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Humphrey L, Deffebach M, Pappas M, et al. Screening for Lung Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jul. (Evidence Syntheses, No. 105.)

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Screening for Lung Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet].

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1INTRODUCTION

Purpose of Review and Prior U.S. Preventive Services Task Force Recommendation

The purpose of this report is to update a previous evidence review1 commissioned by the U.S. Preventive Services Task Force (USPSTF) on screening for lung cancer. In 2004, based on the previous evidence review, the USPSTF found there was insufficient evidence to either recommend for or against routinely screening asymptomatic persons for lung cancer with either low-dose computed tomography (LDCT), chest x-ray (CXR), sputum cytology, or a combination of these tests (I statement).2

The previous evidence review assessed six randomized, controlled trials (RCTs) of poor- or fair-quality of CXR screening with or without sputum cytology examination conducted in the 1960s and 1970s among men at high risk for lung cancer because of exposure to tobacco smoking. No studies showed reduced lung cancer mortality among any of the screened participants.1 However, participants in all studies received some level of screening, limiting conclusions about screening compared with no screening.

The previous evidence review also included five fair-quality case-control studies from Japan of high-risk men and low- or unknown-risk women.1 All studies found lower odds of dying of lung cancer among those screened periodically with CXR, with odds ratios (ORs) ranging from 0.4 to 0.7. One poor-quality case-control study did not show benefit.3 Focusing specifically on the efficacy of lung cancer screening in women, the previous evidence review identified a suggestion of benefit from Japanese case-control studies of CXR screening, but found no RCTs evaluating CXR screening in women.

Screening for lung cancer with LDCT was evaluated in six cohort studies included in the previous evidence review. These studies screened both high- and low-risk individuals and found LDCT identified more early-stage lung cancer than CXR or than is typically identified in clinical practice. The previous evidence review identified no RCTs on the use of LDCT screening for lung cancer.

The current evidence review will be used by the USPSTF to update its 2004 recommendation on screening for lung cancer. This update focuses on evidence that has been published since the previous evidence review on the effectiveness of screening asymptomatic men and women for lung cancer, as well as the risks and harms associated with screening. The report will emphasize evidence applicable to typical practice in the United States.

Condition Definitions

Lung cancer is a proliferation of malignant cells arising in the airways or tissues of the lung. Ninety-five percent of lung malignancies are either non-small cell lung cancer (NSCLC) or small cell carcinoma, with small cell carcinoma accounting for 16 percent of cases. The remaining 5 percent of primary pulmonary malignancies include rare entities such as carcinoid tumor. NSCLC is a heterogeneous designation with subsets including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and undifferentiated carcinoma. Individual tumors can show features of several of these subtypes. Adenocarcinoma is the most common subtype, encompassing 36 percent of all lung cancers, with squamous cell carcinoma making up 20 percent of cases in a large survey of U.S. lung cancer from 1998 to 2001.4 The World Health Organization has recently revised the histology classifications for lung cancer, including several new preinvasive lesions within the adenocarcinoma classification.5

Lung cancer is staged according to the American Joint Committee by the TNM system. The TNM and stage designations have been recently revised and a new breakdown of early-stage primary cancers into T1a (<2 cm) or T1b (2 to 3 cm) has been added.6 Stage IA NSCLC is less than or equal to 3 cm in its greatest dimension, does not invade the visceral pleura or bronchus within 3 cm of the main carina, and has no evidence of lymph node or metastatic spread.7

Prevalence and Burden of Disease

Lung cancer is the second most commonly occurring cancer in the United States among men and women and the leading cause of cancer-related death.8 The American Cancer Society (ACS) predicted there would be approximately 226,160 new cases and 160,340 lung cancer–related deaths in the United States in 2012.4 Notably, lung cancer is expected to account for almost 28 percent of all cancer-related deaths in 2012. Current estimates suggest that almost 7 percent of men and women born today will be diagnosed with lung cancer during their lifetime and almost 6 percent will die from it.4,9,10 Lung cancer and lung cancer–related deaths have been increasing in epidemic proportions throughout the world, with differences between countries largely explained by differences in smoking rates.11 Worldwide, it is estimated there were 1.6 million new cases and 1.4 million deaths from lung cancer in 2008.11 Rates of lung cancer vary by smoking status. In one very large population-based cohort study of approximately 50,000 people ages 40 to 70 years, lung cancer death rates among women and men smoking 20 or more cigarettes per day were 41 and 43 per 1,000 or 16 and 11 percent of all deaths, respectively. Among never smokers, lung cancer mortality was 1.0 and 1.3 per 1,000 for women and men, respectively.12 As a measure of the burden of lung cancer in the population, lung cancer is the leading cause of years of life lost to cancer in the United States, with an estimate of 15 years of life lost on average per person dying of lung cancer.13

Risk Factors

The biggest single risk factor for lung cancer is smoking,14 causing approximately 85 percent of lung cancers in the United States.15 Worldwide, smoking accounts for 75 to 80 percent of cases in men and at least 50 percent in women.11,16 Smoking has been associated most strongly with squamous cell and small cell carcinoma17 and to a lesser degree with adenocarcinoma, including the bronchioloalveolar subtype.18

Utilizing data from 2006 through 2007, the Tobacco Use Supplement Survey from the National Cancer Institute reported 37 percent of adults in the United States as current or former smokers.19 Although the prevalence of current smoking has declined slowly in recent years, in 2010 it was estimated that 19 percent of U.S. adults were current smokers20 and that 17 percent of adults will still be current smokers in 2020.21 Furthermore, it was estimated that in 2008, there were 7 million people in the United States ages 55 to 75 years with at least a 30 pack-year smoking history,22 the approximate target group for lung cancer screening in most trials published to date. In the United States, a high percentage of lung cancer occurs in former smokers because of the large group of former smokers in the population and because lung cancer risk does not decrease until many years after smoking stops.23-25 In recent years, the incidence of lung cancer in the United States has been slowly declining, but given these estimates of both current and former cigarette smoking, it is unlikely to decline significantly for many years, and lung cancer will remain a major public health problem in this country and an increasing problem worldwide.

The incidence of lung cancer also significantly increases with age. Other risk factors for lung cancer include family history,14,15,17 chronic obstructive pulmonary disease,15,18,26 pulmonary fibrosis,14 exposure to passive tobacco smoke,27-29 indoor cooking fumes,11 environmental radon, and occupational exposures such as asbestos, arsenic, chromium, and coal tar.15,26 Some studies suggest women are at higher risk for lung cancer than comparably exposed men.14,28,30,31 In addition to these risk factors, blacks are nearly twice as likely as their white counterparts to have a tobacco-related cancer,32 suggesting that race/ethnicity may also be a risk factor for lung cancer. There is also some evidence suggesting that the incidence of lung cancer is higher among people of disadvantaged socioeconomic status, although this may be due to unmeasured confounding from smoking.33,34

If lung cancer among nonsmokers is considered alone, it would be the seventh leading cause of cancer-related death in the world,16 and as smoking rates decrease, will represent a larger fraction of lung cancer than is currently the case. Notably, there are major sex, clinicopathologic, and molecular differences in lung cancers arising in nonsmokers and smokers.16

Natural History

The rate of progression of lung cancer varies by cell type as well as molecular biology, but generally has a poor prognosis and is the cause of death in more than 90 percent of affected individuals.35 The 5-year survival rate for all stages combined is approximately 16 percent.9 Stage at diagnosis is a strong predictor of lung cancer mortality.7 Unfortunately, 75 percent of patients with lung cancer present with symptoms due to advanced local or metastatic disease that is not amenable to cure.35

For patients diagnosed with localized disease (defined as cancer limited to the lung without spread to other organs or lymph nodes), 5-year relative survival is 52 percent compared with 25 and 4 percent for regional (spread to regional lymph nodes) and distant (metastatic) disease, respectively. For the earliest-stage tumors, median 5-year survival is estimated at 77 percent.7 Currently, however, only 15 percent of lung cancers are diagnosed at an early stage.4 Accordingly, there is considerable interest in the early detection and treatment of lung cancer in order to give patients the highest chance for cure.

Rationale for Screening

Lung cancer has many attributes that make it appropriate to consider screening for, including high morbidity and mortality and a relatively high prevalence in high-risk populations. Lung cancer mortality and survival are related to the initial stage of diagnosis, suggesting that treating early may be beneficial; therefore, an effective screening program for the early detection and treatment of lung cancer could have a significant impact on its high mortality rate.

A good screening test for lung cancer should be sensitive, specific, acceptable to patients and providers, and relatively cost-effective. In this regard, LDCT has emerged from observational studies as a promising new technology for diagnosing early lung cancer. In the early 1990s, LDCT was introduced as a screening test with hope that improved sensitivity might improve lung cancer screening outcomes, and several observational studies and RCTs began to evaluate this modality. Thus, with data now being reported from several ongoing trials, it is appropriate to reexamine the literature to date on the outcomes of screening for lung cancer. Current screening efforts are directed toward the early detection of NSCLC, since small cell lung cancer is less common and often grows and spreads too quickly to be reliably detected by intermittent screening.

Interventions/Treatment

Small cell lung cancer and NSCLC are managed differently. While small cell lung cancer is treated as a systemic disease, except in rare instances, the current standard of care for the treatment of localized NSCLC is surgical resection,27,29,36 whereas advanced NSCLC is often treated with radiation and/or chemotherapy, in addition to surgical resection when possible. For patients with poor performance status, supportive care may be the only appropriate therapy. Detecting and treating early-stage NSCLC is the focus of most screening programs for lung cancer since early treatment can lead to cure of NSCLC.

Current Clinical Practice

Until recently, few patients in the United States were being screened for lung cancer and no professional organizations, including the USPSTF, the ACS, the American College of Chest Physicians (ACCP), and the American Academy of Family Physicians, recommended routine screening. However, since the early 2000s, LDCT for the detection of early lung cancer has been broadly available, and there is evidence that patients and clinicians are already engaging in lung cancer screening.37-39

Recommendations of Other Groups

In May 2012, based primarily on results from the National Lung Screening Trial (NLST), several organizations, including the ACCP, the American Society of Clinical Oncology, and the American Thoracic Society,40 as well as the National Comprehensive Cancer Network (NCCN)22 and the American Lung Association41 recommended lung cancer screening, modeled closely on the NLST, using a LDCT program for individuals ages 55 to 74 years with a 30 pack-year history of cigarette smoking and the ability to partake in organized programs of screening (Table 1). The American Association for Thoracic Surgeons recommends screening select groups from ages 50 to 79 years in its recently developed guidelines, which differ slightly from the NLST study population of 54- to 74-year-olds.42 In January 2013, the ACS also began recommending screening for lung cancer with LDCT.43 In addition, several patient organizations, such as the Lung Cancer Alliance44 and the National Lung Cancer Partnership, are currently advocating screening.45-47

Table 1. Recommendations of Professional Organizations.

Table 1

Recommendations of Professional Organizations.

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