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Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Chest. 2013;143(5_suppl):1S. doi:10.1378/chest.1S
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Chest. 2013;143(5_suppl):2S-5S. doi:10.1378/chest.2s
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Diagnosis and Management of Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (3rdEdition)

Chest. 2013;143(5_suppl):6S. doi:10.1378/chest.6s
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Chest. 2013;143(5_suppl):7S-37S. doi:10.1378/chest.12-2377
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Lung cancer causes as many deaths as the next four leading causes of cancer deaths combined.1 In the developing world, which has seen a dramatic increase in the rate of smoking, the impending number of deaths from this disease is staggering. Although the incidence and death rate in the United States has been declining since around 2000, lung cancer is projected to remain by far the leading cause of cancer deaths for many decades.

Chest. 2013;143(5_suppl):38S-40S. doi:10.1378/chest.12-2342
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In preparing to write this introduction to the third edition of the American College of Chest Physicians (ACCP) Lung Cancer Guidelines (LC III), I took the opportunity to review the introductions to the first two editions. The theme of both the 2003 and the 2007 articles was that (1) the disease is common; (2) the current treatment leaves a lot to be desired; and (3) there is room for optimism, as the pace of relevant research has quickened. The theme for the introduction to this edition is, appropriately, very much the same.

Chest. 2013;143(5_suppl):41S-50S. doi:10.1378/chest.12-2344
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Background:  The objective was to develop high-quality and comprehensive evidence-based guidelines on the diagnosis and management of lung cancer.

Methods:  A carefully crafted panel of lung cancer experts, methodologists, and other specialists was assembled and reviewed for relevant conflicts of interest. The American College of Chest Physicians guideline methodology was used. Population, intervention, comparator, outcome (PICO)-based key questions and defined criteria for eligible studies were developed to inform the search strategies, subsequent evidence summaries, and recommendations. Research studies, systematic reviews, and meta-analyses, where they existed, were assessed for quality and summarized to inform the recommendations.

Results:  Each recommendation was developed with supporting evidence and the consensus of the writing committees. Controversial recommendations were identified for further consultation by the entire panel, with anonymous voting to achieve consensus.

Conclusions:  The final recommendations can be trusted by health-care providers, patients, and other stakeholders since they are based on the current evidence in these areas and were developed with trustworthy processes for guideline development.

Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Online Only Articles

Chest. 2013;143(5_suppl):e1S-e29S. doi:10.1378/chest.12-2345

Background:  Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research.

Methods:  A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk.

Results:  Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application.

Conclusions:  Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers.

Chest. 2013;143(5_suppl):e30S-e39S. doi:10.1378/chest.12-2346

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics.

Chest. 2013;143(5_suppl):e40S-e60S. doi:10.1378/chest.12-2348

Background:  Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention.

Methods:  Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations.

Results:  None of the phase 3 trials with the agents β-carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis.

Conclusions:  By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points.

Chest. 2013;143(5_suppl):e61S-e77S. doi:10.1378/chest.12-2349

Background:  Continued tobacco use in the setting of lung cancer management is frequently confounding and always of critical importance. We summarized the published literature concerning the management of tobacco dependence in patients with lung cancer and offer recommendations for integrating dependence treatment into ongoing oncologic care.

Methodology:  MEDLINE, Embase, CINAHL, PsychINFO, and the Cochrane Collaborative databases were searched for English language randomized clinical trials, cohort studies, case-control studies, secular trend analyses, and case series relevant to the a priori identified clinical questions. Evidence grading, integration, and genesis of recommendations followed the methods described in “Methodology for Development of Guidelines for Lung Cancer” in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed.

Results:  We describe the approach to tobacco dependence in patients with lung cancer at various phases in the evolution of cancer care. For example, among patients undergoing lung cancer screening procedures, we recommend against relying on the screening itself, including procedures accompanied solely by self-help materials, as an effective strategy for achieving abstinence. Among patients with lung cancer undergoing surgery, intensive perioperative cessation pharmacotherapy is recommended as a method for improving abstinence rates. Cessation pharmacotherapy is also recommended for patients undergoing chemotherapy, with specific recommendations to use bupropion when treating patients with lung cancer with depressive symptoms, as a means of improving abstinence rates, depressive symptoms, and quality of life.

Conclusions:  Optimal treatment of lung cancer includes attention to continued tobacco use, with abstinence contributing to improved patient-related outcomes at various phases of lung cancer management. Effective therapeutic interventions are available and are feasibly integrated into oncologic care. A number of important clinical questions remain poorly addressed by the existing evidence. CHEST 2013; 143(5)(Suppl):e61S–e77S

Chest. 2013;143(5_suppl):e78S-e92S. doi:10.1378/chest.12-2350

Background:  Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths.

Methods:  A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer.

Results:  Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature.

Conclusions:  Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale.

Chest. 2013;143(5_suppl):e93S-e120S. doi:10.1378/chest.12-2351

Objectives:  The objective of this article is to update previous evidence-based recommendations for evaluation and management of individuals with solid pulmonary nodules and to generate new recommendations for those with nonsolid nodules.

Methods:  We updated prior literature reviews, synthesized evidence, and formulated recommendations by using the methods described in the “Methodology for Development of Guidelines for Lung Cancer” in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed.

Results:  We formulated recommendations for evaluating solid pulmonary nodules that measure > 8 mm in diameter, solid nodules that measure ≤ 8 mm in diameter, and subsolid nodules. The recommendations stress the value of assessing the probability of malignancy, the utility of imaging tests, the need to weigh the benefits and harms of different management strategies (nonsurgical biopsy, surgical resection, and surveillance with chest CT imaging), and the importance of eliciting patient preferences.

Conclusions:  Individuals with pulmonary nodules should be evaluated and managed by estimating the probability of malignancy, performing imaging tests to better characterize the lesions, evaluating the risks associated with various management alternatives, and eliciting their preferences for management.

Chest. 2013;143(5_suppl):e121S-e141S. doi:10.1378/chest.12-2352

Background:  This guideline is intended to provide an evidence-based approach to the initial evaluation of patients with known or suspected lung cancer. It also includes an assessment of the impact of timeliness of care and multidisciplinary teams on outcome.

Methods:  The applicable current medical literature was identified by a computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians. Data sources included MEDLINE and the Cochrane Database of Systematic Reviews.

Results:  Initial evaluation should include a thorough history and physical examination; CT imaging; pulmonary function tests; and hemoglobin, electrolyte, liver function, and calcium levels. Additional testing for distant metastases and paraneoplastic syndromes should be determined on the basis of these results. Paraneoplastic syndromes may have an adverse impact on cancer treatment, so they should be controlled rapidly with the goal of proceeding with definitive cancer treatment in a timely manner. Although the relationship between timeliness of care and survival is difficult to quantify, efforts to deliver timely care are reasonable and should be balanced with the need to attend to other dimensions of health-care quality (eg, safety, effectiveness, efficiency, equality, consistency with patient values and preferences). Quality care will require multiple disciplines. Although it is difficult to assess the impact, we suggest that a multidisciplinary team approach to care be used, particularly for patients requiring multimodality therapy.

Conclusions:  The initial evaluation of patients with lung cancer should include a thorough history and physical examination, pulmonary function tests, CT imaging, basic laboratory tests, and selective testing for distant metastases and paraneoplastic syndromes.

Chest. 2013;143(5_suppl):e142S-e165S. doi:10.1378/chest.12-2353

Background:  Lung cancer is usually suspected in individuals who have an abnormal chest radiograph or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of lung cancer depends on the type of lung cancer (small cell lung cancer or non-small cell lung cancer [NSCLC]), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. The objective of this study was to determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer.

Methods:  To update previous recommendations on techniques available for the initial diagnosis of lung cancer, a systematic search of the MEDLINE, Healthstar, and Cochrane Library databases covering material to July 2011 and print bibliographies was performed to identify studies comparing the results of sputum cytology, conventional bronchoscopy, flexible bronchoscopy (FB), electromagnetic navigation (EMN) bronchoscopy, radial endobronchial ultrasound (R-EBUS)-guided lung biopsy, transthoracic needle aspiration (TTNA) or biopsy, pleural fluid cytology, and pleural biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer. Recommendations were developed by the writing committee, graded by a standardized method (see the article “Methodology for Development of Guidelines for Lung Cancer” in this guideline), and reviewed by all members of the Lung Cancer Guideline Panel prior to approval by the Thoracic Oncology NetWork, the Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians.

Results:  Sputum cytology is an acceptable method of establishing the diagnosis of lung cancer, with a pooled sensitivity rate of 66% and a specificity rate of 99%. However, the sensitivity of sputum cytology varies according to the location of the lung cancer. For central, endobronchial lesions, the overall sensitivity of FB for diagnosing lung cancer is 88%. The diagnostic yield of bronchoscopy decreases for peripheral lesions. Peripheral lesions < 2 or > 2 cm in diameter showed a sensitivity of 34% and 63%, respectively. R-EBUS and EMN are emerging technologies for the diagnosis of peripheral lung cancer, with diagnostic yields of 73% and 71%, respectively. The pooled sensitivity of TTNA for the diagnosis of lung cancer was 90%. A trend toward lower sensitivity was noted for lesions < 2 cm in diameter. TTNA is associated with a higher rate of pneumothorax compared with bronchoscopic procedures. In a patient with a malignant pleural effusion, pleural fluid cytology is reported to have a mean sensitivity of about 72%. A definitive diagnosis of metastatic disease to the pleural space can be estalished with a pleural biopsy. The diagnostic yield for closed pleural biopsy ranges from 38% to 47% and from 75% to 88% for image-guided closed biopsy. Thoracoscopic biopsy of the pleura carries the highest diagnostic yield, 95% to 97%. The accuracy in differentiating between small cell and non-small cell cytology for the various diagnostic modalities was 98%, with individual studies ranging from 94% to 100%. The average false-positive and false-negative rates were 9% and 2%, respectively. Although the distinction between small cell and NSCLC by cytology appears to be accurate, NSCLCs are clinically, pathologically, and molecularly heterogeneous tumors. In the past decade, clinical trials have shown us that NSCLCs respond to different therapeutic agents based on histologic phenotypes and molecular characteristics. The physician performing diagnostic procedures on a patient suspected of having lung cancer must ensure that adequate tissue is acquired to perform accurate histologic and molecular characterization of NSCLCs.

Conclusions:  The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease, but TTNA has a higher rate of pneumothorax than do bronchoscopic modalities. R-EBUS and EMN bronchoscopy show potential for increasing the diagnostic yield of FB for peripheral lung cancers. Thoracoscopic biopsy of the pleura has the highest diagnostic yield for diagnosis of metastatic pleural effusion in a patient with lung cancer. Adequate tissue acquisition for histologic and molecular characterization of NSCLCs is paramount.

Chest. 2013;143(5_suppl):e166S-e190S. doi:10.1378/chest.12-2395

Background:  This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer.

Methods:  The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee.

Results:  The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V˙ O2peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V˙ O2peak > 20 mL/kg/min or 75% predicted indicates a low risk.

Conclusions:  A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.

Chest. 2013;143(5_suppl):e191S-e210S. doi:10.1378/chest.12-2354

The current Lung Cancer Stage Classification system is the seventh edition, which took effect in January 2010. This article reviews the definitions for the TNM descriptors and the stage grouping in this system.

Chest. 2013;143(5_suppl):e211S-e250S. doi:10.1378/chest.12-2355

Background:  Correctly staging lung cancer is important because the treatment options and prognosis differ significantly by stage. Several noninvasive imaging studies and invasive tests are available. Understanding the accuracy, advantages, and disadvantages of the available methods for staging non-small cell lung cancer is critical to decision-making.

Methods:  Test accuracies for the available staging studies were updated from the second iteration of the American College of Chest Physicians Lung Cancer Guidelines. Systematic searches of the MEDLINE database were performed up to June 2012 with the inclusion of selected meta-analyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables.

Results:  The sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were approximately 55% and 81%, respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, estimates of sensitivity and specificity for identifying mediastinal metastasis were approximately 77% and 86%, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning, but tissue biopsy is still required to confirm PET scan findings. The needle techniques endobronchial ultrasound-needle aspiration, endoscopic ultrasound-needle aspiration, and combined endobronchial ultrasound/endoscopic ultrasound-needle aspiration have sensitivities of approximately 89%, 89%, and 91%, respectively. In direct comparison with surgical staging, needle techniques have emerged as the best first diagnostic tools to obtain tissue. Based on randomized controlled trials, PET or PET-CT scanning is recommended for staging and to detect unsuspected metastatic disease and avoid noncurative resections.

Conclusions:  Since the last iteration of the staging guidelines, PET scanning has assumed a more prominent role both in its use prior to surgery and when evaluating for metastatic disease. Minimally invasive needle techniques to stage the mediastinum have become increasingly accepted and are the tests of first choice to confirm mediastinal disease in accessible lymph node stations. If negative, these needle techniques should be followed by surgical biopsy. All abnormal scans should be confirmed by tissue biopsy (by whatever method is available) to ensure accurate staging. Evidence suggests that more complete staging improves patient outcomes.

Chest. 2013;143(5_suppl):e251S-e262S. doi:10.1378/chest.12-2356

Background:  This article provides evidence-based background and recommendations for the development of American College of Chest Physicians guidelines for the diagnosis and management of lung cancer. Specific population, intervention, comparison, and outcome questions were addressed to arrive at consensus recommendations.

Methods:  A systematic search of the medical and scientific literature using MEDLINE and PubMed was performed for the years 1990 to 2011 and limited to literature on humans and articles written in English. Our approach to examining the evidence and formulating recommendations is described in the “Methodology for Lung Cancer Evidence Review and Guideline Development: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2nd Edition)” and updated in “Methodology for Development of Guidelines for Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.”

Results:  Pathologic examination results of lung cancers should be recorded in a synoptic form to include important prognostic features of histologic type, tumor size and location, involvement of visceral pleura, extension to regional and distant lymph nodes, and metastatic spread to visceral organs and bone to increase completeness of recording. It is important for the surgical pathologist to make distinctions between malignant mesothelioma and pleural adenocarcinomas, small cell and non-small cell carcinomas, adenocarcinomas and squamous cell carcinomas, and primary and metastatic carcinomas of the lung. In challenging cases of pathologic differential diagnosis, additional studies may enable the separation of distinct tumor types.

Conclusions:  Pathologic assessment of lung cancers is a crucial component for the diagnosis, management, and prognosis of lung cancer, making the pathologist a critical member of the clinical and management team. Selective diagnostic techniques, including limited designed immunohistochemical panels, and decision analysis will increase diagnostic accuracy.

Chest. 2013;143(5_suppl):e263S-e277S. doi:10.1378/chest.12-2358

Background:  Bronchial intraepithelial lesions may be precursors of central airway lung carcinomas. Identification and early treatment of these preinvasive lesions might prevent progression to invasive carcinoma.

Methods:  We systematically reviewed the literature to develop evidence-based recommendations regarding the diagnosis and treatment of intraepithelial lesions.

Results:  The risk and timeline for progression of bronchial intraepithelial lesions to carcinoma in situ (CIS) or invasive carcinoma are not well understood. Multiple studies show that autofluorescence bronchoscopy (AFB) is more sensitive that white light bronchoscopy (WLB) to identify these lesions. In patients with severe dysplasia or CIS in sputum cytology who have chest imaging studies showing no localizing abnormality, we suggest use of WLB; AFB may be used as an adjunct when available. Patients with known severe dysplasia or CIS of central airways should be followed with WLB or AFB, when available. WLB or AFB is also suggested for patients with early lung cancer who will undergo resection for delineation of tumor margins and assessment of synchronous lesions. However, AFB is not recommended prior to endobronchial therapy for CIS or early central lung cancer. Several endobronchial techniques are recommended for the treatment of patients with superficial limited mucosal lung cancer who are not candidates for resection.

Conclusion:  Additional information is needed about the natural history and rate of progression of preinvasive central airway lesions. Patients with severe dysplasia or CIS may be treated endobronchially; however, it remains unclear if these therapies are associated with improved patient outcomes.

Chest. 2013;143(5_suppl):e278S-e313S. doi:10.1378/chest.12-2359

Background:  The treatment of stage I and II non-small cell lung cancer (NSCLC) in patients with good or low surgical risk is primarily surgical resection. However, this area is undergoing many changes. With a greater prevalence of CT imaging, many lung cancers are being found that are small or constitute primarily ground-glass opacities. Treatment such as sublobar resection and nonsurgical approaches such as stereotactic body radiotherapy (SBRT) are being explored. With the advent of minimally invasive resections, the criteria to classify a patient as too ill to undergo an anatomic lung resection are being redefined.

Methods:  The writing panel selected topics for review based on clinical relevance to treatment of early-stage lung cancer and the amount and quality of data available for analysis and relative controversy on best approaches in stage I and II NSCLC: general surgical care vs specialist care; sublobar vs lobar surgical approaches to stage I lung cancer; video-assisted thoracic surgery vs open resection; mediastinal lymph node sampling vs lymphadenectomy at the time of surgical resection; the use of radiation therapy, with a focus on SBRT, for primary treatment of early-stage NSCLC in high-risk or medically inoperable patients as well as adjuvant radiation therapy in the sublobar and lobar resection settings; adjuvant chemotherapy for early-stage NSCLC; and the impact of ethnicity, geography, and socioeconomic status on lung cancer survival. Recommendations by the writing committee were based on an evidence-based review of the literature and in accordance with the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians.

Results:  Surgical resection remains the primary and preferred approach to the treatment of stage I and II NSCLC. Lobectomy or greater resection remains the preferred approach to T1b and larger tumors. The use of sublobar resection for T1a tumors and the application of adjuvant radiation therapy in this group are being actively studied in large clinical trials. Every patient should have systematic mediastinal lymph node sampling at the time of curative intent surgical resection, and mediastinal lymphadenectomy can be performed without increased morbidity. Perioperative morbidity and mortality are reduced and long-term survival is improved when surgical resection is performed by a board-certified thoracic surgeon. The use of adjuvant chemotherapy for stage II NSCLC is recommended and has shown benefit. The use of adjuvant radiation or chemotherapy for stage I NSCLC is of unproven benefit. Primary radiation therapy remains the primary curative intent approach for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable. There is growing evidence that SBRT provides greater local control than standard radiation therapy for high-risk and medically inoperable patients with NSCLC. The role of ablative therapies in the treatment of high-risk patients with stage I NSCLC is evolving. Radiofrequency ablation, the most studied of the ablative modalities, has been used effectively in medically inoperable patients with small (< 3 cm) peripheral NSCLC that are clinical stage I.

Chest. 2013;143(5_suppl):e314S-e340S. doi:10.1378/chest.12-2360

Objectives:  Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients.

Methods:  Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews.

Results:  For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival.

Conclusions:  Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.

Chest. 2013;143(5_suppl):e341S-e368S. doi:10.1378/chest.12-2361

Background:  Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good.

Methods:  A systematic literature review was performed to update the previous edition of the American College of Chest Physicians Lung Cancer Guidelines.

Results:  The use of pemetrexed should be restricted to patients with nonsquamous histology. Similarly, bevacizumab in combination with chemotherapy (and as continuation maintenance) should be restricted to patients with nonsquamous histology and an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; however, the data now suggest it is safe to use in those patients with treated and controlled brain metastases. Data at this time are insufficient regarding the safety of bevacizumab in patients receiving therapeutic anticoagulation who have an ECOG PS of 2. The role of cetuximab added to chemotherapy remains uncertain and its routine use cannot be recommended. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line therapy are the recommended treatment of those patients identified as having an EGFR mutation. The use of maintenance therapy with either pemetrexed or erlotinib should be considered after four cycles of first-line therapy in those patients without evidence of disease progression. The use of second- and third-line therapy in stage IV NSCLC is recommended in those patients retaining a good PS; however, the benefit of therapy beyond the third-line setting has not been demonstrated. In the elderly and in patients with a poor PS, the use of two-drug, platinum-based regimens is preferred. Palliative care should be initiated early in the course of therapy for stage IV NSCLC.

Conclusions:  Significant advances continue to be made, and the treatment of stage IV NSCLC has become nuanced and specific for particular histologic subtypes and clinical patient characteristics and according to the presence of specific genetic mutations.

Chest. 2013;143(5_suppl):e369S-e399S. doi:10.1378/chest.12-2362

Background:  This guideline updates the second edition and addresses patients with particular forms of non-small cell lung cancer that require special considerations, including Pancoast tumors, T4 N0,1 M0 tumors, additional nodules in the same lobe (T3), ipsilateral different lobe (T4) or contralateral lung (M1a), synchronous and metachronous second primary lung cancers, solitary brain and adrenal metastases, and chest wall involvement.

Methods:  The nature of these special clinical cases is such that in most cases, meta-analyses or large prospective studies of patients are not available. To ensure that these guidelines were supported by the most current data available, publications appropriate to the topics covered in this article were obtained by performing a literature search of the MEDLINE computerized database. Where possible, we also reference other consensus opinion statements. Recommendations were developed by the writing committee, graded by a standardized method, and reviewed by all members of the Lung Cancer Guidelines panel prior to approval by the Thoracic Oncology NetWork, Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians.

Results:  In patients with a Pancoast tumor, a multimodality approach appears to be optimal, involving chemoradiotherapy and surgical resection, provided that appropriate staging has been carried out. Carefully selected patients with central T4 tumors that do not have mediastinal node involvement are uncommon, but surgical resection appears to be beneficial as part of their treatment rather than definitive chemoradiotherapy alone. Patients with lung cancer and an additional malignant nodule are difficult to categorize, and the current stage classification rules are ambiguous. Such patients should be evaluated by an experienced multidisciplinary team to determine whether the additional lesion represents a second primary lung cancer or an additional tumor nodule corresponding to the dominant cancer. Highly selected patients with a solitary focus of metastatic disease in the brain or adrenal gland appear to benefit from resection or stereotactic radiosurgery. This is particularly true in patients with a long disease-free interval. Finally, in patients with chest wall involvement, provided that the tumor can be completely resected and N2 nodal disease is absent, primary surgical resection should be considered.

Conclusions:  Carefully selected patients with more uncommon presentations of lung cancer may benefit from an aggressive surgical approach.

Chest. 2013;143(5_suppl):e400S-e419S. doi:10.1378/chest.12-2363

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.

Chest. 2013;143(5_suppl):e420S-e436S. doi:10.1378/chest.12-2364

Background:  Physicians are often asked about complementary therapies by patients with cancer, and data show that the interest in and use of these therapies among patients with cancer is common. Therefore, it is important to assess the current evidence base on the benefits and risks of complementary therapies (modalities not historically used in modern Western medicine).

Methods:  A systematic literature review was carried out and recommendations were made according to the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines development methodology.

Results:  A large number of randomized controlled trials, systematic reviews, and meta-analyses, as well as a number of prospective cohort studies, met the predetermined inclusion criteria. These trials addressed many different issues pertaining to patients with lung cancer, such as symptoms of anxiety, mood disturbance, pain, quality of life, and treatment-related side effects. The available data cover a variety of interventions, including acupuncture, nutrition, mind-body therapies, exercise, and massage. The body of evidence supports a series of recommendations. An evidenced-based approach to modern cancer care should integrate complementary therapies with standard cancer therapies such as surgery, radiation, chemotherapy, and best supportive care measures.

Conclusions:  Several complementary therapy modalities can be helpful in improving the overall care of patients with lung cancer.

Chest. 2013;143(5_suppl):e437S-e454S. doi:10.1378/chest.12-2365

Background:  These guidelines are an update of the evidence-based recommendations for follow-up and surveillance of patients after curative-intent therapy for lung cancer. Particular updates pertain to whether imaging studies, health-related quality-of-life (HRQOL) measures, tumor markers, and bronchoscopy improve outcomes after curative-intent therapy.

Methods:  Meta-analysis of Observational Studies in Epidemiology guidelines were followed for this systematic review, including published studies on posttreatment outcomes in patients who received curative-intent therapy since the previous American College of Chest Physicians subject review. Four population, intervention, comparison, and outcome questions were formulated to guide the review. The MEDLINE and CINAHL databases were searched from June 1, 2005, to July 8, 2011, to ensure overlap with the search strategies used previously.

Results:  A total of 3,412 citations from MEDLINE and 431 from CINAHL were identified. Only 303 were relevant. Seventy-six of the 303 articles were deemed eligible on the basis of predefined inclusion criteria after full-text review, but only 34 provided data pertaining directly to the subject of the questions formulated to guide this review. In patients undergoing curative-intent surgical resection of non-small cell lung cancer, chest CT imaging performed at designated time intervals after resection is suggested for detecting recurrence. It is recommended that treating physicians who are able to incorporate the patient’s clinical findings into decision-making processes be included in follow-up and surveillance strategies. The use of validated HRQOL instruments at baseline and during follow-up is recommended. Biomarker testing during surveillance outside clinical trials is not suggested. Surveillance bronchoscopy is suggested for patients with early central airway squamous cell carcinoma treated by curative-intent photodynamic therapy and for patients with intraluminal bronchial carcinoid tumor who have undergone curative-intent bronchoscopic treatment with Nd:YAG laser or electrocautery.

Conclusions:  There is a paucity of well-designed prospective studies specifically targeting follow-up and surveillance modalities aimed at improving survival or QOL after curative-intent therapy. Additional research is warranted to clarify which curative-intent treatment modalities affect HRQOL the most and to identify patients who are at the most risk for recurrence or impaired QOL after treatment. Further evidence is needed to determine how the frequency and duration of surveillance programs that include imaging studies, QOL measurements, tumor markers, or bronchoscopy affect patient morbidity, survival, HRQOL, and health-care costs.

Chest. 2013;143(5_suppl):e455S-e497S. doi:10.1378/chest.12-2366

Background:  Many patients with lung cancer will develop symptoms related to their disease process or the treatment they are receiving. These symptoms can be as debilitating as the disease progression itself. To many physicians these problems can be the most difficult to manage.

Methods:  A detailed review of the literature using strict methodologic review of article quality was used in the development of this article. MEDLINE literature reviews, in addition to Cochrane reviews and other databases, were used for this review. The resulting article lists were then reviewed by experts in each area for quality and finally interpreted for content.

Results:  We have developed recommendations for the management of many of the symptom complexes that patients with lung cancer may experience: pain, dyspnea, airway obstruction, cough, bone metastasis, brain metastasis, spinal cord metastasis, superior vena cava syndrome, hemoptysis, tracheoesophageal fistula, pleural effusions, venous thromboembolic disease, depression, fatigue, anorexia, and insomnia. Some areas, such as dyspnea, are covered in considerable detail in previously created high-quality evidence-based guidelines and are identified as excellent sources of reference. The goal of this guideline is to provide the reader recommendations based on evidence supported by scientific study.

Conclusions:  Improved understanding and recognition of cancer-related symptoms can improve management strategies, patient compliance, and quality of life for all patients with lung cancer.

Chest. 2013;143(5_suppl):e498S-e512S. doi:10.1378/chest.12-2367

Background:  In the United States, lung cancer is a major health problem that is associated with significant patient distress and often limited survival, with some exceptions. The purpose of this article is to address the role of palliative and end-of-life care in the management of patients with lung cancer and to address the need for good communication skills to provide support to patients and families.

Methods:  This article is based on an extensive review of the medical literature up to April 2012, with some articles as recent as August 2012. The authors used the PubMed and Cochrane databases, as well as EBESCO Host search, for articles addressing palliative care, supportive care, lung neoplasm, and quality of life in cancer or neoplasm, with no limitation on dates. The research was limited to human studies and the English language.

Results:  There was no “definitive” work in this area, most of it being concurrence based rather than evidence based. Several randomized controlled trials were identified, which are reviewed in the text. The article focuses on the assessment and treatment of suffering in patients with lung cancer, as well as the importance of communication in the care of these patients over the course of the disease. The aim of medical care for patients with terminal lung cancer is to decrease symptom burden, enhance the quality of remaining life, and increase survival benefit. A second objective is to emphasize the importance of good communication skills when addressing the needs of the patient and his or her family, starting at the time of diagnosis, which in itself is a life-changing event. Too often we do it poorly, but by using patient-centered communication skills, the outcome can be more satisfactory. Finally, the article addresses the importance of advance care planning for patients with lung cancer, from the time of diagnosis until the last phase of the illness, and it is designed to enhance the physician’s role in facilitating this planning process.

Conclusions:  This article provides guidance on how to reduce patient distress and avoid nonbeneficial treatment in patients with lung cancer. The goal is to decrease symptom burden, enhance quality of life, and increase survival benefit. Good communication and advance care planning are vital to the process.

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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543