for the PLCO Project Team
Affiliations of authors: Hubert H. Humphrey Cancer Center, North Memorial Medical Center, Robbinsdale, MN (MMO); Biometry Research Group (PMM, PH, DLL, PCP), Early Detection Research Group (JKG), Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD; Mountain States Tumor Institute, St. Luke's Regional Medical Center, Boise, ID (TMB); Marshfield Clinic Research Foundation, Marshfield, WI (WH); Henry Ford Health System, Detroit, MI (PAK); Environmental and Occupational Health Studies Section, University of Minnesota, Minneapolis, MN (JC); Information Management Systems, Inc., Rockville, MD (TLR, SDW); Westat, Rockville, MD (SP)
Correspondence to: Martin M. Oken, MD, Hubert H. Humphrey Cancer Center, North Memorial Medical Center, 3300 Oakdale Ave. N, Plaza 100, Robbinsdale, MN 55422 (e-mail: martin.oken{at}northmemorial.com).
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ABSTRACT |
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INTRODUCTION |
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Chest radiograph and sputum cytology have been the most common screens for lung cancer. These two methods are currently the only screening procedures that have been evaluated in controlled trials for the detection of early-stage asymptomatic lung cancer that used disease-specific reduction in mortality as the endpoint. Several studies of screening for lung cancer by chest radiograph with or without sputum cytology were conducted in both the United States and the United Kingdom in the 1950s and 1960s, but none found a reduction in lung cancer mortality rate (410).
The efficacy of screening for lung cancer has also been evaluated in four randomized controlled trials (1115), three of which (11,1315) were sponsored by the National Cancer Institute as part of the Cooperative Early Lung Cancer Detection Program (16). All enrolled male smokers only, and all had a primary endpoint of mortality from lung cancer. Two of these studies (11,12) compared periodic chest radiographs done at regular intervals with "no screening," which, in practice, actually consisted of less frequent radiographs. In the other two studies (14,15), all participants received an annual chest radiograph, but the intervention arm participants also received sputum cytologic examinations every 4 months. The Mayo Lung Project (11,1719), the most influential of these four studies, prevalence-screened 10 933 men ages 45 years or older who were current smokers of at least one pack per day and then enrolled and randomly assigned the 9211 who did not have lung cancer or other exclusionary conditions. Participants in the intervention arm received a chest radiograph and sputum cytologic examination every 4 months for 6 years; participants in the control arm received no additional study exams but, at trial entry, did receive standard Mayo advice to obtain annual chest radiographs and sputum cytologic examination for screening. In fact, approximately 50% of the men in the control arm received a chest radiograph in the final year of the study (19). At the conclusion of the study in 1983, 13 years after the first participant and 7.5 years after the last participant were randomly assigned to a study arm, 206 lung cancers had been diagnosed in the screening group, and 160 lung cancers had been diagnosed in the control group. There was no difference in mortality rates between the two groups, even on reanalysis with a median follow-up of 20.5 years (20). For comparison, the Czechoslovakia lung cancer screening study enrolled a total of 6346 male smokers aged 4064 years (12). Participants in the screened arm were evaluated every 6 months for 3 years with a chest radiograph and sputum cytologic examination. They were compared with a no-screen control arm after a baseline prevalence screen in all participants. Control subjects received a chest radiograph during the third study year, and all participants (intervention and control) received annual chest radiographs for an additional 3 years. In the final report (12) at the end of the 6-year screening period, there were 108 lung cancers and 85 deaths in the screening group and 82 lung cancers and 67 deaths in the control group, but there was no statistically significant difference in mortality. The Johns Hopkins and Memorial Sloan-Kettering Lung Projects together enrolled more than 20 000 male smokers older than 45 years (1315). All participants in these studies received an annual chest radiograph and were randomly assigned to receive either sputum cytologic examination every 4 months or no sputum examination. The studies are therefore usually viewed as having assessed the usefulness of sputum cytologic examination. Neither study showed a reduction in lung cancer mortality.
The lack of an observed benefit in these trials led to the current belief that lung cancer screening by chest radiograph with or without sputum cytologic examination is ineffective for reducing lung cancer mortality. Nevertheless, screening with chest radiographs does detect more stage I cancers than are expected in the absence of screening (1315). Longer survival of screened patients, compared with that of patients diagnosed through usual care, is observed as well, but lead time and overdiagnosis explain, at least in part, these apparent benefits (20). Because the chest radiograph is simple, widely available, noninvasive, and relatively inexpensive, it continues to be used as a screening modality, even in the absence of evidence demonstrating a definitive benefit.
Concern about insufficient size of previous studies (1119), as well as difficulties in the interpretation of results of completed studies, raised the possibility that a small but important benefit from annual chest radiograph could have been missed (20). In 1992, the National Cancer Institute initiated the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, the largest and most ambitious cancer screening trial undertaken in the United States (21). This trial differed from the Mayo Lung Project in several key respects. The most important difference was that the Mayo Lung Project was limited to men only, whereas the PLCO included men and women in nearly equal numbers. Furthermore, the PLCO randomly assigned nearly 155 000 participants to a screening group or a control group and was, therefore, able to detect smaller, yet clinically meaningful, lung cancer mortality differences than these prior studies. In contrast to the Mayo Lung Project, there was also no prevalence or baseline screen for control subjects in the PLCO, and control subjects were not instructed at trial entry to obtain chest radiographs outside the study.
We report the results of the initial lung cancer screening round for the intervention arm of the PLCO Trial. The PLCO Trial is unique in that it presents the largest prevalence screen for lung cancer, one that was conducted in a population with a mixture of participants of different sexes, races, and smoking histories. The comparison of data across arms, including lung cancer mortality, will be reported at a later date.
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PARTICIPANTS AND METHODS |
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The components of the PLCO Cancer Screening Trial, including a detailed description of the trial's design and operations, have been described elsewhere (21). The main objective of the study is to determine whether a screening program for prostate, lung, colorectal, or ovarian cancer in healthy subjects can reduce mortality from these diseases.
The study was open to persons between the ages of 55 and 74 years. Study participants could not have been diagnosed with prostate, lung, colorectal, or ovarian cancer at any time or be undergoing treatment for any cancer other than basal cell or squamous cell skin cancer. Exclusions included anyone participating in another cancer screening or primary prevention trial, men who had taken finasteride (Proscar) in the 6 months before entry or who had had more than one prostate-specific antigen blood test in the past 3 years, and individuals who had had colonoscopy, sigmoidoscopy, or a barium enema examination in the past 3 years. Individuals with previous surgical removal of the entire prostate, one lung, or the entire colon were also excluded from the study. Women with prior removal of both ovaries were initially excluded; however, as of 1996, they were allowed to enroll. Recruitment was directed toward volunteers in the general population, and direct mail was used primarily as the recruitment strategy. Enhanced recruitment methods were used to target minority populations. All participants signed informed consent documents approved by both the National Cancer Institute and their local institutional review board.
On entry in the study, subjects were given a self-administered baseline questionnaire that included questions about personal sociodemographic characteristics (age, race, sex, marital status, and education), family history of cancer, personal medical history, cigarette smoking history (status, age started and stopped, and amount smoked), and cancer screening history in the 3 years before entry. The questionnaire covered topics believed to be relevant to risk factors for the PLCO Trial cancers.
The PLCO was designed as a two-armed randomized trial with a target enrollment of 37 000 women and 37 000 men, aged 5574 years at entry, in the screened arm and equal numbers of women and men enrolled in the control arm. The flow of participants into the trial is outlined in Fig. 1. A total of 154 942 participants have been enrolled, with 77 477 assigned to the control group and 77 465 assigned to the intervention group. Randomization and screening were carried out at the following 10 screening centers: University of Colorado Health Sciences Center, Denver, CO; Lombardi Cancer Research Center of Georgetown University, Washington, DC; Pacific Health Research Institute, Honolulu, HI; Henry Ford Health System, Detroit, MI; University of Minnesota School of Public Health, Minneapolis, MN; Washington University School of Medicine, St. Louis, MO; University of Pittsburgh/Pittsburgh Cancer Institute/Magee-Women's Hospital, Pittsburgh, PA; University of Utah School of Medicine, Salt Lake City, UT; Marshfield Clinical Research Foundation, Marshfield, WI; and the University of Alabama at Birmingham, Birmingham, AL. Trial participants are to be followed for at least 13 years from entry.
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When participants received a positive screen result, they were referred to their primary health care provider who then directed the follow-up and evaluation. Medical records were obtained to document follow-up activity.
Statistical Analyses
We used proportions to measure screen positivity, lung cancer detection, and positive predictive value. Chi-square tests of independence (SAS Systems for Windows release 8.01, SAS, Cary, NC) were used to evaluate the statistical significance of differences in proportions. A normal approximation to the binomial distribution (22) was used to calculate 95% confidence intervals [CIs] for proportions. All statistical tests were two-sided.
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RESULTS |
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The PLCO study randomly assigned 154 942 participants from November 8, 1993, through July 2, 2001 (as noted in Fig. 1), to intervention and control arms. Approximately half of the participants, 77 465, were randomly assigned to the intervention arm and were scheduled for an initial screening chest radiograph. Similar numbers of men and women were entered in the study. Consequently, this is also the largest randomized, controlled trial of screening for lung cancer in women, enrolling 78 234 and randomly assigning 39 115 female participants to the intervention (screening) arm.
The characteristics of the intervention arm participants are presented in Table 1. Sixty-four percent of the participants were 5564 years old at enrollment, and 36% were 65 years or older. Most participants who enrolled in this study were white, with blacks accounting for only 5.1% of participants, despite a concerted effort to recruit individuals from minority populations. Other minority populations, including Hispanic, Asian, Pacific Islander, and Native American, accounted for 6.4% of participants.
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Compliance
A total of 10 427 trial participants randomly assigned to the screening arm did not receive their initial chest radiograph. Overall compliance for the first chest radiograph was 86.5% (89.0% for men and 84.1% for women). There was no strong association of age with compliance in this study, although the rate was lowest (84.1%) in subjects aged 7074 years. Compliance was slightly lower among current smokers (84.0%) and among heavy smokers (85.9%) than among other enrolled participants, but overall a compliance rate of more than 85% was generally maintained, as assumed in the original study design and statistical power calculations (21).
Screening Results
The rate of positive results for initial chest radiographs was 8.9% (95% CI = 8.7% to 9.2%). The rate was statistically significantly higher (P<.001) in men (9.6%, 95% CI = 9.3% to 10.0%) than in women (8.2%, 95% CI = 7.9% to 8.5%) (Table 2). The rate of a positive screen result increased with age for both sexes. Men had a higher rate of positive screen results than women in each age group and for each smoking status (data not shown). The rate of positive screen results was different (P<.001) for the various smoking status categories, from never smoker (8.0%, 95% CI = 7.6% to 8.2%), to former smoker (9.5%, 95% CI = 9.2% to 9.9%), to current smoker (11.0%, 95% CI = 10.3% to 11.8%). Never smokers account for 46.8% of the study population and 46.6% of the subjects screened. Their positivity rate of 8.0% is surprisingly high when compared with that of current smokers of at least 30 pack-years (11.6%, 95% CI = 10.7 to 12.6).
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Among those 5991 participants with a positive initial screen, we detected 126 lung cancers within 12 months of the initial chest radiograph (47% in women and 53% in men). Thus, the positive predictive value observed for chest radiograph was 2.1%; i.e., 2.1% (95% CI = 1.7% to 2.5%) of positive screens led to a diagnosis of lung cancer, with a total of 1.9 lung cancers detected for every 1000 initial screening chest radiographs. Despite an apparent sex-related difference in the radiograph positivity rate (Table 2), men and women had similar rates of lung cancer diagnosis, similar positive predictive values, and similar numbers of lung cancers diagnosed per 1000 screens (Table 3).
Among current smokers, lung cancer was diagnosed in 6.3 participants per 1000 screens (Table 4). Former smokers had 4.9 and 1.1 cancers per 1000 screens, respectively, depending on whether they did or did not smoke within the prior 15 years. Fourteen (11.1%, 95% CI = 5.6% to 16.6%) of the 126 cancers were diagnosed in the never smoker population, all but two of which were found in women. Among the 31 257 never smokers, the positive predictive value for a positive chest radiograph was only 0.6% (95% CI = 0.3% to 0.9%), and the lung cancer detection rate was only 0.4 per 1000 screens. There was a pattern of more frequent lung cancer diagnosis among men who were current smokers (8.0 cancers per 1000 screens) than among women who were current smokers (4.0 cancers per 1000 screens) (Table 5). This pattern was not observed in former or never smokers.
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DISCUSSION |
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The rate of lung cancer detection in the initial PLCO screen was similar to that in the prevalence screen of the Mayo Lung Project. The PLCO detected 8.0 lung cancers per 1000 baseline screens of male smokers, compared with 8.3 in the Mayo Lung Project (11).
We detected a high rate of cancer in former smokers but an extremely low rate in never smokers, even though the never smoker group accounted for 41.5% of the positive screens found at baseline. The concerns raised by positive interpretations of screening chest radiographs in never smokers will have to be resolved by additional studies if screening were to become widely practiced.
One premise of any screening effort is that it will lead to earlier detection of cancer so that the cancer can be diagnosed and treated at an earlier, more curable stage. It is well documented (2426) that the 5-year survival rate in stage I nonsmall-cell lung cancer is 50%-70%, which is considerably higher than the rate in stage II nonsmall-cell lung cancer. These more advanced lung cancers are usually fatal within 2 years of diagnosis. If a beneficial stage shift does occur, it would be reflected in the central analysis in this trial, the comparison of lung cancer mortality among participants in the screening arm with that among participants in the control arm. These data will be reported at a later date when sufficiently mature.
An important feature of this study is that 39 115 women were accrued and randomly assigned to the intervention arm. The PLCO is the first major controlled study to evaluate screening for lung cancer in women. It was therefore important, in this preliminary analysis, to compare the results among women with those among men. We found that the incidence of positive screens was lower among women (8.2%) than among men (9.6%). This trend was found in every age group, in current and former smokers, in never smokers, and in smokers with a smoking history of less than 30 pack-years or of 30 or more pack-years. In an analysis of the relationship of sex and smoking status with lung cancer detection among all groups, we found a somewhat higher incidence of lung cancer among men (2.0 lung cancers per 1000 screens) than among women (1.8 lung cancers per 1000 screens). By smoking category, it was only among current smokers that we found a lower incidence of lung cancer among women (4.0 per 1000 screens) than among men (8.0 per 1000 screens) (Table 5). This result may merely reflect a dose difference per category, as suggested by the fact that women represent 59% of the group of current smokers with a smoking history of less than 30 pack-years and only 37% of the group of current smokers with a smoking history of 30 pack-years or more. The observation that 12 of the 14 lung cancers among nonsmokers were found in women could also reflect exposure to passive smoking or other risk factors more prevalent among women. This speculation, however, needs to be substantiated in additional studies.
The histologic type of cancer most frequently identified was adenocarcinoma, which was found in 68% of women and in 48% of men diagnosed with lung cancer. These values are in keeping with prior observations of a temporal shift in the histologic distribution of nonsmall-cell lung cancer, with increased prevalence of lung adenocarcinoma in women and with an increase in the proportion of adenocarcinoma in both sexes accompanied by a gradual decrease in the proportion of squamous cell carcinoma (27,28). The tendency of adenocarcinoma to present as a peripheral lesion suggests the possibility that these cancers might be more readily detected on a chest radiograph than the more centrally located squamous cell carcinomas.
Epidemiologic data support the conclusion that smoking causes lung cancer, accounting for nearly 90% of lung cancer cases diagnosed in the United States and other countries in which cigarette smoking is common (2931). This observation is reflected in the current study, in which 89% of the lung cancers found in the first 12 months after a positive screen occurred in smokers. Lung cancer risk among cigarette smokers increases with the number of cigarettes smoked per day and with the duration of smoking (32). In one study, models were derived to estimate the quantitative risk as a function of the number of cigarettes smoked, the duration of smoking, and the age of the smoker (32). According to these models, smoking duration appears to be a greater risk factor than the number of cigarettes smoked per day (32).
Conversely, smoking cessation is likely to reduce the risk of developing lung cancer, regardless of the age at which the smoker quits. A longer duration of smoking cessation is associated with a reduced risk of developing lung cancer (33). The data in Table 6 therefore are of interest. Current smokers and former smokers who smoked within the past 2 years had an incidence of 6.7 lung cancers per 1000 screens. Former smokers who quit 210 years earlier had an incidence of 4.9 cancers per 1000 screens. Among former smokers who quit more than 10 years earlier, the incidence dropped to 1.5 per 1000 screens. This incidence is still more than triple that identified in never smokers (0.4 cancer per 1000 screens). It has been, however, well documented by others (34) that, even 40 years after smoking cessation, former smokers have a higher risk of developing lung cancer than never smokers.
The question of whether screening by chest radiograph reduces mortality from lung cancer awaits the analysis and comparison of both randomization arms of the PLCO Screening Trial. The National Lung Screening Trial (NLST), which is comparing low-dose computed tomography scans with chest radiographs, builds in part on the experience of the PLCO Trial for generating and managing a very large accrual. It will offer a relevant comparison, regardless of whether the final results of the PLCO Trial support chest radiography as an effective screening modality.
In summary, our results from the baseline lung cancer screening round of the PLCO Trial demonstrate that massive participant accrual can be accomplished in a multi-institutional program with good compliance. Two limitations of the study are the disproportionate numbers of minority participants and never smokers as compared with the U.S. population. Nevertheless, the data suggest a high rate of early detection and possibly important differences between screening for lung cancer in women and in men. The answer to the important question of reduction in lung cancer mortality must await analysis of the two study arms as these data mature.
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NOTES |
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Screening Centers: Birmingham, ALMona Fouad, MD, MPH (PI); Albert Oberman, MD, MPH; Edward Partridge, MD; Donald A. Urban, MD; Darlene Higgins (C); Denver, COE. David Crawford, MD (PI); Sheryl L. Ogden, RN, BSN (C); Detroit, MIPaul A. Kvale,* MD (PI); Christine C. Johnson, PhD, MPH (PI); Karen Broski (C); Lois Lamerato, PhD, MS; Honolulu, HILance Yokochi, MD, MPH (PI); Victoria Jenkins, BSN, MEd (C); Marshfield, WIDouglas Reding, MD, MPH (PI); William Hocking,* MD (PI); Karen Lappe, BSN (C); Minneapolis, MNTimothy R. Church, PhD, MS (PI); Martin M. Oken,* MD (PI); Deborah Engelhard, MA (C); Jill Cordes,* BSN, RN (C); Pittsburgh, PAJoel L. Weissfeld, MD, MPH (PI); Robert E. Schoen, MD, MPH (PI); Betsy Gahagan, RN, BSN (C); Salt Lake City, UTSaundra S. Buys, MD (PI); Thomas M. Beck,* MD (PI); Lisa H. Gren, MSPH (C); Jeffery C. Childs; Bonita Wohlers, RN, MSN (C); St Louis, MOGerald L. Andriole, MD (PI); Heidi Lowery, RN, MS (C); Washington, DCEdward P. Gelmann, MD (PI); Colleen McGuire, RN, MSN (C).
National Cancer Institute: Division of Cancer PreventionChristine D. Berg, MD (PO); Philip C. Prorok,* PhD (PO); John K. Gohagan,* PhD; Barnett S. Kramer, MD, MPH; Richard M. Fagerstrom, PhD; David L. Levin,* MD, MS; Pamela M. Marcus,* PhD, MS; Ping Hu,* ScD; Paul F. Pinsky, PhD; Jian-Lun Xu, PhD; Grant Izmirlian, PhD; Anthony B. Miller, MB (consultant); Division of Cancer Epidemiology and GeneticsRichard B. Hayes, PhD.
Coordinating Center, Westat Inc. Barbara O'Brien, MT, MPH (PI); Lawrence R. Ragard, MD; Susan Yurgalevitch, MS, MPH; Keith Umbel; Beth Bridgeman; Statistical Center, Information Management Systems, Inc.Thomas L. Riley* (PI); Jonathan D. Clapp; Joseph H. Austin; Jerome Mabie; Craig Williams; Stephen D. Winslow*; Specimen LaboratoryDavid Chia, PhD (PI); Jean Reiss, MT.
Supported by individual contracts from the National Cancer Institute to each of the 10 screening centers and to the coordinating center.
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Manuscript received October 1, 2004; revised October 6, 2005; accepted November 8, 2005.
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