index., Results: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001)., Conclusions: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules., Impact: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules.

Background: In an effort to evaluate the single agent activity of temsirolimus in previously untreated non-small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study., Methods: Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity., Results: A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24-week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome., Conclusions: Temsirolimus given as a single agent in frontline therapy in patients with non-small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy.

In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Screening for lung cancer is not currently recommended, even in persons at high risk for this condition. Most patients with lung cancer present with symptomatic disease that is usually at an incurable, advanced stage. The recently reported NLST (National Lung Screening Trial) showed a 20% decrease in deaths from lung cancer in high-risk persons undergoing screening with low-dose computed tomography of the chest compared with chest radiography. The high-risk group included in the trial comprised asymptomatic persons aged 55 to 74 years, with smoking history of at least 30 pack-years. Screening with low-dose computed tomography detected more cases of early-stage lung cancer and fewer cases of advanced-stage cancer, confirming that screening has shifted the stage of cancer at diagnosis and provides more persons with the opportunity for curative treatment. Although computed tomography screening has risks and limitations, the 20% decrease in deaths is the single most dramatic decrease ever reported for deaths from lung cancer, with the possible exception of smoking cessation. Physicians should offer computed tomography screening for lung cancer to patients who fit the high-risk profile defined in the NLST.

Background: The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS., Methods: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) )., Results: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) ≤0.48)., Conclusions: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials., (Copyright © 2010 American Cancer Society.)

Objectives: Several studies have identified airflow obstruction as a risk factor for lung cancer independent of smoking history, but the risk associated with the presence of radiographic evidence of emphysema has not been extensively studied. We proposed to assess this risk using a quantitative volumetric CT scan analysis., Methods: Sixty-four cases of lung cancer were identified from a prospective cohort of 1,520 participants enrolled in a spiral CT scan lung cancer screening trial. Each case was matched to six control subjects for age, sex, and smoking history. Quantitative CT scan analysis of emphysema was performed. Spirometric measures were also conducted. Data were analyzed using conditional logistic regression making use of the 1:6 set groups of 64 cases and 377 matched control subjects., Results: Decreased FEV(1) and FEV(1)/FVC were significantly associated with a diagnosis of lung cancer with ORs of 1.15 (95% CI, 1.00-1.32; P = .046) and 1.29 (95% CI, 1.02-1.62; P = .031), respectively. The quantity of radiographic evidence of emphysema was not found to be a significant risk for lung cancer with OR of 1.042 (95% CI, 0.816-1.329; P = .743). Additionally, there was no significant association between severe emphysema and lung cancer with OR of 1.57 (95% CI, 0.73-3.37)., Conclusions: We confirm previous observations that airflow obstruction is an independent risk factor for lung cancer. The absence of a clear relationship between radiographic evidence of emphysema and lung cancer using an automated quantitative volumetric analysis may result from different population characteristics than those of prior studies, radiographic evidence of emphysema quantitation methodology, or absence of any relationship between emphysema and lung cancer risk.

Autoantibody profiling is a developing approach that incorporates immune recognition of myriad aberrant cancer proteins into a single diagnostic assay. We have previously described methodology to screen T7-phage NSCLC-cDNA libraries for phage-expressed proteins recognized by NSCLC-associated antibodies, and developed a multiplex assay that has excellent ability to discriminate NSCLC from control samples. This follow-up report describes the development and testing of a diagnostic autoantibody assay that uses seven amino-acid peptides as capture proteins. A random-peptide M13-phage library was screened for proteins recognized by cancer-associated antibodies. One hundred twenty-one NSCLC case and control samples were divided into two groups for training and validation, or alternately, evaluated sequentially in a leave-one-out analysis. Candidate antibody-markers were ranked by statistical discrimination between cases and controls. Receiver-Operating-Characteristic (ROC-AUC) suggested the predictive potential of various marker combinations. A five-marker combination (AUC = 0.982) afforded 90% sensitivity and 73% specificity in a training-and-testing strategy. Leave-one-out validation provided similar class prediction. Data confirm the potential of antibody profiling to provide high levels of cancer prediction. Random peptide libraries offer a universal source of capture proteins for antibody profiling that obviates the need for tumor-specific library construction and abrogates inherent problems with tumor heterogeneity during biomarker discovery.

Objectives: The objective of this study was to evaluate the response rate and toxicities of the combination of oral topotecan and carboplatin in patients with untreated extensive stage small cell lung cancer (ES-SCLC). Previous studies have suggested improved outcomes with a topoisomerase I inhibitor in combination with a platinum agent., Methods: Twenty-six patients with previously untreated, ES-SCLC were evaluable in this phase II trial. All patients received oral topotecan 2.0 mg/m per day on days 1 through 5 and carboplatin at an area under curve of 5 on day 5. Treatment was repeated every 21 days up to a total of 6 cycles. All patients received G-CSF., Results: There were no complete responses and 16 partial responses, for an overall response rate of 62% (95% CI: 41-80). Median time to progression was 6.0 months (95% CI: 4-8), with a median overall survival of 12 months (95% CI: 8-16). This study was closed to accrual early with 26 of a planned 39 patients enrolled because of grade 5 adverse events in 4 (15%) patients (3 neutropenic infections, 1 sudden cardiac death). Eighty-five percent of patients experienced grade 3 or higher hematologic events. The most common severe nonhematologic events included diarrhea, vomiting, dyspnea, hypoxia, and hypotension., Conclusions: Although this drug regimen has activity as first-line therapy in ES-SCLC, it is associated with excessive hematologic toxicity, which occurred in spite of growth factor support. Despite promising survival estimates, this particular combination and dose level of oral topotecan and carboplatin cannot be recommended.

Purpose of Review: Considerable advances in genomics, transcriptomics and proteomics have in the recent years transformed our understanding of the molecular mechanisms involved in the pathogenesis of lung cancer and are in the process of revolutionizing our approach to its diagnosis and treatment. Although these techniques have traditionally been described in the context of large volume biopsies from surgically resected tumors, significant technical advances allow their application to smaller samples obtained bronchoscopically, often the only samples available in advanced lung cancer., Recent Findings: Recent data support the use of advanced molecular techniques as an adjunct to conventional histologic examinations of bronchoscopy specimens in the following situations: early diagnosis and screening of nonsmall cell lung cancer by fluorescent in-situ hybridization techniques in particular; accurate histologic diagnosis via novel immunohistochemistry markers; and prognosis and prediction of response to targeted and conventional chemotherapeutic agents., Summary: Molecular biology techniques are increasingly applied to smaller biopsy specimens obtained via bronchoscopy, allowing for their use in advanced, unresectable nonsmall cell lung cancer. Although these techniques have not yet entered the clinical practice arena, they will likely become an unavoidable complement to conventional morphologic examinations and allow for individualized diagnostic and therapeutic approach to lung-cancer patients.

Background: In extensive-stage small cell lung cancer (SCLC), the combination of pemetrexed plus carboplatin has shown activity and appeared to be well-tolerated. We conducted a trial to confirm the efficacy and to assess the tolerability of this chemotherapy combination., Methods: Patients with untreated extensive-stage SCLC were enrolled in this phase 2 open-labeled study. They receive pemetrexed 500 mg/m(2) and carboplatin (area under the curve of 5) every 21 days for a maximum 6 cycles. The primary endpoint for this trial was the confirmed response rate and the accrual goal was 70 patients., Results: Forty-six eligible patients (29 aged <70 years, 17 aged >or=70 years) were accrued to this study. The efficacy outcomes were similar between the 2 age groups. Overall, the confirmed response rate was 35% (16 of 46; 95% confidence interval [CI], 21%-50%), where all 16 were partial responses. On the basis of these results, we had strong evidence that the study would not meet the preset efficacy criteria and was, therefore, closed before full accrual. The median duration of response was 4.4 months (95% CI, 2.9-5.2). Median overall survival for patients aged <70 years and aged >or=70 years was 9.2 months (95% CI, 5.4-11.6) and 10.8 months (95% CI, 2.2-14.3), respectively. Grade 3 or higher toxicity rates were similar between the younger and older patients. Grade 3/4 and grade 4 hematological toxicities were observed in 46% and 26% of patients, respectively., Conclusions: Although well-tolerated, the combination of pemetrexed and carboplatin is not as effective as standard therapy in patients with untreated extensive-stage SCLC., ((c) 2010 American Cancer Society.)

Rationale: Bronchoscopically collected cytology specimens are commonly used to obtain a diagnosis of cancer in patients with pulmonary lesions. However, the sensitivity of cytology is suboptimal, especially for peripheral lesions less than 2 cm in diameter., Objectives: We assessed the performance of a testing algorithm using cytology and fluorescence in situ hybridization (FISH) as part of clinical practice., Methods: Bronchial brushing specimens (n = 343) were obtained from patients undergoing bronchoscopy for indeterminate pulmonary lesions. Routine cytology was performed and specimens without a positive diagnosis (n = 294) were analyzed by FISH, using residual brushing material. Pathology-confirmed lung cancer or clinical/radiographic evidence of disease was considered diagnostic of malignancy., Measurements and Main Results: Routine cytology had a sensitivity and specificity of 41% (23 of 56) and 100% (45 of 45) for central lesions and 20% (26 of 133) and 100% (109 of 109) for peripheral nodules, respectively. FISH detected an additional 32% of lung cancers (18 central and 43 peripheral) not detectable by cytology alone, while producing false positive diagnoses in 22% (10 of 45) and 6% (6 of 109) benign central and peripheral lesions, respectively. In peripheral nodules, FISH detected (relative to routine cytology) an additional 44% (15 of 34) and 28% (25 of 91) of lung cancers less than 2 cm and 2 cm or more in size, respectively. A positive FISH result had a likelihood ratio of 1.45 and 5.87 for central and peripheral lesions and 3.44 and 15.38 for peripheral nodules less than 2 cm and 2 cm or more in size, respectively., Conclusions: FISH testing significantly increases the detection of lung cancer over routine cytology alone. It is especially useful for peripheral nodules.

Background: Although no study has prospectively documented the rate at which lung cancers grow, many have assumed exponential growth. The purpose of this study was to document the growth of lung cancers detected in high-risk participants receiving annual screening chest CT scans., Methods: Eighteen lung cancers were evaluated by at least four serial CT scans (4 men, 14 women; age range, 53 to 79 years; mean age, 66 years). CT scans were retrospectively reviewed for appearance, size, and volume (volume [v] = pi/6[ab(2)]). Growth curves (x = time [in days]; y = volume [cubic millimeters]) were plotted and subcategorized by histology, CT scan attenuation, stage, survival, and initial size., Results: Inclusion criteria favored smaller, less aggressive cancers. Growth curves varied, even when subcategorized by histology, CT scan attenuation, stage, survival, or initial size. Cancers associated with higher stages, mortality, or recurrence showed fairly steady growth or accelerated growth compared with earlier growth, although these growth patterns also were seen in lesser-stage lung cancers. Most lung cancers enlarged at fairly steady increments, but several demonstrated fairly flat growth curves, and others demonstrated periods of accelerated growth., Conclusions: This study is the first to plot individual lung cancer growth curves. Although parameters favored smaller, less aggressive cancers in women, it showed that lung cancers are not limited to exponential growth. Tumor size at one point or growth between two points did not appear to predict future growth. Studies and equations assuming exponential growth may potentially misrepresent an indeterminate nodule or the aggressiveness of a lung cancer.

Respiratory illnesses are a huge and rising burden to health-care systems and societies worldwide. Research is crucial to tackle the enormous problem of chest diseases. However the vast number of research questions and available research approaches often creates confusion and risks dilution of resources by spreading them too diffusely. Clear research directions will help to use research funds efficiently to provide treatment advances that benefit patient care. This paper presents the visions of leading experts on future research directions, focusing on what should rather than what is going to be done. These opinions provide a guide for new investigators and a platform for intellectual debates through which coordinated research efforts can help progress towards respiratory health.

Background: Malignant pleural mesothelioma (MPM) is a primary malignancy characterized by local invasion of the pleura and metastasis. Despite advances in computed tomography (CT) and magnetic resonance imaging (MRI), accurately staging patients remains challenging. Recent studies have examined the use of integrated CT-positron emission tomography (PET) for staging patients., Materials and Methods: Mayo Clinic databases were queried to identify cases with a histologic diagnosis of MPM from 2000 to 2006. Inclusion criteria were a diagnosis of MPM, an available CT scan, and an initial staging integrated CT-PET scan. A total of 35 patients were identified who met the inclusion criteria. Computed tomography and integrated CT-PET scans were reviewed by experienced radiologists. Laboratory parameters were reviewed. The Mayo Clinic tumor registry and Social Security database were queried for survival data in patients in which no follow-up was available., Results: Findings on integrated CT-PET excluded 14 of 35 patients from surgical intervention. Extrapleural pneumonectomies (EPPs) were performed in 8 patients, and partial pleurectomies were performed in 2 patients. Upstaging from integrated CT-PET occurred in 70% of the patients when surgical pathology was available, 2 cases to an inoperable stage. Although not statistically significant, median survival was 20 months for patients undergoing an EPP and 12 months for patients excluded from surgical intervention by integrated CT-PET., Conclusion: Malignant pleural mesothelioma is a difficult disease to accurately stage. The most common reason for upstaging in our series was an increase in T (tumor; tumor-node-metastasis staging system) disease. Our data suggest that integrated CT-PET is excellent for detecting nodal and distant metastases. However, the ability of this imaging modality to correctly stage locoregional disease is not superior to the combination of CT and MRI as reported in the literature.

Background: An analysis of 14 small cell lung cancer (SCLC) trials was performed to improve the current understanding of potential prognostic factors for overall survival (OS) and progression-free survival (PFS) in groups of patients with limited-stage disease SCLC (LD-SCLC) and extensive-stage disease SCLC (ED-SCLC) separately., Methods: Data on 688 patients with LD-SCLC and 910 patients with ED-SCLC were included. Clinical and laboratory factors were tested for their prognostic significance using Cox regression models that were stratified by protocol. Recursive partitioning and amalgamation (RPA) analyses were used to identify prognostic subgroups., Results: Poorer performance status (PS) led to worse OS and PFS in the ED-SCLC group but not in the LD-SCLC group. The prognostic impact of PS was strong for men but weak for women in the ED-SCLC group (interaction P value <.012 for OS and PFS). Other negative prognostic factors included increased age and men for the LD-SCLC group and increased age, men, increased number of metastatic sites at baseline, and increased creatinine levels for the ED-SCLC group. In patients with the ED-SCLC, RPA analyses identified 5 subgroups with different prognosis based on baseline PS, creatinine levels, sex, and the number of metastatic sites., Conclusions: The current pooled analysis identified baseline creatinine levels and the number of metastatic sites as important prognostic factors in patients with ED-SCLC in addition to the well established factors of sex, age, and PS. There was a significant interaction between sex and PS within the ED-SCLC group, suggesting that PS is highly prognostic in men but has no significant impact in women. Within the LD-SCLC group, only age and sex were identified as important prognostic factors. RPA analyses confirmed many of these findings., ((c) 2009 American Cancer Society.)