Lung Cancer Screening with Sputum Cytologic Examination, Chest Radiography, and Computed Tomography: An Update for the U.S. Preventive Services Task Force

No major medical professional organization currently recommends screening for lung cancer. The U.S. Preventive Services Task Force (USPSTF) gave lung cancer screening a grade D recommendation in both 1985 and 1996, meaning that there were fair-quality data to recommend against screening for lung cancer (1) 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 cancerassociated deaths were predicted (2). Worldwide, lung cancer and lung cancerrelated 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 is 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 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 after smoking cessation (15-17). Household exposure to secondhand smoke is substantial and is also associated with lung cancer (18). These smoking exposure rates, combined with large numbers of individuals 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 fatal 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 related to incurable advanced local or metastatic disease (19). Since lung cancer mortality is closely associated with disease stage at the time of diagnosis, it is believed (primarily on the basis of indirect evidence) (22-28) that early surgical resection is associated with better outcomes. Therefore, the current standard of practice is to resect most nonsmall-cell lung cancer without evidence of metastatic spread. For many of these reasons, screening for and treating early lung cancer is intuitively appealing. Methods This review discusses studies of chest radiography, sputum cytologic examination, and low-dose computed 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 USPSTF (30) (Appendix). For the purposes of this review, high-risk persons are those who currently smoke or have ever smoked and low-risk persons are those who have never smoked. To rate each of the 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 radiography 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 as fair or better quality are described in the text. Methodologic 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 periodically screened sample) (31), and volunteer bias (a type of selection bias in which volunteers are compared with nonvolunteers) (32). Overdiagnosis occurs when cancer that would never have been important during an individual's lifetime is diagnosed and treated. These biases can be eliminated only in randomized, controlled trials that include death as an outcome. Therefore, public health guidelines and this review place the most emphasis on information from randomized, controlled trials. This research was funded by the Agency for Healthcare Research and Quality. Agency staff and USPSTF members reviewed interim analyses and the final report. Before preparation of this manuscript, the full report was reviewed by 17 content experts in lung cancer screening and was revised accordingly. Data Synthesis In our searches, we identified 809 citations and abstracts; 149 full-text papers were reviewed. Of these, 1 randomized trial of chest radiography in conjunction with a multiphasic screening program (33, 34) and 5 randomized, controlled trials of chest radiography, sputum cytologic examination, or both as screening for lung cancer (35-40) were reviewed. In addition, 6 casecontrol studies (41-46), 1 nonrandomized, controlled trial (47), and 4 older cohort studies (48-52) were reviewed (Appendix Table 2). We also reviewed 6 recent cohort studies of lung cancer screening with CT (53-62). Lung Cancer Screening with Chest Radiography with or without Sputum Cytologic Examination Controlled Trials The methods and quality of the 6 randomized, controlled trials and the single nonrandomized, controlled trial of lung cancer screening (33-40, 47, 63-85) are shown in Tables 1 and 2. The Figure shows the relative risks and 95% CIs of these randomized trials. In the 1960s, the Northwest London Mass Radiography Service conducted a cluster randomized trial of chest radiography screening in approximately 55 000 men older than 40 years of age (35, 36). In this trial, 29 723 male factory workers from 75 randomly identified firms were offered chest radiography 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 was 0.7 per 1000 person-years in the intervention group and 0.8 per 1000 person-years in the control group, not a statistically significant difference. Table 1. Controlled Trials of Lung Cancer Screening with Chest Radiography with or without Sputum Cytologic Examination Table 2. Methods and Quality of Controlled Trials of Lung Cancer Screening Figure. Mortality in randomized, controlled trials of lung cancer screening with chest radiography with or without sputum cytologic examination. The National Cancer Institute sponsored 3 randomized, controlled trials of lung cancer screening in male smokers in the United States in the 1970s (37-39, 63, 64, 68, 73-75, 80). The Memorial Sloan-Kettering Study (37, 63-67) and the Johns Hopkins Study (38, 68-72) were identical in design and were conducted to evaluate the incremental benefit of adding sputum cytologic examination to annual chest radiography. Of the 20 427 male smokers ( 20 pack-years of smoking) age 45 years or older who volunteered for these 2 studies, 10 234 were randomly assigned to a dual-screening group that was offered screening with chest radiography annually and sputum cytologic examination every 4 months for 5 years; 10 233 were assigned to a chest radiography group that was offered annual screening for 5 years. Each group was followed for 5 to 8 years. In the Memorial Sloan-Kettering Study, baseline screening identified 30 (6.0 per 1000) malignant tumors in the dual-screening group and 23 (4.6 per 1000) in the chest radiography group (63). After prevalence screening, 114 subsequent (incident) cases of lung cancer were identified in the dual-screening group and 121 were identified in the annual radiography group during the screening period. Thirty-three and 32 cases, respectively, were diagnosed in the 2 years following screening. When the incidence and prevalence tumors are combined, 144 cases of lung cancer were detected in each group during the study (37, 64, 67); 40% of all lung cancer detected was stage I. The mortality rate was 2.7 per 1000 person-years in both the chest radiography and dual-screening groups. In the Johns Hopkins Study, prevalence screening identified 39 malignant tumors in the dual-screening group and 40 in the chest radiography group (38, 71). After 8 years of follow-up, 194 incident cases of cancer were identified in the dual-screening group and 202 were identified in the chest radiography group. The mortality rates were 3.4 per 1000 person-years in the dual-screening group and 3.8 per 1000 person-years in the control group (not statistically significant differences) and were similar t