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Diagnosis and Management of Lung Cancer: ACCP Guidelines (2nd Edition)

Diagnosis and Management of Lung Cancer Executive Summary*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):1S-19S. doi:10.1378/chest.07-1860
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In the 19th century, lung cancer was an unusual tumor; so much so that single case reports of the rare cancer were published in the scientific literature of the day. Things have changed. Other than skin cancer, lung cancer is now the most common cancer and is the most frequent cause of death from cancer in both men and women.

Chest. 2007;132(3_suppl):20S-22S. doi:10.1378/chest.07-1345
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To reprise but paraphrase the opening line of the Introduction to the First Edition of the Guidelines: The numbers are still staggering. It is projected that in 2007, cancer of the lung will be diagnosed in 213,380 individuals in the United States (up from 169,400 in 2002; 114,760 men and 98,620 women).1 More disconcerting is that 160,390 individuals (up from 154,900 in 2002) will succumb to this disease (89,510 men and 70,880 women) during the year.1 Interestingly, however, the death rate (as opposed to raw numbers) for lung cancer in men has dropped on average by 1.9%/yr from 1991 to 2003. Unfortunately, the death rate in women is up by 0.3% each year from 1995 to 2003. If these current trends continue, the incidence of lung cancer will be identical for men and women during the next decade.

Methodology for Lung Cancer Evidence Review and Guideline Development*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):23S-28S. doi:10.1378/chest.07-1346
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Background: To assemble a geographically diverse panel of experts in the diagnosis and treatment of lung cancer, representative of multiple clinical specialties, with the intention of developing clinically relevant practice guidelines for chest medicine and primary care physicians, including recommendations covering the full spectrum of care of the patient with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Methods: The Duke University Center for Clinical Health Policy Research was selected to review and summarize the current evidence in the treatment of NSCLC. The BlueCross BlueShield Association Technology Evaluation Center was chosen and funded by the Agency for Healthcare Research and Quality to review and synthesize the current evidence on treatment of SCLC. Other chapters received existing guidelines, systematic reviews, and metaanalyses that were published since the first edition of these guidelines, as collected by the Duke University Evidence-based Practice Center. The writing committees for these chapters conducted searches for the primary articles and additional evidence in their topic area. The expert panel established clinical recommendations founded on the synthesis of this evidence.

Conclusions: This section describes the approach used to develop the guidelines, including identifying, evaluating, and synthesizing the evidence, assessing the strength of evidence and grading the individual recommendations, and suggestions for implementation of the guidelines.

Epidemiology of Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):29S-55S. doi:10.1378/chest.07-1347
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Background: The objective of this study was to summarize the published literature concerning the epidemiology of lung cancer.

Methods: A narrative review of published evidence was conducted, identifying and summarizing key reports that describe the occurrence of lung cancer in populations and factors that affect lung cancer risk.

Results: In the United States, lung cancer remains the leading cause of cancer death in both men and women, even though an extensive list of modifiable risk factors has long been identified. The predominant cause of lung cancer is exposure to tobacco smoke, with active smoking causing most cases but passive smoking also contributing to the lung cancer burden.

Conclusions: The reductions in smoking prevalence in men that occurred in the late 1960s through the 1980s will continue to drive lung cancer mortality rates downward in men during the first portion of this century, but rates in women have not yet begun to decrease. Fortunately, exposures to major occupational respiratory carcinogens have largely been controlled, but the population is still exposed to environmental causes of lung cancer, including radon, the second leading cause of lung cancer death.

Lung Cancer Chemoprevention*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):56S-68S. doi:10.1378/chest.07-1348
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Background: Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk for lung cancer compared with lifetime never-smokers. Chemoprevention is 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 III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. For facilitating the evaluation of promising agents and for lessening the need for a large sample size, extensive time commitment, and expense, focus is now turning toward the assessment of surrogate end point biomarkers for lung carcinogenesis. With the understanding of important cellular signaling pathways, various inhibitors that may prevent or reverse lung carcinogenesis are being developed.

Conclusions: By integrating biological knowledge, more 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.

Screening for Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):69S-77S. doi:10.1378/chest.07-1349
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Background: Lung cancer typically exhibits symptoms only after the disease has spread, making cure unlikely. Because early-stage disease can be successfully treated, a screening technique that can detect lung cancer before it has spread might be useful in decreasing lung cancer mortality.

Objectives: In this article, we review the evidence for and against screening for lung cancer with low-dose CT and offer recommendations regarding its usefulness for asymptomatic patients with no history of cancer.

Results: Studies of lung cancer screening with chest radiograph and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates. Published studies of newer screening technologies such as low-dose CT and “biomarker” screening report primarily on lung cancer detection rates and do not present sufficient data to determine whether the newer technologies will benefit or harm. Although researchers are conducting randomized trials of low-dose CT, results will not be available for several years. In the meantime, cost-effectiveness analyses and studies of nodule growth are considering practical questions but producing inconsistent findings.

Conclusions: For high-risk populations, no screening modality has been shown to alter mortality outcomes. We recommend that individuals undergo screening only when it is administered as a component of a well-designed clinical trial with appropriate human subjects’ protections.

Diagnostic Surgical Pathology in Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):78S-93S. doi:10.1378/chest.07-1350
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Objective: The objective of this study was to provide evidence-based background and recommendations for the development of American College of Chest Physicians guidelines for the diagnosis and management of lung cancer.

Methods: A systematic search of the medical and scientific literature using MEDLINE, MDCONSULT, UpToDate, Cochrane Library, NCCN guidelines, and NCI/NIH search engines was performed for the years 1990 to 2006 to identify evidence-based and consensus guidelines. The search was limited to literature on humans and articles in the English language.

Results: The pathologic assessment of lung cancers is based on a set of well-accepted findings, including histologic type, tumor size and location, involvement of visceral pleura, and extension to regional and distant lymph nodes and organs. Bronchial-based incipient neoplasia needs to be recognized both grossly and microscopically because these lesions may be multifocal and represent multistep carcinogenesis and may be amenable to therapy. Cytologic assessment of the individual with no symptoms is, as yet, of insufficient clinical benefit for screening of lung cancer. In challenging situations of pathologic differential diagnosis, additional studies may provide information that enables the separation of distinct tumor types. Pathobiological and molecular biological studies may yield prognostic and predictive information for clinical management and should be considered as part of protocol studies. Enhanced pathologic and molecular techniques may identify the presence of micrometastatic disease within lymph nodes; however, the clinical utility of these approaches is still unresolved. Intraoperative consultations have high diagnostic accuracy and may aid ongoing treatment and management decisions.

Conclusions: Pathologic assessment is a crucial component for the diagnosis, management, and prognosis of lung cancer. Selective diagnostic techniques and decision analysis will increase diagnostic accuracy. Cytologic screening, molecular characterization of tumors, and micrometastatic analysis are potential but not yet proved modalities for the evaluation of lung cancers.

Evidence for the Treatment of Patients With Pulmonary Nodules: When Is It Lung Cancer?*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):94S-107S. doi:10.1378/chest.07-1352
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Background: The solitary pulmonary nodule (SPN) is a frequent incidental finding that may represent primary lung cancer or other malignant or benign lesions. The optimal management of the SPN remains unclear.

Methods: We conducted a systematic literature review to address the following questions: (1) the prevalence of SPN; (2) the prevalence of malignancy in nodules with varying characteristics (size, morphology, and type of opacity); (3) the relationships between growth rates, histology, and other nodule characteristics; and (4) the performance characteristics and complication rates of tests for SPN diagnosis. We searched MEDLINE and other databases and used previous systematic reviews and recent primary studies.

Results: Eight large trials of lung cancer screening showed that both the prevalence of at least one nodule (8 to 51%) and the prevalence of malignancy in patients with nodules (1.1 to 12%) varied considerably across studies. The prevalence of malignancy varied by size (0 to 1% for nodules < 5 mm, 6 to 28% for nodules 5 to 10 mm, and 64 to 82% for nodules > 20 mm). Data from six studies of patients with incidental or screening-detected nodules showed that the risk for malignancy was approximately 20 to 30% in nodules with smooth edges; in nodules with irregular, lobulated, or spiculated borders, the rate of malignancy was higher but varied across studies from 33 to 100%. Nodules that were pure ground-glass opacities were more likely to be malignant (59 to 73%) than solid nodules (7 to 9%). The sensitivity of positron emission tomography imaging for identifying a malignant SPN was consistently high (80 to 100%), whereas specificity was lower and more variable across studies (40 to 100%). Dynamic CT with nodule enhancement yielded the most promising sensitivity (sensitivity, 98 to 100%; specificity, 54 to 93%) among imaging tests. In studies of CT-guided needle biopsy, nondiagnostic results were seen approximately 20% of the time, but sensitivity and specificity were excellent when biopsy yielded a specific benign or malignant result.

Conclusions: The prevalence of an SPN and the prevalence of malignancy in patients with an SPN vary widely across studies. The interpretation of these variable prevalence rates should take into consideration not only the nodule characteristics but also the population at risk. Modern imaging tests and CT-guided needle biopsy are highly sensitive for identifying a malignant SPN, but the specificity of imaging tests is variable and often poor.

Evaluation of Patients With Pulmonary Nodules: When Is It Lung Cancer?*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):108S-130S. doi:10.1378/chest.07-1353
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Background: Pulmonary nodules are spherical radiographic opacities that measure up to 30 mm in diameter. Nodules are extremely common in clinical practice and challenging to manage, especially small, “subcentimeter” nodules. Identification of malignant nodules is important because they represent a potentially curable form of lung cancer.

Methods: We developed evidence-based clinical practice guidelines based on a systematic literature review and discussion with a large, multidisciplinary group of clinical experts and other stakeholders.

Results: We generated a list of 29 recommendations for managing the solitary pulmonary nodule (SPN) that measures at least 8 to 10 mm in diameter; small, subcentimeter nodules that measure < 8 mm to 10 mm in diameter; and multiple nodules when they are detected incidentally during evaluation of the SPN. Recommendations stress the value of risk factor assessment, the utility of imaging tests (especially old films), the need to weigh the risks and benefits of various management strategies (biopsy, surgery, and observation with serial imaging tests), and the importance of eliciting patient preferences.

Conclusion: Patients with pulmonary nodules should be evaluated by estimation of the probability of malignancy, performance of imaging tests to characterize the lesion(s) better, evaluation of the risks associated with various management alternatives, and elicitation of patient preferences for treatment.

Initial Diagnosis of Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):131S-148S. doi:10.1378/chest.07-1357
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Background: Lung cancer is usually suspected in individuals who have an abnormal chest radiograph finding or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of suspected lung cancer depends on the type of lung cancer (ie, small cell lung cancer [SCLC] or non-SCLC [NSCLC]), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient.

Objectives: To determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer.

Methods: To update previous recommendations on the initial diagnosis of lung cancer, a systematic search of MEDLINE, Healthstar, and Cochrane Library databases to July 2004, and print bibliographies was performed to identify studies comparing the results of sputum cytology, bronchoscopy, transthoracic needle aspiration (TTNA), or 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, and reviewed by all members of the lung cancer panel prior to approval by the Thoracic Oncology Network, Health and Science Policy Committee, and the Board of Regents of the American College of Chest Physician.

Results: Sputum cytology is an acceptable method of establishing the diagnosis of lung cancer with a pooled sensitivity rate of 0.66 and specificity rate of 0.99. However, the sensitivity of sputum cytology varies by location of the lung cancer. For central, endobronchial lesions, the overall sensitivity of flexible bronchoscopy (FB) for diagnosing lung cancer is 0.88. The diagnostic yield of bronchoscopy decreases for peripheral lesions. Peripheral lesions smaller or larger than 2 cm in diameter showed a sensitivity of 0.34 and 0.63, respectively. In recent years, endobronchial ultrasound (EBUS) has shown potential in increasing the diagnostic yield of FB while dealing with peripheral lesions without adding to the risk of the procedure. In appropriate situations, its use can be considered before moving on to more invasive tests. The pooled sensitivity for TTNA for the diagnosis of lung cancer is 0.90. A trend toward lower sensitivity was noted for lesions < 2 cm in diameter. The accuracy in differentiating between SCLC and NSCLC cytology for the various diagnostic modalities was 0.98, with individual studies ranging from 0.94 to 1.0. The average false-positive rate and FN rate were 0.09 and 0.02, respectively.

Conclusions: The sensitivity of bronchoscopy is high for the detection of endobronchial disease and poor for peripheral lesions < 2 cm in diameter. Detection of the latter can be aided with the use of EBUS in the appropriate clinical setting. The sensitivity of TTNA is excellent for malignant disease. The distinction between SCLC and NSCLC by cytology appears to be accurate.

Chest. 2007;132(3_suppl):149S-160S. doi:10.1378/chest.07-1358
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Background: This chapter of the guidelines is intended to provide an evidence-based assessment of the initial evaluation of patients recognized as having lung cancer and the recognition of paraneoplastic syndromes.

Methods: The current medical literature that is applicable to this issue was identified by a computerized search and was evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee of the American College of Chest Physicians.

Results: Patients with lung cancer usually present with multiple symptoms, both respiratory related and constitutional. There is usually a time delay between symptom recognition by the patient and the ultimate diagnosis of lung cancer by the physician. Whether this time delay impacts prognosis is unclear, but delivering timely and efficient care is an important component in its own right. Lung cancer may be accompanied by a variety of paraneoplastic syndromes. These syndromes may not necessarily preclude treatment with a curative intent.

Conclusions: The initial evaluation of the patient with known or suspected lung cancer should include an assessment of symptoms, signs, and laboratory test results in a standardized manner as a screen for identifying those patients with paraneoplastic syndromes and a higher likelihood of metastatic disease.

Physiologic Evaluation of the Patient With Lung Cancer Being Considered for Resectional Surgery*: ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):161S-177S. doi:10.1378/chest.07-1359
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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: Current guidelines and medical literature applicable to this issue were identified by computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee.

Results: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1. If diffuse parenchymal lung disease is evident on radiographic studies or if there is dyspnea on exertion that is clinically out of proportion to the FEV1, the diffusing capacity of the lung for carbon monoxide (Dlco) should also be measured. In patients with either an FEV1 or Dlco < 80% predicted, the likely postoperative pulmonary reserve should be estimated by either the perfusion scan method for pneumonectomy or the anatomic method, based on counting the number of segments to be removed, for lobectomy. An estimated postoperative FEV1 or Dlco < 40% predicted indicates an increased risk for perioperative complications, including death, from a standard lung cancer resection (lobectomy or greater removal of lung tissue). Cardiopulmonary exercise testing (CPET) to measure maximal oxygen consumption (V̇o2max) should be performed to further define the perioperative risk of surgery; a V̇o2max of < 15 mL/kg/min indicates an increased risk of perioperative complications. Alternative types of exercise testing, such as stair climbing, the shuttle walk, and the 6-min walk, should be considered if CPET is not available. Although often not performed in a standardized manner, patients who cannot climb one flight of stairs are expected to have a V̇o2max of < 10 mL/kg/min. Data on the shuttle walk and 6-min walk are limited, but patients who cannot complete 25 shuttles on two occasions will likely have a V̇o2max of < 10 mL/kg/min. Desaturation during an exercise test has not clearly been associated with an increased risk for perioperative complications. Lung volume reduction surgery (LVRS) improves survival in selected patients with severe emphysema. Accumulating experience suggests that patients with extremely poor lung function who are deemed inoperable by conventional criteria might tolerate combined LVRS and curative-intent resection of lung cancer with an acceptable mortality rate and good postoperative outcomes. Combining LVRS and lung cancer resection should be considered in patients with a cancer in an area of upper lobe emphysema, an FEV1 of > 20% predicted, and a Dlco of > 20% predicted.

Conclusions: A careful preoperative physiologic assessment will be useful to identify those patients who are at increased risk with standard lung cancer resection and to enable an informed decision by the patient about the appropriate therapeutic approach to treating their 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 for this disease.

Noninvasive Staging of Non-small Cell Lung Cancer*: ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):178S-201S. doi:10.1378/chest.07-1360
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Background: Correctly staging lung cancer is important because the treatment options and the prognosis differ significantly by stage. Several noninvasive imaging studies including chest CT scanning and positron emission tomography (PET) scanning are available. Understanding the test characteristics of these noninvasive staging studies is critical to decision making.

Methods: Test characteristics for the noninvasive staging studies were updated from the first iteration of the lung cancer guidelines using systematic searches of the MEDLINE, HealthStar, and Cochrane Library databases up to May 2006, including selected metaanalyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables.

Results: The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% confidence interval [CI], 47 to 54%) and 85% (95% CI, 84 to 88%), respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, the pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69 to 79%) and 85% (95% CI, 82 to 88%), respectively. These findings demonstrate that PET scanning is more accurate than CT scanning. If the clinical evaluation in search of metastatic disease is negative, the likelihood of finding metastasis is low.

Conclusions: CT scanning of the chest is useful in providing anatomic detail, but the accuracy of chest CT scanning in differentiating benign from malignant lymph nodes in the mediastinum is poor. PET scanning has much better sensitivity and specificity than chest CT scanning for staging lung cancer in the mediastinum, and distant metastatic disease can be detected by PET scanning. With either test, abnormal findings must be confirmed by tissue biopsy to ensure accurate staging.

Invasive Mediastinal Staging of Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):202S-220S. doi:10.1378/chest.07-1362
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Background: The treatment of non-small cell lung cancer (NSCLC) is determined by accurate definition of the stage. If there are no distant metastases, the status of the mediastinal lymph nodes is critical. Although imaging studies can provide some guidance, in many situations invasive staging is necessary. Many different complementary techniques are available.

Methods: The current guidelines and medical literature that are applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee of the American College of Chest Physicians.

Results: Performance characteristics of invasive staging interventions are defined. However, a direct comparison of these results is not warranted because the patients selected for these procedures have been different. It is crucial to define patient groups, and to define the need for an invasive test and selection of the best test based on this.

Conclusions: In patients with extensive mediastinal infiltration, invasive staging is not needed. In patients with discrete node enlargement, staging by CT or positron emission tomography (PET) scanning is not sufficiently accurate. The sensitivity of various techniques is similar in this setting, although the false-negative (FN) rate of needle techniques is higher than that for mediastinoscopy. In patients with a stage II or a central tumor, invasive staging of the mediastinal nodes is necessary. Mediastinoscopy is generally preferable because of the higher FN rates of needle techniques in the setting of normal-sized lymph nodes. Patients with a peripheral clinical stage I NSCLC do not usually need invasive confirmation of mediastinal nodes unless a PET scan finding is positive in the nodes. The staging of patients with left upper lobe tumors should include an assessment of the aortopulmonary window lymph nodes.

Bronchial Intraepithelial Neoplasia/Early Central Airways Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):221S-233S. doi:10.1378/chest.07-1377
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Background: An evidence-based approach is necessary for the localization and management of intraepithelial and microinvasive non-small cell lung cancer in the central airways.

Methods: Material appropriate to this topic was obtained by literature search of a computerized database. Recommendations were developed by the writing committee and then reviewed by the entire guidelines panel. The final recommendations were made by the Chair and were voted on by the entire committee.

Results: White light bronchoscopy has diagnostic limitations in the detection of microinvasive lesions. Autofluorescence bronchoscopy (AFB) is a technique that has been shown to be a sensitive method for detecting these lesions. In patients with moderate dysplasia or worse on sputum cytology and normal chest radiographic findings, bronchoscopy should be performed. If moderate/severe dysplasia or carcinoma in situ (CIS) is detected in the central airways, then bronchoscopic surveillance is recommended. The use of AFB is preferred if available. In a patient being considered for curative endobronchial therapy to treat microinvasive lesions, AFB is useful. A number of endobronchial techniques as therapeutic options are available for the management of CIS and can be recommended to patients with inoperable disease. In patients with operable disease, surgery remains the mainstay of treatment, although patients may be counseled about these techniques.

Conclusions: AFB is a useful tool for the localization of microinvasive neoplasia. A number of endobronchial techniques available for the curative treatment can be considered first-line therapy in inoperable cases. For operable cases, the techniques may be considered and discussed with the patients.

Treatment of Non-small Cell Lung Cancer Stage I and Stage II*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):234S-242S. doi:10.1378/chest.07-1378
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Background: The surgical treatment of stage I and II non-small cell lung cancer (NSCLC) continues to evolve in the areas of intraoperative lymph node staging (specifically the issue of lymph node dissection vs sampling), the role of sublobar resections instead of lobectomy for treatment of smaller tumors, and the use of video-assisted techniques to perform anatomic lobectomy. Adjuvant therapy (both chemotherapy and radiation therapy) and the use of larger fractions of radiotherapy delivered to a smaller area for nonoperative treatment of early stage NSCLC have shown promising results.

Methods: The panel selected the following areas for review based on clinical relevance and the amount and quality of data available for analysis: surgical approaches to resecting early stage NSCLC, methods of lymph node staging at the time of surgical resection, adjuvant chemotherapy in the treatment of early stage NSCLC, and the use of radiation therapy for primary treatment of early stage NSCLC as well as in the adjuvant setting. Recommendations by the multidisciplinary writing committee were based on literature review using established methods.

Results and conclusions: Surgical resection remains the treatment of choice for stage I and II NSCLC, although surgical methods continue to evolve. Adjuvant chemotherapy for patients with stage II, but not stage I, NSCLC is well established. Radiotherapy remains an important treatment for either cases of early stage NSCLC that are medically inoperable or patients who refuse surgery.

Treatment of Non-small Cell Lung Cancer-Stage IIIA*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):243S-265S. doi:10.1378/chest.07-1379
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Study objectives: Stage IIIA non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. This review explores the published clinical trials to make treatment recommendations in this controversial subset of lung cancer.

Design, setting, and participants: Systematic searches were made of MEDLINE, HealthStar, and Cochrane Library databases up to May 2006, focusing primarily on randomized trials, with inclusion of selected metaanalyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables.

Measurement and results: The evidence derived from the literature now appears to support routine adjuvant chemotherapy after complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. However, using neoadjuvant therapy followed by surgery for known stage IIIA lung cancer as a routine therapeutic option is not supported by current published randomized trials. Combination chemoradiotherapy, especially delivered concurrently, is still the preferred treatment for prospectively recognized stage IIIA lung cancer with all degrees of mediastinal lymph node involvement. Current and future trials may modify these recommendations.

Conclusions: Multimodality therapy of some type appears to be preferable in all subsets of stage IIIA patients. However, because of the relative lack of consistent randomized trial data in this subset, the following evidence-based treatment guidelines lack compelling evidence in most scenarios.

Treatment of Non-small Cell Lung Cancer, Stage IIIB*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):266S-276S. doi:10.1378/chest.07-1380
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Objective: To develop evidence-based guidelines on best available treatment options for patients with stage IIIB non-small cell lung cancer (NSCLC).

Methods: A review was conducted of published English-language (abstract or full text) phase II or phase III trials and guidelines from other organizations that address management of the various categories of stage IIIB disease. The literature search was provided by the Duke University Center for Clinical Health Policy Research and supplemented by any additional studies known by the authors.

Results: Surgery may be indicated for carefully selected patients with T4N0-1M0. Patients with N3 nodal involvement are not considered to be surgical candidates. For individuals with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy (RT) alone. Concurrent chemoradiotherapy seems to be associated with improved survival compared with sequential chemoradiotherapy. Multiple daily fractions of RT when combined with chemotherapy have not been shown to result in improved survival compared with standard once-daily RT combined with chemotherapy. The optimal chemotherapy agents and the number of cycles of treatment to combine with RT are uncertain.

Conclusion: Prospective trials are needed to answer important questions, such as the role of induction therapy in patients with potentially resectable stage IIIB disease. Future trials are needed to answer the questions of optimal chemotherapy agents and radiation fractionation schedule. The role of targeted novel agents in combination with chemoradiotherapy is just starting to be investigated.

Treatment of Non-small Cell Lung Cancer, Stage IV*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):277S-289S. doi:10.1378/chest.07-1381
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Background: Stage IV non-small cell lung cancer (NSCLC) remains a treatable but incurable disease.

Methods: A MEDLINE search was performed to identify pertinent peer-reviewed articles that addressed the questions posed for this section. The writing committee developed and graded recommendations, which were subsequently approved by the American College of Chest Physicians.

Results: Platinum-based doublets remain the standard of care in patients with good performance status (PS); there is no evidence that the addition of a third cytotoxic agent improves survival. Likewise, with only one exception, the addition of a new targeted or biological agent to platinum-based doublets does not improve survival. The one exception is the addition of bevacizumab, an antiangiogenic agent, to carboplatin/paclitaxel in patients with stage IV disease and good PS. Patients for whom bevacizumab is recommended must also be selected on the basis of histology (nonsquamous), absence of brain metastases and hemoptysis, and no indication for therapeutic anticoagulation. In patients with stage IV NSCLC and PS of 2, chemotherapy is recommended, but the optimal approach has not been defined. Elderly patients, defined as ≥ 70 years old, also derive benefit from chemotherapy. Most elderly patients should receive single-agent chemotherapy, but elderly patients with good PS and without significant comorbidities seem to derive a similar benefit from platinum-based doublets compared with their younger counterparts without a prohibitive difference in treatment toxicities. Because stage IV NSCLC is incurable, quality-of-life issues are important, and tools exist to monitor a patient’s quality of life during therapy. Last, patients need to be informed of the implication of the diagnosis of stage IV NSCLC and be educated about treatment options that are available to them.

Conclusions: Advances have been made in stage IV NSCLC, and the appropriate use of chemotherapy continues to evolve on the basis of well-designed clinical trials that address critical issues in this population.

Special Treatment Issues in Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):290S-305S. doi:10.1378/chest.07-1382
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Background: This chapter of the guidelines addresses patients who have particular forms of non-small cell lung cancer that require special considerations. This includes patients with Pancoast tumors, T4N0,1M0 tumors, satellite nodules in the same lobe, synchronous and metachronous multiple primary lung cancers (MPLCs), solitary brain and adrenal metastases, and chest wall involvement.

Methods: The nature of these special clinical cases is such that in most cases, metaanalyses or large prospective studies of patients are not available. For ensuring that these guidelines were supported by the most current data available, publications that were appropriate to the topics covered in this chapter were obtained by performance of a literature search of the MEDLINE computerized database. When possible, we also referenced other consensus opinion statements. Recommendations were developed by the writing committee, graded by a standardized method (see “Methodology for Lung Cancer Evidence Review and Guideline Development” chapter), and reviewed by all members of the lung cancer panel before approval by the Thoracic Oncology NetWork, Health and Science Policy Committee, and the Board of Regents of the American College of Chest Physicians.

Results: In patients with a Pancoast tumor, a multimodality approach seems to be optimal, involving chemoradiotherapy and surgical resection, provided appropriate staging has been conducted. Patients with central T4 tumors that do not have mediastinal node involvement are uncommon. Such patients, however, seem to benefit from resection as part of the treatment as opposed to chemoradiotherapy alone when carefully staged and selected. Patients with a satellite lesion in the same lobe as the primary tumor have a good prognosis and require no modification of the approach to evaluation and treatment than what would be dictated by the primary tumor alone. However, it is difficult to know how best to treat patients with a focus of the same type of cancer in a different lobe. Although MPLCs do occur, the survival results after resection for either a synchronous presentation or a metachronous presentation with an interval of < 4 years between tumors are variable and generally poor, suggesting that many of these patients may have had a pulmonary metastasis rather than a second primary lung cancer. A thorough and careful evaluation of these patients is warranted to try to differentiate between patients with a metastasis and a second primary lung cancer, although criteria to distinguish them have not been defined. Selected patients with a solitary focus of metastatic disease in the brain or adrenal gland seem to benefit substantially from resection. This is particularly true in patients with a long disease-free interval. Finally, in patients with chest wall involvement, as long as tumors can be completely resected and there is absence of N2 nodal involvement, primary surgical treatment should be considered.

Conclusions: Carefully selected patients may benefit from an aggressive surgical approach.

Bronchioloalveolar Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):306S-313S. doi:10.1378/chest.07-1383
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Objectives: To review the current evidence on special issues relating to the diagnosis, imaging, prognosis, and treatment of bronchioloalveolar carcinoma (BAC).

Methods: This guideline focuses on aspects of BAC that are unique and ways in which BAC differs importantly from other forms of non-small cell lung cancer (NSCLC). The author reviewed published literature reporting on BAC using key words “histology,” “CT scans,” “fluorodeoxyglucose positron emission tomography scan,” “sensitivity,” “specificity,” “surgical resection,” “sublobar resection,” and “epidermal growth factor receptor tyrosine kinase inhibitor” and selected references from published review articles. Also included was a review of the 1999 World Health Organization (WHO) revised classification system for lung tumors, which established a more restrictive definition of BAC to tumors with a pure lepidic spreading pattern and no evidence of stromal, vascular, or pleural invasion.

Results: With the notable exception of a lower likelihood of a positive positron emission tomography finding in the presence of BAC, staging, diagnosis, and treatment are the same as for other histologic subtypes of NSCLC, but additional treatment options that may prove to be equivalent, if not more effective, for more patients exist (eg, epidermal growth factor receptor tyrosine kinase inhibitor therapy, sublobar resection).

Conclusions: BAC is a form of adenocarcinoma with unique clinical, radiologic, and epidemiologic features. The diagnosis of BAC should be reserved for tumors that meet the WHO criteria. Additional clinical trials are needed on this population of patients, using strict definitions and enrollment criteria to allow the results to be applied to appropriate patient populations.

Evidence for Management of Small Cell Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):314S-323S. doi:10.1378/chest.07-1384
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Purpose: This systematic review addressed the following key questions on managing small cell lung cancer (SCLC): the sequence, timing, and dosing characteristics of primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensive-stage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography (PET) for staging; treatment of mixed histology tumors; surgery; and second-line and subsequent-line treatment for relapsed/progressive disease.

Methods: The review methods were defined prospectively in a written protocol. We primarily sought randomized controlled trials that compared the interventions of interest.

Results: Robust evidence was lacking for all questions except PCI, for which a patient-level metaanalysis showed that PCI improves survival of SCLC patients who achieved complete response after primary therapy from 15.3 to 20.7% (p = 0.01). The case for concurrent over sequential radiation delivery rests largely on a single multicenter trial. Support for early concurrent therapy comes from one multicenter trial, but two other multicenter trials found no advantage. Metaanalysis did not find significant reductions in 2-year and 3-year mortality rates for early TRTx. Favorable results from a single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. Relevant comparative studies were nonexistent for management of mixed histology disease and surgery for early limited SCLC. PET may be more sensitive in detecting extracranial disease than conventional staging modalities, but studies were of poor quality.

Conclusions: PCI improves survival among those with a complete remission to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components.

Management of Small Cell Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):324S-339S. doi:10.1378/chest.07-1385
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Purpose: This guideline is for the management of patients with small cell lung cancer (SCLC) and is based on currently available information. As part of the guideline, an evidence-based review of the literature was commissioned that enables the reader to assess the evidence as we have attempted to put the clinical implications into perspective.

Methods: We conducted a comprehensive review of the available literature and the previous American College of Chest Physicians guidelines of SCLC. Controversial and less understood areas of the management of SCLC were then subject to an exhaustive review of the literature and detail analyses. Experts in evidence-based analyses compiled the accompanying systematic review titled “Evidence for Management of SCLC.” The evidence was then assessed by a panel of experts to incorporate “clinical relevance.” The resultant guidelines were then scored according to the grading system outlined by the American College of Chest Physicians grading system task force.

Results: SCLC accounts for 13 to 20% of all lung cancers. Highly smoking related and initially responsive to treatment, it leads to death rapidly in 2 to 4 months without treatment. SCLC is staged as limited-stage and extensive-stage disease. Limited-stage disease is treated with curative intent with chemotherapy and radiation therapy, with approximately 20% of patients achieving a cure. For all patients with limited-stage disease, median survival is 16 to 22 months. Extensive-stage disease is primarily treated with chemotherapy with a high initial response rate of 60 to 70% but with a median survival of 10 months. All patients achieving a complete remission should be offered prophylactic cranial irradiation. Relapsed or refractory SCLC has a uniformly poor prognosis.

Conclusion: In this section, evidence-based guidelines for the staging and treatment of SCLC are outlined. Limited-stage SCLC is treated with curative intent. Extensive-stage SCLC has high initial responses to chemotherapy but with an ultimately dismal prognosis with few survivors beyond 2 years.

Complementary Therapies and Integrative Oncology in Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):340S-354S. doi:10.1378/chest.07-1389
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Background: This chapter aims to differentiate between “alternative” therapies, often promoted falsely as viable options to mainstream lung cancer treatment, and complementary therapies, adjunctive, effective techniques that treat symptoms associated with cancer and its mainstream treatment, and to describe the evidence base for use of complementary therapies.

Methods and design: A multidisciplinary panel of experts in oncology and integrative medicine evaluated the evidence for complementary (not alternative) therapies in the care of patients with lung cancer. Because few complementary modalities are geared to patients with only a single cancer diagnosis, symptom-control research conducted with other groups of patients with cancer was also included. Data on complementary therapies such as acupuncture, massage therapy, mind-body therapies, herbs and other botanicals, and exercise were evaluated. Recommendations were based on the strength of evidence and the risk-to-benefit ratio.

Results: Patients with lung and other poor-outlook cancers are particularly vulnerable to heavily promoted claims for unproved or disproved “alternatives.” Inquiring about patients’ use of these therapies should be routine because these practices may be harmful and can delay or impair treatment. Mind-body modalities and massage therapy can reduce anxiety, mood disturbance, and chronic pain. Acupuncture assists the control of pain and other side effects and helps reduce levels of pain medication required. Trials of acupuncture for chemotherapy-induced neuropathy and postthoracotomy pain show promising results. Herbal products and other dietary supplements should be evaluated for side effects and potential interactions with chemotherapy and other medications.

Conclusions: Complementary therapies have an increasingly important role in the control of symptoms associated with cancer and cancer treatment.

Follow-up and Surveillance of the Lung Cancer Patient Following Curative Intent Therapy*: ACCP Evidence-Based Clinical Practice Guideline (2nd Edition)
Chest. 2007;132(3_suppl):355S-367S. doi:10.1378/chest.07-1390
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Background: To develop an evidence-based approach to follow-up of patients after curative intent therapy for lung cancer.

Methods: Guidelines on lung cancer diagnosis and management published between 2002 and December 2005 were identified by a systematic review of the literature, and supplemental material appropriate to this topic was obtained by literature search of a computerized database (Medline) and review of the reference lists of relevant articles.

Results: Adequate follow-up by the specialist responsible for the curative intent therapy should be ensured to manage complications related to the curative intent therapy and should last at least 3 to 6 months. In addition, a surveillance program should be considered to detect recurrences of the primary lung cancer and/or development of a new primary lung cancer early enough to allow potentially curative retreatment. A standard surveillance program for these patients, coordinated by a multidisciplinary tumor board and overseen by the physician who diagnosed and initiated therapy for the original lung cancer, is recommended based on periodic visits with chest imaging studies and counseling patients on symptom recognition. Smoking cessation and, if indicated, facilitation in participation in special programs is recommended for all patients following curative intent therapy for lung cancer.

Conclusions: The current evidence favors follow-up of complications related to curative intent therapy, and a surveillance program at regular intervals with imaging and review of symptoms. Smoking cessation after curative intent therapy to prevent recurrence of lung cancer is strongly supported by the available evidence.

Palliative Care in Lung Cancer*: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest. 2007;132(3_suppl):368S-403S. doi:10.1378/chest.07-1391
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Goals/objectives: To review the scientific evidence on symptoms and specific complications that are associated with lung cancer, and the methods available to palliate those symptoms and complications.

Methods: MEDLINE literature review (through March 2006) for all studies published in the English language, including case series and case reports, since 1966 using the following medical subject heading terms: bone metastases; brain metastases; cough; dyspnea; electrocautery; hemoptysis; interventional bronchoscopy; laser; pain management; pleural effusions; spinal cord metastases; superior vena cava syndrome; and tracheoesophageal fistula.

Results: Pulmonary symptoms that may require palliation in patients who have lung cancer include those caused by the primary cancer itself (dyspnea, wheezing, cough, hemoptysis, chest pain), or locoregional metastases within the thorax (superior vena cava syndrome, tracheoesophageal fistula, pleural effusions, ribs, and pleura). Respiratory symptoms can also result from complications of lung cancer treatment or from comorbid conditions. Constitutional symptoms are common and require attention and care. Symptoms referable to distant extrathoracic metastases to bone, brain, spinal cord, and liver pose additional problems that require a specific response for optimal symptom control. There are excellent scientific data regarding the management of many of these issues, with lesser evidence from case series or expert opinion on other aspects of providing palliative care for lung cancer patients.

Conclusions: Palliation of symptoms and complications in lung cancer patients is possible, and physicians who provide such care must be knowledgeable about these issues.

Chest. 2007;132(3_suppl):404S-422S. doi:10.1378/chest.07-1392
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Objective: To develop clinical practice guidelines for application of palliative care consultation, quality-of-life measurements, and appropriate bereavement activities for patients with lung cancer.

Methods: To review the pertinent medical literature on palliative care consultation, quality-of-life measurements, and bereavement for patients with lung cancer, developing multidisciplinary discussions with authorities in these areas, and evolving written guidelines for end-of-life care of these patients.

Results: Palliative care consultation has developed into a new specialty with credentialing of experts in this field based on extensive experience with patients in end-of-life circumstances including those with lung cancer. Bereavement studies of the physical and emotional morbidity of family members and caregivers before, during, and after the death of a cancer patient have supported truthful communication, consideration of psychological problems, effective palliative care, understanding of the patient’s spiritual and cultural background, and sufficient forewarning of impending death.

Conclusion: Multidisciplinary investigations and experiences, with emphasis on consultation and delivery of palliative care, timely use of quality-of-life measurements for morbidities of treatment modalities and prognosis, and an understanding of the multifaceted complexities of the bereavement process, have clarified additional responsibilities of the attending physician.

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