Description of the Evidence
Incidence and mortality
Lung cancer is the most commonly occurring noncutaneous cancer in men and women combined in the United States and is the leading cause of cancer deaths. In 2013 alone, it is estimated that there will be 228,190 new cases diagnosed, and 72,220 women and 87,260 men will die from this disease. The lung cancer death rate rose rapidly over several decades in both sexes, with a persistent decline for men commencing in 1991. From 2005 to 2009, death rates decreased by 2.8% per year in men and by 1.0% per year in women.Risk factors
Tobacco use, second hand smoke, and other risk factors
The most important risk factor for lung cancer (as for many other cancers) is tobacco use.[2,3] Cigarette smoking has been definitively established by epidemiologic and preclinical animal experimental data as the primary cause of lung cancer. This causative link has been widely recognized since the 1960s, when national reports in Great Britain and the United States brought the cancer risk of smoking prominently to the public’s attention. The percentages of lung cancers estimated to be caused by tobacco smoking in males and females are 90% and 78%, respectively.
Environmental or secondhand tobacco smoke is also implicated in causing lung cancer. Environmental tobacco smoke has the same components as inhaled mainstream smoke, although in lower absolute concentrations; between 1% and 10%, depending on the constituent. Carcinogenic compounds in tobacco smoke include the polynuclear aromatic hydrocarbons (PAHs), including the classical carcinogen benzo[a]pyrene and the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In rodents, total doses of both PAH and NNK that are similar to doses received by humans in a lifetime of smoking induce pulmonary tumors. Elevated biomarkers of tobacco exposure, including urinary cotinine, tobacco-related carcinogen metabolites, and carcinogen-protein adducts, are seen in passive or secondhand smokers.[6-10]
Many other exposures have been established as causally associated with lung cancer, but even the combined effect of these additional factors is very small compared with cigarette smoking. These additional causal factors are primarily related to occupational exposures to agents such as asbestos, arsenic, chromium, nickel, and radon. Radon, a naturally occurring gas, is of relevance to the general public because of the potential exposure in homes.Evidence of benefit associated with screening
Screening by low-dose helical computed tomography
There have been intensive efforts to improve lung cancer screening with newer technologies, including low-dose helical computed tomography (LDCT) and molecular techniques.[12,13] LDCT was shown to be more sensitive than chest radiography. In the Early Lung Cancer Action Project (ELCAP), LDCT detected almost six times as many stage I lung cancers as chest radiography, and most of these tumors were no larger than 1 cm in diameter. The ability of LDCT to reduce lung cancer mortality was demonstrated in the randomized, controlled National Lung Screening Trial (NLST): a statistically significant relative reduction of 20% in lung cancer mortality was observed, as was a statistically significant 6.7% relative reduction in all-cause mortality.
Eight observational studies of LDCT in various parts of the world have been reported and summarized. These are relatively small studies, ranging from about 600 to 8,000 participants, which began between 1992 and 2000. Most of the studies include a substantial percentage of females, and the studies in Japan include nonsmokers. Findings include a nodule or positivity rate of 5% to 51%, 0.4% to 3% lung cancers, 50% to 95% adenocarcinomas, 50% to 91% stage I or IA cancers, and estimates of sensitivity ranging from 40% to 95%.
False-positive test results and overdiagnosis must be considered when lung cancer screening with LDCT is being evaluated. The false-positive test result, which is more common than overdiagnosis, may lead to anxiety and invasive diagnostic procedures such as percutaneous needle biopsy or thoracotomy. In the ELCAP study, which used a CT slice thickness of 10 mm, noncalcified nodules were detected in 21% of patients without lung cancer at the prevalence screen. Thirty-one (13%) of 233 individuals with noncalcified nodules underwent biopsies, of which close to 90% (27 of 31 patients) resulted in a diagnosis of malignancy, and the prevalence of cancers detected was 2.7%.
In a case series that defined the population at high risk of lung cancer by occupations associated with asbestos exposure, 58% accepted an invitation to participate in an LDCT screening program. The ELCAP screening protocol was applied in 1,119 asbestos-exposed people whose average age was 57 years. Twenty-five biopsies resulted in the detection of one stage IA and four late stage lung cancers. The authors concluded the screening program was not able to replicate the ELCAP results and was not cost effective for lung cancer screening in this population.
A study in Ireland, which aimed to reproduce the ELCAP study in high-risk but younger individuals, revealed a similar proportion of noncalcified nodules were detected using 10 mm CT slice thickness. In the Irish study (N = 449), however, the prevalence of cancers detected was substantially smaller (0.46%). Furthermore, several individuals underwent invasive procedures for ultimately benign conditions (three of four patients with nodules >10 mm who underwent biopsy had benign cytology; one had a thoracotomy that confirmed benign disease; three patients with mediastinal masses underwent biopsy and two had benign cysts). In two other studies, which used 5 mm CT slices, noncalcified nodules were detected in a much higher proportion of patients.[18,19]
In the Mayo Clinic study, noncalcified nodules were detected in 51% of 1,520 patients at the prevalence screen and cumulatively in 74% after five subsequent annual screens. Ninety-five percent of these nodules were less than 8 mm in diameter, for which the recommended follow-up was noncontrast CT in 3 to 6 months. However, eight patients had surgery for benign lesions, five of which appeared to grow on follow-up CT. In addition, screening with LDCT can detect abnormalities other than noncalcified nodules, including enlarged lymph nodes, abdominal aortic aneurysms, and renal and adrenal masses. During the first three rounds of screening in the Mayo Clinic study, 696 such abnormalities were found in the 1,520 patients.
In a 2008 systematic review of chest CT lung cancer screening studies, the mean proportion of patients with any incidental abnormality was 65.2% (95% confidence interval [CI], 63.5%–66.9%). The mean proportion of patients with clinically significant incidental findings—defined as any abnormality considered to require additional diagnostic workup—was 14.2% (95% CI, 13.2%–15.2%). It is not clear whether the detection of these abnormalities produces a net benefit or a net harm.
A less familiar harm is overdiagnosis, the diagnosis of a condition that would not have become clinically significant had it not been detected by screening. In the case of screening with LDCT, overdiagnosis could lead to unnecessary diagnosis of lung cancer requiring some combination of surgery (e.g., lobectomy), chemotherapy, and radiation therapy. Although overdiagnosis is almost impossible to document in a living individual, autopsy studies suggest that many individuals die with lung cancer rather than from it. In one study, about one-sixth of all lung cancers found at autopsy had not been clinically recognized before death. Even this may be an underestimate because autopsy probably fails to detect many small lung cancers that are detectable by CT. Studies in Japan provide additional evidence that screening with LDCT could lead to a substantial amount of overdiagnosis. In a study in which smokers and nonsmokers were annually screened for lung cancer between 1996 and 1998 using LDCT, the overall rate of screen-detected lung cancers was very similar in the two groups: 0.46% for smokers (mainly men) and 0.41% for nonsmokers (mainly women). The nonsmoking group may have included individuals who were at an elevated risk for lung cancers for other reasons, but no information is provided on this point. A second study involving both smokers and nonsmokers reported a similar finding of a 1.1% lung cancer detection rate in both groups. Confirmative studies are needed to establish the level of overdiagnosis that might be associated with CT screening for lung cancer. In that same population, the volume-doubling times of 61 lung cancers were estimated using an exponential model and successive CT images. Lesions were classified into three types: (1) type G (ground glass opacity), (2) type GS (focal glass opacity with a solid central component), and (3) type S (solid nodule). The mean-doubling times were 813 days, 457 days, and 149 days for types G, GS, and S, respectively. In this study, annual CT screening identified a large number of slowly growing adenocarcinomas that were not visible on chest x-ray.
With completion of the NLST, there is now evidence that screening with LDCT can reduce lung cancer mortality risk in ever-smokers who have smoked 30 pack-years or more. The NLST included 33 centers across the United States. Eligible participants were between the ages of 55 years and 74 years at the time of randomization, had a history of at least 30 pack-years of cigarette smoking, and, if former smokers, had quit within the past 15 years. A total of 53,454 persons were enrolled; 26,722 persons were randomly assigned to screening with LDCT and 26,732 persons were randomly assigned to screening with chest x-ray. Any noncalcified nodule found on LDCT measuring at least 4 mm in any diameter and x-ray images with any noncalcified nodule or mass were classified as positive, although radiologists had the option of not calling a final screen positive if a noncalcified nodule had been stable on the three screening exams. The LDCT group had a substantially higher rate of positive screening tests than did the radiography group (round 1, 27.3% vs. 9.2%; round 2, 27.9% vs. 6.2%; and round 3, 16.8% vs. 5.0%). Overall, 39.1% of participants in the LDCT group and 16.0% in the radiography group had at least one positive screening result. Of those who screened positive, the false-positive rate was 96.4% in the LDCT group and 94.5% in the chest radiography group. This was consistent across all three rounds.
In the LDCT group, 649 cancers were diagnosed after a positive screening test, 44 after a negative screening test, and 367 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. In the radiography group, 279 cancers were diagnosed after a positive screening test, 137 after a negative screening test, and 525 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. A total of 356 and 443 deaths from lung cancer occurred in the LDCT and chest x-ray groups, respectively, with a relative reduction in the rate of death from lung cancer of 20.0% (95% CI, 6.8–26.7) with LDCT screening. Overall mortality was reduced by 6.7% (95% CI, 1.2–13.6). The number needed to screen with low-dose CT to prevent one death from lung cancer was 320.
Other randomized controlled trials of LDCT are under way in a number of countries. Furthermore, NLST data are being analyzed to examine other important issues in lung cancer screening, including cost effectiveness, quality of life, and whether screening would benefit individuals younger than those enrolled in NLST and those with fewer than 30 pack-years of smoking exposure.Evidence of no benefit associated with screening
Screening by chest x-ray and/or sputum cytology
The question of lung cancer screening dates back to the 1950s. Five studies of chest imaging, two of which were controlled, were undertaken during the 1950s and 1960s.[31-38] Two included sputum cytology as well.[31-35] The results of these studies suggested no overall benefit of screening, although design limitations prevented the studies from providing definitive evidence.
In the early 1970s, the National Cancer Institute funded the Cooperative Early Lung Cancer Detection Program, which was designed to assess the ability of screening with radiologic chest imaging and sputum cytology to reduce lung cancer mortality in male smokers. The program comprised three separate randomized controlled trials, each enrolling about 10,000 male participants aged 45 years and older who smoked at least one pack of cigarettes a day in the previous year. One study was conducted at the Mayo Clinic,[40-42] one at Johns Hopkins University,[43-45] and one at Memorial Sloan-Kettering.[45-48] The Hopkins and Sloan-Kettering studies employed the same design: persons randomly assigned to the intervention arm received sputum cytology every 4 months and annual chest imaging, while persons randomly assigned to the control arm received annual chest imaging. Neither study observed a reduction in lung cancer mortality with screening. The two studies were interpreted as showing no benefit of frequent sputum cytology when added to an annual regimen of chest x-ray.
The design of the Mayo Clinic study (known as the Mayo Lung Project, or MLP), was different. All potential participants were screened with chest imaging and sputum cytology, and those known or suspected to have lung cancer, as well as those in poor health, were excluded. Remaining persons were randomly assigned to either an intervention arm that received chest imaging and sputum cytology every 4 months for 6 years, or to a control arm that received a one-time recommendation at trial entry to receive the same tests on an annual basis. No reduction in lung cancer mortality was observed. The MLP was interpreted in the 1970s as showing no benefit of an intense screening regimen with chest x-ray and sputum cytology. The Czechoslovakian study began with a prevalence screen (chest imaging and sputum cytology) of 6,364 males aged 40 to 64 years who were current smokers with a lifetime consumption of at least 150,000 cigarettes.[49,50] All participants except the 18 diagnosed with lung cancer as a result of the prevalence screen were randomly assigned to one of two arms: an intervention arm, which received semi-annual screening for 3 years, or a control arm, which received screening during the third year only. The investigators reported 19 lung cancer deaths in the intervention arm and 13 in the control arm, and concluded that frequent screening was not necessary.
At the end of the 1980s, the relationship between screening with chest imaging (using traditional chest x-ray) and lung cancer mortality was not well understood. Although previous studies showed no benefit, they were not definitive, partly due to lack of statistical power. A multiphasic trial with ample statistical power, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, began in 1992. PLCO enrolled 154,901 participants aged 55 to 74 years, including women (50%) and never smokers (45%). Half were randomly assigned to screening, and the other half were advised to receive their usual medical care. PLCO had 90% power to detect a 20% reduction in lung cancer mortality.
The lung component of PLCO addressed the question of whether annual single-view (posterior-anterior) chest x-ray was capable of reducing lung cancer mortality as compared with usual medical care. When the study began, all participants randomly assigned to screening were invited to receive a baseline and three annual chest x-ray screens, although the protocol ultimately was changed to screen never-smokers only three times. At 13 years of follow-up, 1,213 lung cancer deaths were observed in the intervention group, compared with 1,230 lung cancer deaths in the usual-care group (mortality relative risk, 0.99; 95% CI, 0.87–1.22). Sub-analyses suggested no differential effect by sex or smoking status.
Given the abundance and consistency of evidence, as well as the lack of benefit observed in the PLCO trial, it is appropriate to conclude that lung cancer screening with chest x-ray and/or sputum cytology, regardless of sex or smoking status, does not reduce lung cancer mortality.References
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