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Final Evidence Summary

Lung Cancer: Screening, May 2004

May 15, 2004

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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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.

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.

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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.

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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.

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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.

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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

Lung Cancer Screening with Chest X-Ray with or without Sputum Cytology

Controlled Trials

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, e.g., over-diagnosis.

Case-Control Studies

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.

Lung Cancer Screening with Low-Dose CT

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 Screening among Women

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.

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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 (e.g., 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 results (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.

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Role of the Funding Source

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.

Acknowledgments

The authors would like to thank Kathryn Krages, A.M.L.S., M.A.; Susan Wingenfeld; and Kim Peterson, M.S., for their help in preparation of the full Systematic Evidence Review and this manuscript. They also thank Mark Helfand, M.D., M.P.H.; William Holden, M.D.; John McAnulty, M.D.; and James Reuler, M.D., for their helpful reviews of the manuscript.

This study was conducted by the Oregon Health & Science University Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality Contract No. 290-97-0018, Task Order No. 2, Rockville, MD.

Author Affiliations

[a] Oregon Health & Science University, Evidence-based Practice Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239
[b] Portland Veterans Affairs Medical Center, Portland, OR 97239
[c] Merck and Co., Inc., West Point, PA 19437
[d] University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ 07103

Copyright and Source Information

This document is in the public domain within the United States.

Requests for linking or to incorporate content in electronic resources should be sent via the USPSTF contact form.

Source: Humphrey LL, Teutsch S, Johnson MS. Lung Cancer Screening with Sputum Cytologic Examination, Chest Radiography, and Computed Tomography: An Update for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:740-53.

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Search No. Search Terms
1

Exp lung neoplasms or lung cancer.mp (mp = text words from title and abstracts)
bronchogenic carcinoma
pulmonary coin lesions
Pancoast's syndrome
pulmonary blastoma
2

Exp mass screening or screen.mp
genetic screening
mass chest x-ray
multiphasic screening
mandatory testing
3 1 and 2
4

Exp clinical trials or clinical trials.mp
clinical trials, phase 1 through 4
controlled clinical trials
multicenter studies
5 Cohort studies.mp
6

Exp epidemiologic studies or epidemiologic studies.mp
case-control studies
cohort studies
longitudinal studies
followup studies
prospective studies
cross-sectional studies
seroepidemiologic studies
7 Review$.mp
8 4 or 5 or 6 or 7
9 3 and 8
10 Limit 9 to human
11 Limit 10 to English (foreign-language articles that had English abstracts were included)
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Randomized Controlled Trials (RCTs)

Criteria:

  • Initial assembly of comparable groups: adequate randomization, including first concealment and whether potential confounders were distributed equally among groups.
  • Maintenance of comparable groups (includes attrition, crossovers, adherence, contamination).
  • Levels of followup: differential loss between groups; overall loss to followup.
  • Measurements: equal, reliable, and valid, and including masking of outcome assessment.
  • Clear definition of interventions.
  • Important outcomes considered.
  • Analysis: intention-to-treat analysis.

Definition of ratings based on above criteria:

Good: Meets all criteria: comparable groups are assembled initially and maintained throughout the study; followup at least 80%; reliable and valid measurement instruments applied equally to the groups; interventions clearly defined; important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for RCTs, intention-to-treat analysis is used.

Fair: Generally comparable groups assembled initially, but some question remains whether some (although not major) differences occurred in followup; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention-to-treat analysis is done for RCTS.

Poor: Groups assembled initially are not close to being comparable or maintained throughout the study; measurement instruments are unreliable or invalid or not applied at all equally among groups; outcome assessment not masked; and key confounders are given little or no attention. For RCTs, no intention-to-treat analysis.

Case-Control Studies

Criteria:

  • Accurate ascertainment of cases.
  • Nonbiased selection of cases and controls with exclusion criteria applied equally to both.
  • Response rate.
  • Diagnostic testing procedures applied equally to each group.
  • Measurement of exposure accurate and applied equally to each group.
  • Appropriate attention to potential confounding variables.

Definition of ratings based on above criteria:

Good: Appropriate ascertainment of cases and nonbiased selection of case and control participants; exclusion criteria applied equally to cases and controls; response rate equal to or greater than 80%; diagnostic procedures and measurements accurate and applied equally to cases and controls; and appropriate attention to confounding variables.

Fair: Appropriate ascertainment of cases and controls and exclusion criteria applied equally to cases and controls, and without major apparent selection or diagnostic work-up bias; response rate less than 80%; or attention to some but not all important confounding variables.

Poor: Major selection or diagnostic work-up biases; response rates less than 50%; or inattention to confounding variables.

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Study, Year Study Population Intervention Number Malignancies (%) Percent Resectable Survival
Philadelphia Neoplasm Research Project, 195148,49 6,136 men, age 45+ Photofluorograms and questionnaires every 6 mos for 10 yrs

Prevalence:
84 (1.37)
Incidence:
121

 35 8% (5 yrs)
Tokyo Metropolitan Government Study, 195351 1,871,374 men and women, all ages Intermittent CXR over 26 yrs (sputum cytology in some) 193 (0.01) 56 44% (5 yrs for resectable tumors) (usual 5-yr survival at that time, 20%)
Veterans Administration Trial, 195850 141,607 men, median age 62.8 CXR and sputum cytology 73 (0.052) 36 17% (32 mos)
South London Cancer Study, 195952 67,400 men, age 45+ CXR every 6 mos 234 (0.35) 56 18% (4 yrs) (usual survival at that time, 9%)
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Study, Year (Study Began) Population Intervention Prevalence
(%)		 Incident Lung Cancer (No) Advanced Tumors Stage III, IV (%) Non-resectable Tumors (%) Mortality Rate/1,000 Person-Yearsa
Northwest London Mass Radiography Service, 196035,36 Males >40 yrs; 19% former smokers; 67% current smokers 29,723 offered CXR every 6 mos over 3 yrs; 25,300 offered CXR at baseline and at 3 yrs Intervention:
31 ( 0.10 )
Control:
20 ( 0.08 )		 Intervention:
101
Control:
76		 Intervention:
NR
Control:
NR		 Intervention:
56
Control:
71		 3 yr followup
Intervention:
0.7
Control:
0.8
Kaiser Permanente, 196433,34 10,713 members aged 35-54;
17% smokers		 Intervention: 5,156 encouraged to have annual multiphasic health checkup including CXR
Control: 5,557 usual care		 NR NR NR NR 16 yr followup
Intervention:
8.6
Usual care:
7.6
Memorial Sloan-Kettering, 197437,63-67 10,040 male smokers aged ≥45 All participants: baseline CXR; 4,968 annual CXR and sputum cytology every 4 mos for 5-8 yrs; 5,072 annual CXR and screened over 5-8 yrs Dual screen:
30 (0.6)
CXR:
23 (0.46)		 Dual screen:
146
CXR:
155		 Dual screen:
64 (1.2) (incidence)
CXR:
63 (1.2) (incidence)		 Dual screen:
49
CXR:
47		 5-8 yr followup
Dual screen:
2.7
CXR:
2.7
Johns Hopkins, 197338,68-72 10,387 male smokers aged ≥45 All participants: baseline CXR; 5,266 CXR and sputum cytology at baseline and every 4 mos; 5,161 annual CXR for 5-8 yrs Dual screen:
39 (0.75)
CXR:
40 (0.78)		 Dual screen:
194
CXR:
202		 NR Dual screen:
53
CXR:
56		 5-8 yr followup
Dual screen:
3.4
CXR:
3.8
Mayo Lung Project, 197139,74-76,80 10,933 male smokers aged ≥45 All participants: baseline CXR, 3-day pooled sputum cytology; 4,618 to CXR and 3-day pooled sputum cytology every 4 mos for 6 yrs; 4,593 received usual care with advice for annual CXR and sputum cytology 91 (0.83) Dual screen:
206
Usual care:
160		 Dual screen:
107 (2.3)
Usual care:
109 (2.4)		 Dual screen:
32
Usual care:
19		 20 yr followup
Intervention:
4.4
Usual care:
3.9
Czech, 197540,84,85 6,345 male smokers aged 40-64 After baseline CXR: 3,171 received CXR every 6 mos over 3 yrs and 3,174 received usual care; at end of study (yrs 4-6), CXR performed annually in each group 19 (0.30) Dual screen:
108
Control:
82		 Dual screen:
53 (1.7)
Control:
46 (1.4)		 Dual screen:
77
CXR:
77		 15 yr followup:
Dual screen:
7.8
Control:
6.8
Wilde, 1972-197747 b All men in 14 districts aged 40-65 (n = 143,880) Intervention: 41,532 in 4 districts offered chest fluorography every 6 mos
Control: 102,348 in 10 districts offered chest fluorography every 12-24 mos		 Intervention:
54
Control:
68		 Intervention:
320
Control:
599		 NR Intervention:
72
Control:
81		 10 yr followup:
Intervention:
0.8
Control:
0.6

Notes: CXR, chest x-ray; NR, not reported.

a Between-group differences were not statistically significant for all studies.
b Non-randomized study.

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Study Assembly of Comparable Groups: Randomization/Allocation Concealment Maintenance of Comparable Groups Outcomes Assessment: Validity of Method, Masking Attendance, Compliance, Contamination, Crossovers Analysis, Exclusions, and External Validity Study Quality
Northwest London Mass Radiography Service35,36 Cluster randomized by random number; examiners not clearly blind; comparable in age structure and smoking habits; no apparent occupational exposures 99% followup Cause of death determined from hospital records and General Register's office; blinding not described Intervention: 63%
Control: 63%
Cross-over: NR		 Intention-to-treat analysis; no reported exclusions; age and smoking habits similar Fair
Kaiser Permanente33,34 Randomized by patient record numbers with concealed code; more chronic lung disease in intervention group (8.9% vs 7.5%) Poor followup Blind review of death Intervention:
60% underwent MHC
(mean, 6.8 exams)
Cross-over:
64% of controls had MHC
(mean, 2.8 exams)		 Very low-risk population Poor
Memorial Sloan-Kettering37,63-67 Computer-generated randomization (not described); all cause mortality similar Formal protocol/algorithm for followup; 55 lost to followup All deaths reviewed by statisticians, clinicians, and pathologists blind to study group Dual screen:
63.2%
CXR:
65.2%		 Intention-to-treat analysis; only exclusion was prior lung cancer Fair
Johns Hopkins38,68-72 Computer generated randomization (not described); allocation concealment unclear; fairly comparable when evaluated by age, smoking history, non-tobacco carcinogen exposure Formal algorithm for followup; 1.3% lost to followup All deaths reviewed by statisticians, clinicians, and pathologists blind to study group Uncertain; 19% withdrew from active screening Intention-to-treat analysis; formal protocol for evaluation; only exclusion was prior lung cancer Fair
Mayo Lung Project39,74-76,80 Randomization method not described; allocation concealment unclear; similar distribution age, smoking exposure to non-tobacco carcinogens, and pulmonary disease Adequate; good followup of all participants in both groups All deaths reviewed by statisticians, clinicians, and pathologists blind to study group; National Death Index used for latest followup Intervention:
75%
Cross-over:
73% of controls had CXR within last 2 yrs of study		 Intention-to-treat analysis; formal protocol for evaluation; Mayo Clinic population with life expectancy estimates of 5 yrs Fair
Czech40,84,85 Randomization stratified by age, smoking history, socioeconomic status, residence, occupational exposure; allocation concealment unclear; no differences observed in these characteristics; all cause mortality, smoking-related deaths higher in intervention group Not well reported Cause of death ascertained from death certificates; autopsy in 1/3 of patients; blind review not described Intervention: 92.5%
Cross-over: rare		 Significantly higher all-cause mortality in screened group, suggesting bias in randomization Poor
Wilde47 Nonrandomized; similar community distribution of smoking habits and economic structure; similar all-cause mortality rates; population age not described Adequate description; greater number dropouts in control group Blinding not described; nonsystematic ascertainment of cause of death NR Intention-to-treat analysis; no reported exclusions; mortality rates not adjusted for age Poor

Notes: CXR, chest x-ray; MHC, multiphasic health checkups; NR, not reported.

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Study, Setting, Year Cases: Patients with Fatal Lung Cancer Controls Matching/Adjustment Factors Odds Ratio for Lung Cancer Mortality Associated with Screening (95% Confidence Interval) Study Quality
Ebeling and Nischan, Berlin, 198741 130 men aged <70 204 patients from community center Age; opportunity for screening; location 0.88 (0.53-1.45) Poorb c
194 patients from hospital outpatient department Age; opportunity for screening 1.09 (0.67-1.78)
Okamoto et al, Japan, 199942 158 men and 35 women aged 40-74 579a National Health Insurance; smoking status; opportunity for screening; location 0.54 (0.34-0.85) ≤12 mos
0.54 (0.30-0.96) ≤24 mos
0.50 (0.30-1.15) 24-36 mos		 Fair
Sobue, Japan, 200043 208 high-risk men, 65 low-risk women 1,269a National Health Insurance; smoking status; opportunity for screening; health checkups 0.72 (0.5-1.03) ≤12 mosd
0.83 (0.56-1.23) ≤12-24 mosd		 Fair
Sagawa et al, Japan, 200144 258 smoking and nonsmoking men and 70 nonsmoking women aged >39 1,886a Smoking status; opportunity for screening (all screened negative in 1989); location 0.54 (0.41-0.73) ≤12 mosd
1.24 (0.59-2.59) 12-24 mosd e
0.62 (0.42-0.92) ≤24 mosd
0.64 (0.36-1.14) ≤36 mosd
2.41 (0.54-10.7) ≤48 mosd		 Fair
Tsukada et al, Japan, 200145 149 high-risk men and 25 non-high-risk (nonsmoking) women aged >40 801a National Health Insurance; smoking status; opportunity for screening 0.40 (0.27-0.59) ≤12 mosd
1.42 (0.63-3.17) ≤12-24 mosd		 Fair
Nishii et al, Japan, 200146 412 men and women aged 40-79 3,490a National Health Insurance; smoking status; opportunity for screening; location 0.59 (0.46-0.74) ≤12 mosd Fair

Notes: CXR, chest x-ray.

a All matched by age, sex, and location.
b Received a poor score because selection of controls was potentially biased.
c Received a poor score for not controlling for smoking.
d High-risk individuals were also screened with sputum cytology.
e Excluding screening <12 months.

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Study, Year Screening Type Screening Interval (Months) Number of Screens Positive Test Results (%) Recommendation for Followup Based on LDCT (Number) Surgery for Diagnosis (Benign) (Number) Lung Cancerb (%) Stage 1 Disease (%)
HRCT Referral Biopsy
Diederich et al, 200253 Baseline LDCT   817 350 (43) 269 29 13 1 (1) 11 (1.3)
(1 interval)		 58
Henschke et al, 1999, 200154,55 Baseline LDCT 6-18 1,000 237 (24) 233 104 27 0 31 (3.1) 85
Incidence LDCTa 1,184 40 40 NR 9 NR 9 (0.9) 67
Baseline CXR 1,000 68 (6.8)
(33) (3.3)c		 33 NR NR 0 7 (0.7)  
Nawa et al, 200256 Baseline LDCT 12 7,956 2,099 (26.4) 541 64 NR NR 36 (0.5) 86
Incidence LDCTa 5,568 NR 148 7 NR NR 4 (0.1) 100
Sone et al, 200158 Baseline LDCT 12 5,483 279 (5.1) 266 NR NR NR (7) 22 (0.4) 100
Incidence LDCTa 8303b 309 297 NR NR NR(9) 37 (0.6) 86
Sobue et al, 200259 Baseline LDCT 6 1,611 186 (11.5) 186 25 21 0 13 (0.8) 77
Incidence LDCTa 7,891 721 721 57 35 1 (0) 19 (0.2) 79
Baseline CXR 1,611
7,891		 55 (3.4)
202		 22
89		 9
7		 8
4		 0
0		 5 (0.3)
3 (0.2)		 60
0
Swensen et al, 2002, 200361,62 Baseline LDCT 12 1,520 782 (51.4) NR NR NR   27 (1.8)d  
Combined data           NR (8)   66
Incidence LDCTa 2,916 336 NR NR NR   11 (0.7)
(+ 2 interval)d		  

Notes: CXR, chest x-ray; HRCT, high-resolution computerized tomography; LDCT, low-dose computerized tomography; NR, not reported.

a All data presented by individual except incidence, which indicates screening tests performed.
b Percentage of lung cancer for incidence = cases of lung cancer identified with incidence screening/cases of lung cancer in cohort minus cases of prevalence cancer.
c After LDCT.
d One case of malignant disease.

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Study, Year Study Type Setting Description of Sample Intervention Odds Ratio or Relative Risk or Number of Malignancies Identified
Sobue, 200043 Case-control Japan 65 low-risk patients CXR with or without sputum cytology 0.42 (0.20-0.87) for screening < 12 mos
Sagawa et al, 200144 Case-control Japan 70 low-risk patients aged > 39 CXR with or without sputum cytology 0.57 (0.30-1.11) for screening < 12 mos
Tsukada et al, 200145 Case-control Japan 25 low-risk patients aged > 40 CXR with or without sputum cytology 0.61 (0.23-1.68) for screening < 12 mos
Nishii et al, 200146 Case-control Japan 412 mixed-risk patients aged 40-79 CXR 0.39 (0.24-0.64) for screening < 12 mos
Henschke et al, 1999, 200154,55 Cohort U.S. 460 high-risk participants Baseline LDCT and repeated LDCT NR by sex
Sone et al, 200158 Cohort Japan

2,512 participants

1,816 participants

Baseline LDCT

Repeated LDCT

11 malignancies identified

4 malignancies identified
Diederich et al, 200253 Cohort Germany 229 high-risk participants Baseline LDCT NR by sex
Nawa et al, 200256 Cohort Japan 1,367 participants (4.3% current or former smokers)

Baseline LDCT

 
Annual repeated LDCT

12 malignancies identified,
all in nonsmokers

0
Swensen et al, 2002, 200361,62 Cohort U.S. 735 participants Baseline and repeated LDCT NR by sex

Notes: CXR, chest x-ray; LDCT, low-dose computerized tomography; NR, not reported.

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Chart showing the relative risks and 95-percent confidence intervals for mortality outcomes in 6 randomized controlled trials of lung cancer screening with chest radiography with or without sputum cytology. Go to Text Description for details.

Text Description

Figure 1 represents the relative risks and 95% confidence intervals for mortality outcomes in randomized controlled trials of lung cancer screening with chest radiography with or without sputum cytology. A footnote to the title further explains that followup ranged from 3 to 20 years among the 6 studies. The top of the figure has the text, "Relative risk," with "95% confidence interval" written below it. (Confidence interval has been described as the range of two values within which it is probable that the true value lies for the whole population of participants from whom the study participants were selected. Relative risk has been described as the ratio of the risk of an event among an exposed population to the risk among the unexposed.)

Six studies are listed down the left side of the diagram. Each has a corresponding relative risk rate data point represented by a variably sized black box, on a horizontal line, directly across from the name of the study. The solid black square size represents Mantel-Haenszel weight (represented in a footnote at the bottom of the figure). The data point is representative of the relative risk rate, listed on a horizontal line at the bottom of the figure (y axis), ranging from .5 on the far left, to 2.0 on the far right. A vertical line cuts down the middle of the figure ending at the 1.0 on the relative risk line. Data points fall either to the left or the right of the vertical 1.0 relative risk rate line. (A data point on the left side, or lower than 1.0, represents a decreased risk, while a data point on the right side, or greater than 1.0, represents an increased risk.)

The 6 studies, and their black box size compared to each other (e.g., 1-6, 1=largest, 6=smallest) and orientation related to the vertical 1.0 relative risk line, are as follows:

Study 1. Northwest London Mass Radiography Service Study, 1968, 4 for black box, left side of line.
Study 2. Kaiser Permanente Study, 1979 with data point, 6 for black box, right side of line.
Study 3. Memorial Sloan-Kettering, 1984 with data point, 3 for black box, left side of line.
Study 4. Johns Hopkins Study, 1982 with data point, 5 for black box, left side of line.
Study 5. Mayo Lung Project, 2000 with data point, 1 for black box, right side of line.
Study 6. Czech Study, 2000 with data point, 2 for black box, right side of line.

a Followup ranged from 3 to 20 years among the 6 studies.
b Solid black square size represents Mantel-Haenszel weight.

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