Linda L. Humphrey, M.D., M.P.H.;a,b Steven Teutsch, M.D., M.P.H.;c Mark S. Johnson, M.D., M.P.H.d
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, or Merck and Co., Inc.
Address correspondence to: Linda Humphrey, M.D., M.P.H.; Oregon Health & Science University; Mail code: BICC; 3181 SW Sam Jackson Park Road; Portland, OR 97239-3098.
Select for copyright and reprint information. The USPSTF recommendations based on this review are online.
The summaries of the evidence briefly present evidence of effectiveness for preventive health services used in primary care clinical settings, including screening tests, counseling, and chemoprevention. They summarize the more detailed Systematic Evidence Reviews, which are used by the U.S. Preventive Services Task Force (USPSTF) to make recommendations.
Abstract
Introduction
Methods
Data Synthesis
Discussion
Role of the Funding Source
Acknowledgments
References
Notes
Background: Lung cancer is the leading cause of cancer-related death in the United States and worldwide. No major professional organizations, including the U.S. Preventive Services Task Force (USPSTF), currently recommend screening for lung cancer.
Purpose: To examine the evidence evaluating screening for lung cancer with chest x-ray, sputum cytology, and low-dose computerized tomography (CT) to aid the USPSTF in updating its recommendation on lung cancer screening.
Data Sources: MEDLINE®, the Cochrane Library, reviews, editorials, and experts.
Study Selection: Studies that evaluated mass-screening programs for lung cancer involving the tests of interest. All studies were reviewed, but only studies with control groups were rated in quality since these would most directly influence the USPSTF screening recommendation.
Data Extraction: Data were abstracted to data collection forms. Studies were graded according to criteria developed by the USPSTF.
Data Synthesis: None of the 6 randomized trials of screening for lung cancer with chest x-ray alone or with sputum cytology have been shown to benefit those screened. All studies were limited by some level of screening occurring in the control population. Five case-control studies from Japan have suggested benefit to both high- and low-risk men and women. All studies are limited by potential healthy screenee bias. Six cohort studies evaluated screening CT and showed that when CT is used to screen for lung cancer, lung cancer was diagnosed at an earlier stage than in usual clinical care. However, these studies did not have control groups, making mortality evaluation difficult. In addition, the studies demonstrated a high rate of false-positive findings.
Conclusions: Current data do not support screening for lung cancer with any method. These data, however, are also insufficient to conclude that screening does not work, particularly in women. Two randomized trials of screening with chest x-ray or low-dose CT are currently underway and will better inform lung cancer screening decisions.
Screening for lung cancer is not currently recommended by any major medical professional organization. The U.S. Preventive Services Task Force (USPSTF) gave lung cancer screening a "D" recommendation in both 1985 and 1996, meaning that there were fair-quality data to recommend against screening for lung cancer1 based largely on 3 negative trials conducted in the United States in the 1970s. Since the last Task Force review, several new studies of lung cancer screening have been reported, and greater attention has been directed toward the limitations of existing literature. This review was conducted to aid the current USPSTF in updating its lung cancer screening recommendation.
Lung cancer is the leading cause of cancer-related death among men and women in the United States; in 2003, approximately 171,900 new cases and 157,200 lung cancer-associated deaths were predicted in the United States.2 Worldwide, lung cancer and lung cancer-related deaths have been increasing in epidemic proportions,3,4 with an estimated 1 million deaths in the year 2000.5
Although there are other important risk factors for lung cancer,3,6-10 cigarette smoking is the major risk factor; approximately 87% of all lung, bronchial, and tracheal cancer are attributed to smoking.3 Consequently, the most important public health intervention that could reduce lung cancer incidence and deaths is changing smoking habits. Unfortunately, although overall prevalence rates of smoking in the United States have decreased over the past 2 decades, the prevalence of current adult smokers remains high at 24%.10,11 In the clinical setting, smoking cessation programs, even in conjunction with drug therapy, have long-term smoking cessation rates of only approximately 20% to 35% at 1 year among motivated volunteers in good-quality studies.12-14 In addition, in 1999, approximately 45.7 million adults (23.1%) were former smokers; currently a high percentage of lung cancer cases occur in former smokers, since the risk for lung cancer does not decrease for many years following smoking cessation.15-17 Household exposure to secondhand smoke is substantial and also associated with lung cancer.18 These smoking exposure rates, in addition to large numbers of persons with past or passive exposure to smoking, indicate that lung cancer will continue to be a major public health problem in the United States and worldwide.
Lung cancer is the cause of death in more than 90% of affected persons.19 Survival is directly related to the stage of lung cancer at the time of diagnosis, ranging from 70% for stage I disease to less than 5% for stage IV disease.20,21 Seventy-five percent of patients with lung cancer present with symptoms due to advanced local or metastatic disease that is incurable.19 Since lung cancer mortality is closely associated with disease stage at the time of diagnosis, it is believed (based primarily on indirect evidence)22-28 that early surgical resection is associated with better outcomes. Therefore, the current standard of practice is to resect most non-small-cell lung cancer without evidence of metastic spread. For many of these reasons, screening for and treating early lung cancer is intuitively appealing.
This review discusses studies of chest x-ray, sputum cytology, and low-dose computerized tomography (CT) for lung cancer screening and focuses on the outcomes of screening in populations. We reviewed the MEDLINE® and Cochrane databases from their inception through January 2003 using the search terms lung neoplasms, lung cancer, and any screening. The search strategy is detailed in Appendix Table 1. To ensure complete ascertainment, we reviewed the bibliographies of reviews, editorials, book chapters, and letters discussing lung cancer screening, as well as a recent Cochrane review and analysis.29 We sought studies evaluating screening in the general population, as well as in high-risk populations, and included observational studies and clinical trials. Observational studies with control groups and controlled trials evaluating disease-specific mortality were evaluated for quality according to criteria created by the USPSTF30 (Appendix Table 2). For the purposes of this review, high-risk populations include those who currently or have ever smoked and low-risk populations include those who have never smoked. To rate each of these studies, we reviewed all original articles discussing the study's methods or findings. We also used studies of the various screening methods to estimate the screening test characteristics of chest x-ray and low-dose CT. Finally, we used data from screening studies, when available, as well as clinical series, to evaluate the harms associated with screening and treatment. For completeness, all studies are described in the tables; however, only studies rated of fair or better quality are described in the text.
Methodological issues relevant to understanding screening studies include lead-time bias (when the time of diagnosis is advanced by screening but the time of death is unchanged), length bias (bias toward detecting less aggressive tumors in a population being periodically screened),31 and volunteer bias (a type of selection bias in which volunteers are compared with non-volunteers).32 Over-diagnosis occurs when cancer that would never have been important during an individual's lifetime is diagnosed and treated. These biases can be eliminated in randomized controlled trials (RCTs) with mortality as an outcome. Therefore, most emphasis in public health guideline and in this review is placed on information from RCTs.
In our searches, we identified 809 citations and abstracts; 149 full-text papers were reviewed. Of these, 1 randomized trial of chest x-ray, in conjunction with a multiphasic screening program,33,34 and 5 RCTs35-40 of chest x-ray and/or sputum cytology screening for lung cancer were reviewed. In addition, 6 case-control studies,41-46 1 non-RCT47 and 4 older cohort studies (Appendix Table 3)48-52 were reviewed. Finally, we reviewed 6 recent cohort studies of lung cancer screening with CT.53-62
Table 1 and Table 2 summarize the methods and quality of the 6 RCTs and 1 non-RCT of lung cancer screening.33-40,47,63-85 Figure 1 shows the relative risks and confidence intervals (CIs) of these randomized trials. In the 1960s, a cluster randomized trial of chest x-ray screening involving approximately 55,000 men older than age 40 was conducted by the Northwest London Mass Radiography Service.35,36 In this trial, 29,723 male factory workers from 75 randomly identified firms were offered chest x-ray every 6 months and were compared with 25,300 controls from other factories who were offered screening at baseline and at 3 years. After 3 years, the annual mortality rate from lung cancer in the intervention group was 0.7/1,000; the rate was 0.8/1,000 in the control population, not different statistically.
Three National Cancer Institute (NCI)-sponsored RCTs of lung cancer screening in male smokers were conducted in the United States in the 1970s.37-39,63,64,68,73-75,80 The Memorial Sloan-Kettering (MSK)37,63-67 and the Johns Hopkins (JH) studies38,68-72 were identical in design and were conducted to evaluate the incremental benefit of adding sputum cytology to annual chest x-ray. Of the 20,427 male smokers (> 20 pack-years of smoking) aged 45 and older who volunteered for these 2 studies, 10,234 were randomized into a dual-screening group that was offered screening with annual chest x-ray and sputum cytology every 4 months for 5 years; 10,233 were assigned to a chest x-ray group that was offered annual chest x-ray screening for 5 years. Each group was followed for 5 to 8 years.
In the MSK study, the baseline screen identified 30 (6.0/1,000) lung malignancies in the dual-screening group and 23 (4.6/1,000) in the chest x-ray group.63 Following the prevalence screen, 114 subsequent (incident) lung cancer cases were identified in the dual-screening group and 121 in the annual x-ray group during the screening period, with 33 and 32 cases, respectively, diagnosed in the 2 years following screening. Combining the incidence and prevalence tumors, 144 cases of lung cancer were detected in each group during the study37,64,67; 40% of all lung cancer detected was stage I. The mortality rate was 2.7/1,000 person-years in both the chest x-ray and dual-screening groups.
In the JH study, the prevalence screen identified 39 malignancies in the dual-screening group and 40 in the chest x-ray group.38,71 After 8 years of followup, 194 incident cases of cancer were identified in the dual-screening group and 202 in the chest x-ray group. The mortality rates were 3.4/1,000 person-years in the dual-screening group and 3.8/1,000 person-years in the control group (not statistically significant differences) and were similar to community lung cancer mortality rates at the time.71,72
The first trial to evaluate the value of intense screening with chest x-ray was the Mayo Lung Project (MLP) involving 10,933 male smokers aged 45 or older.39,73-83 All participants underwent a prevalence screen with sputum cytology and chest x-ray, and 91 cases of cancer were identified (prevalence 0.83%).39,73,75 After the prevalence screen, 4,618 men were randomized to a study group screened with chest x-ray and pooled 3-day sputum cytology every 4 months for 6 years, and 4,593 to a control group were advised to have annual chest x-ray and sputum cytology. During the study period, 206 incident cases of lung cancer were identified in the dual-screening group and 160 in the control group. After 20 years of followup, lung cancer death rates were 4.4 (95% CI, 3.9-4.9) and 3.9 (95% CI, 3.5-4.4) per 1,000 person-years in the dual-screening and control groups, respectively.80
The MLP was the first individual RCT to specifically evaluate the role of chest x-ray in lung cancer screening, and was the most influential in determining current public health policy. Although it is rated as fair quality by USPSTF criteria, there are several limitations of the study. First, a prevalence screen detected 91 cases of lung cancer (0.83%). Thus, there was no completely unscreened control group. Also, these cases were followed separately and were not evaluated in the randomized comparison. Thus, any effect of these cases on mortality could not be determined. Second, nearly half of the controls obtained annual chest x-rays during the course of the study, with one-third of the malignancies in the control group discovered by screening chest x-ray; 73% of the controls received chest x-rays during the study's last 2 years. Third, compliance of the intervention group was 75%, reducing the study's power.73
The incidence of lung cancer in the MLP intervention group was approximately 22% higher than in the control group.73 The possibility of nonrandom distribution of lung cancer risk factors was evaluated by Marcus and Prorok81; the distribution was not found to vary significantly between the intervention and control groups. Although little detailed information is provided, there is evidence on review of the MLP publications that not all patients were asymptomatic,39,73 which could alter the findings of the screening study if patients with symptoms were disproportionately enrolled in the intervention group. However, there is no evidence to support this. The radiation exposure associated with chest x-ray in the MLP is generally thought insufficient to increase lung cancer incidence.86 Finally, another possibility is that the higher incidence of lung cancer in the screened population may represent the diagnosis of insignificant disease, eg, over-diagnosis.
Five fair-quality case-control studies were conducted in Japan between 1992 and 2001 (Table 3).42-46 As a generalization, the cases were comprised of fatal lung cancer and included high-risk men and low- or unknown-risk women. All cases were matched to controls by age, gender, and health insurance status. Some studies included adjustment for geographic region, number of prior health examinations, or both, and all accounted for smoking either by matching or statistical adjustment. For screening with chest x-ray, with or without sputum cytology occurring within 1 year of diagnosis, the odds ratios ranged from 0.40 to 0.72, 4 with statistically significant findings.
Several recent cohort studies, all without control groups, have evaluated screening for lung cancer with CT. The details of these studies are shown in Table 4. The Early Lung Cancer Action Project (ELCAP)54 involved 1,000 asymptomatic volunteers (46% female) aged 60 or older, with a median of 45 pack-years of smoking, and no prior malignancy, who were evaluated as medically fit for surgery and who each underwent chest x-ray and CT. Baseline chest x-ray identified 68 persons with concerning nodules, of which 33 were confirmed by CT; 7 patients were malignant, and all were resectable. Baseline CT identified 233 persons with nodules. After followup of 30 recommended biopsies, 27 malignancies were identified, of which 26 were resectable and 23 were stage I.54 Four other cases of lung cancer were also diagnosed based on non-nodule CT abnormalities. Approximately 1,184 subsequent annual examinations resulted in 40 persons (4%) requiring further evaluation, usually high-resolution CT, 9 biopsies, and 9 lung cancer diagnoses (7.2/1,000) (6 stage IA).55 There are no mortality data available yet on this cohort.
Three CT studies conducted in Japan involved large numbers of both high- and low-risk men and women aged 40 and older.56,58,59 Each study used a different protocol but also included chest x-ray and sputum cytology; at least 2 were conducted in areas where lung cancer screening with chest x-ray and sputum cytology had been conducted for many years. Among 15,050 baseline screens, 993 (6.6%) had abnormalities requiring high-resolution CT, at least 21 underwent biopsy; 71 lung tumors were identified (prevalence 0.47%), 63 of them stage I (89%). Researchers performed 21,762 incidence screens that resulted in at least 1,166 subsequent high-resolution CTs and identified 60 lung cancer cases (2.76/1,000), of which 45 were stage I (Table 4).
A study conducted at the Mayo Clinic involved 1,520 men and women aged 50 and older with 20 or more pack-years of smoking.60-62 A baseline screen identified 782 (51.4%) persons with 1 or more nodules requiring further evaluation; 26 (1.7%) were diagnosed with primary lung cancer based on CT alone. Among this cohort, 2,916 annual incidence screens identified 336 persons (12%) with new nodules; 10 new diagnoses of lung cancer (6.7/1,000) were made with CT alone. There were 2 cases of interval cancer and 2 diagnosed with sputum cytology only. Of the 40 persons with malignancies, 36 were non-small-cell lung cancer, of which 31 (86%) were resected for cure; 8 patients underwent surgery for benign disease.
Finally, a German study53 involving 817 asymptomatic volunteers aged 40 and older, with at least 20 pack-years of smoking, was conducted between November 1995 and July 1999. Baseline CT identified 350 persons with nodules, 269 of these persons underwent high-resolution CT, ultimately identifying nodules in 29 persons. Thirteen of the 29 persons with nodules underwent biopsy; malignancy was diagnosed in 10 of the persons, as well as 1 interval cancer. After an average of 2.7 years of followup, 6 patients are alive without evidence of recurrence.
Lung cancer is the leading cause of cancer-related death among women in the United States, and most cases are attributed to smoking.2 In addition, women have substantial exposure to passive smoking, and a significant proportion of lung cancer in nonsmoking women is attributed to passive smoking.18 Furthermore, although controversial, some studies suggest that for any level of smoking, women are at higher risk for developing lung cancer than men.4,87,88 For unknown reasons, women also tend to develop adenocarcinoma of the lung disproportionately to men,17,88,89 and adenocarcinoma is also found more commonly among nonsmokers.17 This cell type tends to occur peripherally89,90 and may be more apt to be detected with chest x-ray, CT, or both than other cell types. Consequently, radiological imaging and screening for lung cancer may perform differently among women. Unfortunately, no randomized trials of lung cancer screening have included women. The only data evaluating screening among women and including control populations come from 4 Japanese case-control studies evaluating screening among primarily nonsmoking women (passive smoking not assessed).43-46 These studies are summarized in Table 5 and show lung cancer mortality odds ratios for screening conducted within 12 months of lung cancer diagnosis ranging from 0.39 to 0.61; 2 studies found statistically significant differences; however, interpretation is limited by the screening biases discussed in this review. Five studies of CT have included women; mortality data are not yet available. In addition, randomized trials of lung cancer screening with chest x-ray and/or low-dose CT involving women are currently underway.
The personal and public health importance of lung cancer in the United States and worldwide is enormous, and even a small benefit associated with screening could save many lives. However, the outcomes of screening, as shown in this report, are mixed, with some lower grades of evidence evaluating chest x-ray with or without sputum cytology (case-control studies) showing benefit, and higher-grade evidence (RCTs) not showing benefit. The CT screening studies show that lung cancer can be diagnosed at an earlier stage than in usual clinical practice, but little is known about patient outcomes. Unfortunately, none of the existing randomized trials answer the question faced by clinicians: Should patients be screened for lung cancer at all?
The case-control studies from Japan give some support to chest x-ray screening for lung cancer. Although case-control studies are not considered the gold standard in evaluating screening efficacy and effectiveness, several authors believe they can be a useful and efficient way to evaluate a screening method.31,91,92 However, it is very difficult to overcome the possibility of volunteer/healthy screenee bias in case-control studies, even well-conducted ones; this might bias the study toward benefit, since persons choosing screening may differ from those not being screened in factors which of themselves influence lung cancer mortality.93
The CT cohort studies indicate that earlier-stage lung cancer can be detected. However, drawing conclusions from the uncontrolled CT studies is difficult because of the methodological biases discussed earlier. It is possible, based on the stage distribution of the detected tumors, that mortality may be reduced. However, because of lead-time and length bias, survival may be prolonged but mortality unchanged. Randomized trials of CT with mortality as an outcome are needed to definitively evaluate this issue. The higher rate of abnormal CT findings and lung cancer in U.S. and German studies compared with Japanese studies most likely result from (1) higher-risk populations being screened in the U.S. and Germany; (2) prior population lung cancer screening has been conducted in Japan; (3) different CT methods among studies; and (4) possible higher rates of histoplasmosis in the U.S.
The hope of benefit from lung cancer screening is high; however, the implications of screening, especially in the absence of proven benefit, are also great. Evaluating harm or potential harm associated with screening for lung cancer is difficult. One approach to this issue is to evaluate the 4 possible outcomes of screening: false-positive, false-negative, true-positive, and true-negative findings. The best data about outcomes from chest x-ray screening come from the recent CT studies, since data from the chest x-ray trials accumulated prior to the use of CT for evaluation of x-ray abnormalities, and many patients previously underwent thoracotomy or biopsy than would have in current clinical practice. Table 4 shows positive chest x-ray rates and the diagnostic outcomes associated with chest x-ray from the CT studies; most chest x-ray abnormalities are resolved or found to be false-positive results when evaluated by CT.54,59 For x-rays identified as suspicious for cancer in the NCI studies, the positive predictive value for cancer ranged from 41% to 60%.29
In the CT studies, the false-positive rate was the number of patients with CTs requiring further evaluation who did not have cancer. Using this criterion, the false-positive rates in the CT studies ranged from 5% to 50% in prevalence screens and 3% to 12% in incidence screens; most abnormalities were resolved with high-resolution CT. Among the CT studies reporting referral rates, 4.8% to 14.5% of patients undergoing high-resolution CT were referred for biopsy, from which most (63% to 90%) were diagnosed with cancer. These data are shown in Table 4. For comparison, in U.S. and European clinical practices, approximately half of patients undergoing surgical biopsy of indeterminate nodules subsequently receive a benign diagnosis.61,94 In the current practice setting, positron emission tomography scans are commonly used as a noninvasive means of discriminating between malignant and nonmalignant lesions95 and may reduce the rate of invasive procedures performed to evaluate indeterminate nodules.
Persons with false-positive results can experience a period of time potentially associated with high anxiety and concern, and for those pursuing further evaluation, the cost and risk associated with it. Although the false-positive rate is high in the lung cancer screening studies, the meaning of a false-positive lung cancer screening study (either chest x-ray or CT) to a patient may be different than for other types of cancer screening tests, since patients who currently smoke potentially have some control over their subsequent risk and may be able to more effectively modify their high-risk behavior. Data from the ELCAP study suggest that CT scan results, in combination with smoking cessation counseling, improved smoking cessation rates among all participants54 and that an abnormal CT finding was associated with nearly 2-fold greater odds of decreased smoking or cessation among current smokers.96 It is reasonable to assume that an abnormal screening chest x-ray might also influence smoking behavior.
An important and controversial issue in lung cancer screening is the question of over-diagnosis (and consequent over-treatment). The relatively high prevalence of unrecognized lung cancer in several studies suggests that there is a significant preclinical pool of lung cancer in high-risk populations.38,54,97 Whether all of these tumors would eventually present clinically is uncertain. Supporting over-diagnosis are data from the MLP showing increased rates of early tumors in the screened group compared with the control group without a change in the number of advanced tumors or subsequent mortality rates, suggesting diagnosis of a pool of indolent tumors.98 Although the higher lung cancer mortality rate among the intervention group in the MLP was not statistically significant, a major concern is that the increase in mortality might not be due to chance and may be a consequence of screening (eg, more persons undergo evaluation and treatment in the screened group and with treatments-associated risk, result in a true increase in mortality). Alternatively, an increase in lung cancer mortality rates among screened persons may be a consequence of misclassification of cause of death or "sticky-diagnosis bias,"98 meaning that in the absence of autopsy data, there is a propensity to label any diagnosed malignancy as the cause of death, regardless of the tumor's clinical course, which results in bias against screening when evaluating disease-specific mortality.99 Black et al100 noted that the excess lung cancer mortality observed among the screened group in the MLP, particularly death from metastatic adenocarcinoma, was probably at least partially a consequence of this type of differential misclassification.
Arguments against an important role for over-diagnosis in lung cancer are based on autopsy studies showing low rates (0.8%) of unrecognized lung cancer.101 Whether autopsy data are generalizable to living populations is questionable, particularly given selection biases for autopsy. Further data against over-diagnosis come from 2 natural history studies of both screen- and symptom-detected unresected stage I non-small-cell lung cancer that have shown that almost all patients die of lung cancer over 5 to 10 years.25,26 Whether a strong case for over-diagnosis should be made on the basis of current data is uncertain. However, it is possible that with an increasingly sensitive detection tool, such as CT, over-diagnosis may occur. The issue of over-diagnosis is particularly relevant to the harm associated with lung resection for cancer, where there is significant mortality and morbidity associated with treatment. More data are needed to definitively evaluate this issue.
Another potential harm of screening is false-negative findings with possible false reassurance. In current practice, the best estimate of the rate of false-negative results on chest x-rays comes from the CT studies, where false-negative rates as high as 75% were shown.54,59 Clinical series of chest x-ray suggest retrospective identification of lung cancer ranges from 12% to 90%.102,103 While CT is considered the gold standard for evaluating nodules, it has also been shown to have false-negative results62; and the potential for false reassurance with CT certainly exists, particularly if those screened believe that they are undergoing a definitive examination.
The rate of complications associated with biopsy was not described in the CT studies. The morbidity and/or mortality associated with thoracotomy for positive test resutls (true or false) is also difficult to evaluate. Studies of symptomatic patients suggest that the more lung tissue removed the greater the morbidity and mortality. Overall, mortality rates range from 1.3% to 11.6% and morbidity rates from 8.8% to 44% among several series reviewed, with lower rates among patients undergoing smaller resections, less comorbidity, and centers with greater surgical volume.28,47,104-110 Complication rates from studies among symptomatic patients are likely to be greater than complication rates among asymptomatic persons in screening programs directed at those judged healthy enough to undergo surgery.
Currently, most patients in the United States are not screened for lung cancer.111 However, because conclusions about lung cancer screening have been based on limited data and no trials have compared screening with no screening or screening among women, the issue is being reevaluated. Routine annual chest x-ray is being compared with usual care in the Prostate, Lung, Ovarian, and Colorectal Cancer trial (PLCO), which involves over 100,000 men and women aged 55 to 74.112,113 Data from this study should be available in 2010. The National Lung Screening Trial (NLST) will compare routine screening CT with chest x-ray in high-risk men and women aged 55 to 74.114
New technologies may also contribute to the early detection of lung cancer and potentially screening for lung cancer. Some currently being investigated include: immunocytochemical analysis of sputum with monoclonal antibodies115; identification of genetic mutations116; abnormal DNA methylation117,118; abnormal patterns of immunostaining, and other molecular changes.119-122 There are several other potential targets in sputum, bronchial fluid, and expired air that may have a role in early lung cancer detection and are currently being investigated.123,124
In summary, studies evaluating chest x-ray screening for lung cancer have had mixed findings, with stronger types of evidence from 30-year-old trials suggesting no benefit among male smokers and possible over-diagnosis, and weaker study designs suggesting benefit to men and women. There are important methodological limitations to all of these studies. The studies of CT have demonstrated that lung cancer can be diagnosed at a significantly earlier stage than what currently occurs in clinical practice. However, whether this will translate to a mortality benefit is unclear. In addition, even if CT is shown to be effective, the issue of cost-effectiveness remains.125 Critical information will come from the current RCTs of screening CT. Given the uncertainty associated with chest x-ray screening, it is unfortunate that the NLST does not include non-screened control groups. However, data will be available on chest x-ray screening from the PLCO trial in the next 5 to 8 years. In the meantime, other approaches for evaluation of screening should be considered, such as rigorously conducted case-control studies of chest x-ray and/or screening CT. We hope that new methods of screening for lung cancer will be developed and refined. Even a small decrease in lung cancer mortality attributed to screening would save thousands of lives each year.
This research was funded by the Agency for Healthcare Research and Quality (AHRQ). AHRQ staff and USPSTF members reviewed interim analyses and the final report. Prior to preparation of this manuscript, the full report was reviewed by 17 content experts in the area of lung cancer screening and revised accordingly.