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RELATED INTEREST Clinics in Chest Medicine, December 2011 (Volume 34, Issue 4) Respiratory Tract Infections: Advances in Diagnosis, Management and Prevention Michael S. Niederman, MD, Guest Editor
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Pulmonary Diseases
Contributors GUEST EDITOR ALI I. MUSANI, MD, FCCP, FACP Associate Professor of Medicine and Pediatrics, Director, Interventional Pulmonology Program, National Jewish Health; Associate Professor of Medicine, University of Colorado, Denver, Colorado
AUTHORS ESAM H. ALHAMAD, MD, FCCP, FACP Assistant Professor of Medicine, Division of Pulmonary Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia RON BALKISSOON, MD, DIH, MSc, FRCP(C) National Jewish Health, Denver, Colorado TODD M. BULL, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado BRENDAN CAROLAN, MD National Jewish Health, Denver, Colorado LAURIE L. CARR, MD Assistant Professor of Medicine, Division of Oncology, National Jewish Health, Denver, Colorado AHMAD CHEBBO, MD Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Scott and White Healthcare/Texas A&M Health Science Center, Temple, Texas GREGORY P. COSGROVE, MD, FCCP Assistant Professor of Medicine, Interstitial Lung Disease Program, National Jewish Health, Denver, Colorado JAMES H. FINIGAN, MD Assistant Professor of Medicine, Division of Oncology, National Jewish Health, Denver, Colorado STEPHEN K. FRANKEL, MD Associate Professor of Medicine, Interstitial Lung Disease Program, Autoimmune Lung Center, National Jewish Health, Denver; Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado Denver, Aurora, Colorado NABEEL HAMZEH, MD, FCCP Assistant Professor, Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, Colorado
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Contributors
DAVID HSIA, MD Division of Respiratory and Critical Care Physiology and Medicine, Harbor–University of California, Los Angeles Medical Center, Torrance, California JAMES M. HUNT, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado SHIRLEY F. JONES, MD, FCCP, FAASM Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Scott and White Healthcare/Texas A&M Health Science Center, Temple, Texas JEFFREY A. KERN, MD Director of Lung Cancer Center, Professor, Division of Oncology, National Jewish Health, Denver, Colorado RICHARD W. LIGHT, MD Professor of Medicine, Division of Allergy, Pulmonary & Critical Care, Vanderbilty University Medical Center, Nashville, Tennessee STEVE LOMMATZSCH, MD National Jewish Health, Denver, Colorado BARRY MAKE, MD National Jewish Health, Denver, Colorado ALI I. MUSANI, MD, FCCP, FACP Associate Professor of Medicine and Pediatrics, Director, Interventional Pulmonology Program, National Jewish Health; Associate Professor of Medicine, University of Colorado, Denver, Colorado GIRISH B. NAIR, MD Fellow, Pulmonary and Critical Care Medicine, Winthrop-University Hospital, Mineola, New York MICHAEL S. NIEDERMAN, MD Chairman, Department of Medicine, Winthrop-University Hospital, Mineola; Professor and Vice-Chairman, Department of Medicine, SUNY at Stony Brook, Stony Brook, New York AMY L. OLSON, MD, MSPH Assistant Professor of Medicine, Interstitial Lung Disease Program, Autoimmune Lung Center, National Jewish Health, Denver; Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado Denver, Aurora, Colorado RODOLFO M. PASCUAL, MD Assistant Professor of Internal Medicine, and Translational Science, Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Department of Internal Medicine, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina EVANS R. FERNA´NDEZ PE´REZ, MD, MS Assistant Professor of Medicine, Interstitial Lung Disease Program, Autoimmune Lung Center, National Jewish Health, Denver, Colorado
Contributors
STEPHEN P. PETERS, MD, PhD Professor of Internal Medicine, Pediatrics, and Translational Science, Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Department of Internal Medicine, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina AMER TFAILI, MD Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Scott and White Healthcare/Texas A&M Health Science Center, Temple, Texas
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Preface
Ali I. Musani, MD, FCCP Guest Editor
Pulmonary medicine is arguably one of the most complex and exciting disciplines in medicine. It overlaps with critical care medicine, sleep medicine, infectious diseases, and thoracic surgery, making it one of the largest contributors to the field of medicine. Within the field of pulmonary medicine, technological and biomedical advances continue to yield new treatments for some of the most common and deadly diseases. The subspecialty of interventional pulmonology, for example, has revolutionized the diagnosis and staging of lung cancer and now shows promise in treating asthma and emphysema. Identification of clinically significant genetic mutations in lung cancer has led to targeted chemotherapeutic agents that expand treatment options and prolong survival. In community-acquired pneumonia, increasingly complex patients, new pathogens, and drug-resistant organisms pose continuing challenges, which may be met with new patient assessment tools, including biomarkers. Advances in molecular phenotyping have shed light on the pathogenesis and treatment of hypereosinophilic syndrome. As an understanding of these heterogeneous diseases unfolds, we may anticipate further advances in our ability to impact disease course and progression. In this issue of Medical Clinics of North America, we are fortunate to have contributors who are experts in their fields, and who have spearheaded progress in their respective subspecialties. I am profoundly grateful to them for their dedication and efforts in creating this evidence-based, state-of-the-art edition. I sincerely hope that the comprehensive and succinct articles in this issue will enhance the knowledge of general practitioners and subspecialists alike, with the ultimate, shared goal of creating better outcomes for our patients. Ali I. Musani, MD, FCCP Interventional Pulmonology Program National Jewish Health University of Colorado J 225, Molly Blank, 1400 Jackson Street Denver, CO 80206, USA E-mail address:
[email protected] Med Clin N Am 95 (2011) xiii doi:10.1016/j.mcna.2011.10.001 medical.theclinics.com 0025-7125/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
E v a l u a t i o n an d Tre a t m e n t o f P a t i e n t s w i t h N o n – S m a l l Ce l l Lung Cancer Laurie L. Carr, MDa,*, James H. Finigan, MDb, Jeffrey A. Kern, MDc KEYWORDS Lung cancer Treatment Staging Molecular testing
This article reviews the current diagnosis and treatment of patients with lung cancer, focusing on the role of the internist in lung cancer screening, staging, and follow-up. Historically, lung cancer is associated with high mortality rates and little effective therapy. Because this disease predominantly affects those of advanced age with significant comorbidities, treatment can be difficult to deliver safely with manageable adverse effects. All these factors can lead to a sense of futility among clinicians and patients when discussing lung cancer therapy. However, in the last several years, novel therapies have emerged to make lung cancer therapy better tolerated and more effective, even among those with significant comorbidities. Advances in surgical and radiation techniques, as well as the introduction of better-tolerated cytotoxic chemotherapy and targeted agents, have made lung cancer therapy tenable for many more patients. In addition, advances in lung cancer screening using low-dose computed tomography (CT) scans have demonstrated a benefit in lung cancer mortality for the first time and will make the early detection of lung cancer an active part of the management plan of high-risk individuals. Thus, although the morbidity and mortality of lung cancer remain high, novel approaches to screening and therapy have begun to make a significant impact on the burden of this disease.
The authors have nothing to disclose. a Division of Oncology, National Jewish Health, 1400 Jackson Street, J-326a, Denver, CO 80206, USA b Division of Oncology, National Jewish Health, 1400 Jackson Street, K-736a, Denver, CO 80206, USA c Division of Oncology, National Jewish Health, 1400 Jackson Street, J-213, Denver, CO 80206, USA * Corresponding author. E-mail address:
[email protected] Med Clin N Am 95 (2011) 1041–1054 doi:10.1016/j.mcna.2011.08.001 medical.theclinics.com 0025-7125/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
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EPIDEMIOLOGY
More men and women in the United States die of lung cancer than any other form of cancer.1 Although more women are diagnosed with breast cancer each year, nearly twice as many women die of lung cancer than breast cancer. One reason for the high mortality rate of lung cancer is the advanced stage at diagnosis.2 For example, only 16% of new lung cancer cases are diagnosed with localized disease that is potentially curable compared with 61.2% of breast cancer cases and 39.8% of colon cancer cases. This is one of the main reasons that the 5-year overall survival rate of lung cancer is only 15% compared with 89.1% for breast cancer and 65.2% for colon cancer. Not only is the 5-year survival rate for lung cancer low, it has also remained relatively unchanged since 1977 (12.3%). Currently, small cell lung cancer (SCLC) constitutes approximately 13% of newly diagnosed lung cancer cases; non–small cell lung cancer (NSCLC), which includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, makes up most of the remaining cases (85.3%). Over time, there has been a change in the type of lung cancer diagnosed. In the late 1980s, adenocarcinoma became the most common histologic lung cancer type diagnosed in the United Sates, overtaking squamous cell carcinoma.3 The change in the histology of NSCLC is attributed to changes in cigarette design introduced in the late 1950s. The introduction of filter-tip cigarettes and blended tobacco allowed for deeper inhalation and delivery of tobacco carcinogens more distally to the bronchoalveolar junction where adenocarcinomas often arise. Lung cancer is a growing health problem on a global level because the prevalence of tobacco smoking in developing countries has steadily increased. The most recent global statistics provided by the World Health Organization for 2008 report an incidence of more than 1.6 million cases of lung cancer. Globally, more than 1.3 million men and women died of lung cancer in 2008, making lung cancer the leading cause of cancer death worldwide. The number of deaths attributed to lung cancer is expected to continue to increase up to 2030 because of smoking trends in developing countries in the past several decades.4 In 2009, 57% of the adult male population of China and India smoked. The use of solid fuels for cooking and heating in poorly ventilated living spaces contributes to the risk of lung cancer, predominantly in lowincome homes in Asia. Several studies of never-smoking women in China demonstrated an increased risk of lung cancer associated with the use of indoor coal burning for cooking.5 In the United States, cigarette smoking remains the most important risk factor for lung cancer. The lung cancer mortality rate for a nonsmoking man is 11.9/100,000 person-years; that rate increases to 224.3/100,000 person-years for a man who has smoked a pack per day for 20 years.3 Trends for lung cancer occurrence follow cigarette-smoking trends with approximately a 20-year lag. The most recent data (2009) provided by the Centers for Disease Control document that 20.6% of US adults currently smoke (smoked >100 cigarettes in their lifetime, now smoke every or some days). Although smoking rates have decreased since 1997 (24.7%), they have remained unchanged in the past several years. Former smokers in the United States also make up a significant part of the population at just more than 20%. Unfortunately, even after smoking cessation, the risk of lung cancer remains high for many years, although it does slowly decrease. When compared with a never smoker, the risk of lung cancer for an individual who smoked a pack per day remains nearly sevenfold higher even 10 years after quitting.6 The risk decreases with longer cessation intervals and lower amounts of former smoking. For those with high levels of previous exposure, the risk remains increased for more than
Evaluation and Treatment of Non–Small Cell Lung Cancer
20 years. Today, more than 40% of new lung cancer cases are diagnosed in patients who are former smokers. Approximately 15% of all lung cancers are diagnosed in those who have never smoked.7 Analysis of 2 large American Cancer Society Cancer Prevention Study cohorts, CPS-I (1959–1972) and CPS-II (1982–2000), revealed that the rate of lung cancer death between nonsmoking women and men is the same and that the total rate of lung cancer among never smokers has not increased with time.7 Certainly, other risk factors, such as environmental tobacco smoke (ETS), radon gas exposure, and occupational exposures, contribute to the incidence of lung cancer in this population. Multiple studies have analyzed the association between ETS and lung cancer. A comprehensive meta-analysis performed in 1997 estimated an excess risk of lung cancer for never smokers married to smoking spouses at 23% (95% CI 13%–43%), accounting for 3000 to 5000 lung cancer deaths annually in the United States.8 Radon gas exposure was originally shown to be associated with lung cancer through analysis of uranium miners. A recent analysis in North America demonstrated a significant risk associated with increased levels of indoor radon gas (10% increased risk per 100 Bq/ m3 increase in radon exposure).9 The occupational exposure to asbestos, arsenic, and silica has consistently been reported to increase the risk of lung cancer among never smokers.10–12 Each of these occupational exposures has a positive relationship between duration of exposure and cumulative exposure to lung cancer risk. Other agents implicated in case-control studies include pesticides, metal dust and fumes, and organic solvents.13 Although not an occupational exposure, previous treatment with radiation to the chest for medical purposes has also been shown to increase future lung cancer diagnoses.14 A cohort study of patients with Hodgkin disease who received greater than 9 Gy of thoracic radiation therapy demonstrated an increased risk of future lung cancer versus those patients who did not receive thoracic radiation. PATHOPHYSIOLOGY
Advances in molecular biology have enabled the search for novel molecular abnormalities in lung cancer that provide insights into tumorigenesis as well as potential therapeutic targets. The identification of driver mutations, those mutations that drive neoplastic transformation and contribute to tumor progression, has provided at least 2 clinically important targets to date. Epidermal growth factor receptor (EGFR) is a member of the human epidermal growth factor receptor (HER) family, a group of 4 transmembrane tyrosine kinase receptors expressed on epithelial cells of many organs, including the lung. In response to ligand binding, EGFR (HER1) forms a homodimer with another EGFR molecule or heterodimerizes with a different HER family receptor (HER 2, 3, or 4). This leads to tyrosine phosphorylation on the EGFR intracellular domain and activation of EGFR’s kinase activity, resulting in phosphorylation of target proteins and initiation of downstream signaling. Normal functions of EGFR include epithelial growth and differentiation, cell-cell adhesion, and cell migration.15 Many NSCLCs harbor at least one EGFR mutation. Most EGFR mutations are in the tyrosine kinase domain and result in EGFR activation and unregulated signaling.16,17 The discovery of these mutations forms the basis for the use of the EGFR tyrosine kinase inhibitors (TKI) erlotinib and gefitinib as a treatment for lung cancer. The presence of EGFR mutations strongly predicts a response to TKI therapy. One pooled analysis of 3 studies demonstrated a response rate to TKI treatment of 81% in mutation-positive cancers compared with less than 10% in mutation-negative cancers.18 Given the poor response of mutation-negative cancers, therapy selection based on molecular characteristics is superior to using standard clinical criteria.
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However, further analyses have revealed growing complexity and certain EGFR mutations are associated with resistance to TKI treatment. In addition, over time, almost all TKI responsive lung cancers acquire secondary mutations rendering them resistant to further treatment and relapse is inevitable.19 Certain clinical characteristics are associated with EGFR mutation-positive lung cancer. Mutation-positive cancers are almost exclusively NSCLC, specifically adenocarcinoma.16 EGFR mutations have been reported in 10% to 15% of Western and 25% to 30% of Asian patients with lung cancer. EGFR mutations are significantly more common in women and nonsmokers. Mutation status is not associated with tumor stage and some studies suggest a survival benefit in patients with EGFR-mutated lung cancer, regardless of treatment.20 Currently, our practice is to test all adenocarcinomas of the lung for the presence of an EGFR mutation. Use of a TKI as first-line therapy is reserved for those with mutation-positive tumors. However, TKI therapy can be used as third-line or fourth-line therapy in mutation-negative cancers. Another clinically relevant molecular subset of NSCLC are those that are driven by the newly discovered echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) translocation.21 The EML4-ALK translocation in NSCLC leads to the constitutive activation of the ALK kinase domain and promotes cell growth and survival. This translocation is found in approximately 2% to 5% of NSCLC, most commonly seen in never smokers or light smokers with adenocarcinomas. It is rarely found in tumors that harbor activating mutations in EGFR. As discussed later, a novel TKI, crizotinib, has been developed to target ALK mutations. Genome-wide studies of multiple lung cancers have revealed other recurring mutations within additional signaling pathways that could provide additional targets and may account for most NSCLC cases. A recently reported study of 1000 cases of adenocarcinoma revealed that 60% of the tumors contained 1 of 10 individual driver mutations that were analyzed (Fig. 1).22 SCREENING
Although currently there are no accepted recommendations for lung cancer screening, the recent publication of the results of the National Lung Screening Trial (NLST) has the potential to change our approach to lung cancer screening. Based on previous observational studies demonstrating that low-dose helical CT scans increased the detection of early-stage lung cancer,23 the NLST is the first large randomized lung cancer
Fig. 1. Frequency of driver mutations in adenocarcinoma.
Evaluation and Treatment of Non–Small Cell Lung Cancer
screening trial to decrease lung cancer mortality.24 From 2002 to 2004, the NLST randomized more than 50,000 subjects (aged 55–74 years who had a history of cigarette smoking of at least 30 pack-years and were either actively smoking or had quit within the past 15 years) to low-dose helical CT scan or chest radiograph with a baseline imaging study and annual studies for 2 additional years. The study demonstrated a relative reduction in lung cancer mortality of 20.0% (P 5 .004) after a median 6.5 years of follow-up. The authors estimate that 7 million Americans would currently meet the eligibility criteria used for this study. Although this study is a major step forward in the efforts to find an effective lung cancer screening tool, many questions remain unanswered. There were many false-positive findings. More than 23% of the low-dose helical CT scans had a false-positive result, leading to concerns of expense and morbidity associated with unnecessary diagnostic procedures in follow-up. The NLST reported that the rate of complications from diagnostic procedures for nodule evaluation was low (1.4%) with only 0.06% leading to a major complication. However, the cost-effectiveness of CT screening is yet to be analyzed. In addition, the number of lung cancer diagnoses remained stable at each round of imaging, leading to the question of whether screening should continue longer than 2 years. Although the dose of radiation with these scans is reduced (1.5 mSv, approximately one-third the dose of a conventional chest CT), there is concern regarding the risk of repeated radiation exposure. The use of additional predictors for lung cancer risk, such as serum biomarkers, could potentially improve the risk assessment for a given individual (beyond age and smoking history) to focus on those who will benefit the most from CT screening. WORK-UP
Although NSCLC can be asymptomatic and incidentally found on chest imaging performed for other reasons, often patients present with nonspecific pulmonary symptoms. For those at increased risk (significant smoking history, age >55 years, and family history of lung cancer), there are several signs/symptoms that necessitate a closer evaluation for lung cancer. New or worsening cough, dyspnea, and chest wall pain are often manifestations of a lung tumor, although they are also common complaints in nonmalignant disease. However, when these symptoms are accompanied by hemoptysis, weight loss, or progressive fatigue in a high-risk patient, consideration of lung cancer should be included in the work-up. Patients may present with signs and symptoms of postobstructive pneumonitis, including cough, fever, and increased sputum production. Therefore, it is important that high-risk patients who present with a consolidation thought to be caused by infection are evaluated following treatment to ensure that the consolidation has cleared. If imaging and clinical evaluation are concerning for lung cancer, assessment of underlying comorbidities, including pulmonary function, is important when considering further diagnostic procedures and treatment. The initial evaluation of a patient with chest imaging suspicious for lung cancer centers on obtaining tissue for pathologic evaluation. The safest and least invasive procedure should be chosen based on radiographic evidence that ideally could provide not only a tissue diagnosis but also staging information. The approach chosen must be balanced by obtaining sufficient material to enable the pathologist to make a histologic determination, including enough tissue for immunohistochemistry (IHC) and molecular testing, if needed.25 For example, testing pleural effusions for malignant cells can establish an advanced stage, but often leads to insufficient tissue for molecular testing and the patient requires an additional biopsy procedure. If a patient has
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radiologic evidence of a solitary site of metastatic disease, attempts should be made to sample that site to provide a diagnosis and have pathologic confirmation of advanced disease. For patients with evidence of extensive metastatic disease, if the metastatic site is not safe or easily amenable to biopsy, it is often most efficient to sample the primary lung lesion. Bronchoscopy can be used in the diagnosis and local staging of both central and peripheral lesions. Standard bronchoscopy has a low yield for diagnosis of peripheral lesions less than 2 cm in size, with a 28% to 30% diagnostic accuracy.26 However, emerging technology in interventional pulmonary techniques now allows for navigational bronchoscopy with an increased ability to sample small peripheral lesions with a diagnostic yield of 70%27 and should be considered before referring the patient for a transthoracic approach.28 In addition, the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) allows for sampling of mediastinal and hilar lymph nodes. EBUS-TBNA can be used to confirm suspicious findings on CT and positron emission tomography (PET) scans. Coupling EBUS-TBNA with esophageal ultrasound techniques allows noninvasive access to almost all nodal stations important to the staging evaluation. CT-guided transthoracic needle aspiration (TTNA) can be used to sample peripheral lesions, with a diagnostic yield for malignancy of 85% to 90%. The amount of nondiagnostic procedures, as well as complications with pneumothorax, increases with more centrally located tumors.29 For a small peripheral lung lesion that is highly suspicious for lung cancer (spiculated, increasing in size, PET avid, and so forth), often a surgical resection provides both diagnosis and treatment. STAGING
Accurate staging of newly diagnosed lung cancer provides information regarding prognosis and risk of disease recurrence. This information is necessary to develop the appropriate therapeutic plan for each patient and provide patients with the necessary information to determine risk versus benefit of therapy. Staging is based on an algorithm that encompasses primary tumor size and invasion, nodal involvement, and the identification of metastases. The current staging algorithm for lung cancer was revised in 2009 and published in TNM Classification of Malignant Tumors, 7th edition (Table 1).30 Initial clinical staging involves a CT of the chest that includes the adrenal glands to determine tumor size, invasion, and local and regional nodal status. The addition of an fluorodeoxyglucose (FDG)-PET scan to evaluate for metastatic disease and further assess possible involvement of the mediastinal lymph nodes has been proven to prevent futile thoracotomies.31 The specificity and sensitivity for mediastinal lymph node involvement, when assessed by CT scan, are 69% and 71%, respectively.32 These are increased to 86% and 85% when PET/CT is added. EBUS with TBNA of suspected lymph nodes can be used to confirm suspicious hilar and mediastinal lymph nodes that are positive on imaging studies. However, mediastinoscopy should be used to confirm a negative EBUS evaluation for those tumors at high risk for nodal involvement (based on size and central location). Magnetic resonance imaging (MRI) of the brain is recommended for stage II and III disease before initiating aggressive local therapy. This should also be considered for stage I disease when the primary tumor is a centrally located adenocarcinoma.33 TREATMENT
The treatment for lung cancer is determined by stage, patient preference, comorbidities, and overall performance status (Table 2). Treatment planning should include presentation and discussion at a multidisciplinary tumor board with review of
Evaluation and Treatment of Non–Small Cell Lung Cancer
Table 1 Staging of NSCLC T (Primary Tumor) T1 (T1a/T1b)
Tumor 3 cm in greatest dimension, surrounded by lung or visceral pleura, without evidence of invasion more proximal than the lobar bronchus
T2 (T2a/T2b)
Tumor >3 cm but 7 cm or tumor with any of the following: involves main bronchus, 2 cm distal to the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
T3
Tumor >7 cm or one that involves any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or tumor in the main bronchus
