This report describes the findings of lung cancer screening with CXR in the intervention arm of the PLCO trial and extends our observations from the baseline screen (19
) to three subsequent annual screens. With additional screening rounds and follow-up time, we are now able to assess changes over time in screening results, diagnostic follow-up, and characteristics of screen-detected cancers as well as compare screen-detected cancers with interval cancers. Screening compliance remained high throughout the study and decreased only slightly from baseline (T0) to the fourth annual screening round (T3). Screen positivity rates, which decreased modestly from baseline to T3, showed a high degree of dependence on past results, evidenced by the fact that subjects with a previous positive screen were much more likely to have a positive screening result (23%) than subjects with no previous positive screens (4.7%). At screening round T3, almost one half of positive screens were in subjects with previous positive screens. Yet, for the entire screening period, the majority of subjects with a positive screen had a negative screen the following year.
Our results showed that among all participants with positive screens, the PPV of a positive screen was 1.7%; among current and former smokers who quit within 15 years, PPVs were 4.7% and 3.4%, respectively. In the T0 round, PPVs for all, current, and former smokers who quit within 15 years were 2.0%, 5.9%, and 4.7%, respectively; this round was most comparable to the Mayo Lung Project prevalence screen (13
). In the Mayo Lung Project prevalence screen, the PPV for a suspicious screen was 59%, but if “indeterminate” screens were also considered positive, the PPV decreased to 18.6% (13
). In the Johns Hopkins Lung Cancer Screening Trial, the PPV for screens that were considered to be “cancer” or suspicious was 11.2% (15
). In the Memorial Sloan-Kettering Lung Cancer Screening Trial, the PPV was 3.8% for indeterminate plus suspicious screens (14
). These previous trials included only smokers or former smokers. In PLCO, suspicious and indeterminate abnormalities were considered positive. In recent spiral CT scan lung cancer screening trials, which also included primarily smokers, PPVs ranged from 1.7% to 12.8% (21
). The PPV for prostate-specific antigen screening for prostate cancer is 10.5%–32% (22
), for digital rectal examination 2.9%–21% (22
), for mammography 3%–12.7% (24
), and for stool occult blood (for detection of colorectal cancer) 2.2%–17.2% (26
). Variability in PPVs is dependent on the definition of a positive screen, disease prevalence in the screened population, and the sensitivity and specificity of the screening test. In this context, the PPV for CXR in the PLCO trial seems consistent with other studies.
We observed that the PPV of an abnormal screen decreased moderately from the baseline to later annual screening rounds. The presence of repeat positive screens at later rounds contributed to this decrease but only explained a relatively small portion of it. Breaking down the post-baseline positive screens into first and repeat positives, the PPV was 4.0% among first positives compared with 3.0% among repeat positives. Thus, even among first positive screens, the PPV was still about 25% less at subsequent rounds than at baseline. Across all screening rounds, type of radiological abnormality and smoking status had the greatest association with PPV. The PPV for a mass was 8.7%, which is approximately seven times higher than that (1.2%) for a nodule or other abnormality; the PPV for current smokers was 4.7%, which is approximately 11 times higher than that (0.41%) for never-smokers.
Roughly half of the screen-detected cancers were potentially curable stage I or stage II NSCLC. This stage distribution was generally similar to that seen among screen-detected lung cancers in the Mayo Clinic, Memorial Sloan-Kettering, and Johns Hopkins randomized screening trials (13
). In both reports by the Memorial Sloan-Kettering and Mayo Clinic, early-stage lung cancers represented a statistically significantly greater proportion of later vs baseline round screen-detected cancers. In contrast, in the PLCO trial, the stage distribution of screen-detected cancers at baseline and at subsequent screening rounds was essentially identical. This difference between the PLCO findings and the Mayo and Memorial Sloan-Kettering findings may relate to differences in the PLCO population, including inclusion of never-smokers and women. In addition, 53% of PLCO participants had a CXR within 3 years of random assignment, which might have reduced the number of advanced-stage cancers discovered at T0. As in PLCO, the interval cancers in all studies had a less favorable stage distribution than the screen-detected cancers. Because of well-known potential screening-related biases of overdiagnosis and length-biased sampling, comparison with an unscreened control group is necessary to conclusively determine whether a true reduction in the rate of advanced-stage and increase in early-stage lung cancers (stage shift) have occurred. Such a comparison in PLCO must await the final outcome of the trial.
In this study, the histological distribution of lung cancers was generally consistent with that observed in nonscreening populations in the United States. Adenocarcinoma was the most common NSCLC histology, consistent with the reported trends (27
). Also consistent with the trends in the United States was the increased relative frequency of adenocarcinoma in women, as compared with men (27
Tobacco smoking is a major risk factor for lung cancer. Over 4 years in this PLCO Screening Trial, where just over half of the cancers were detected by screening, the observed relative risks for current, recent former, and distant former smokers, as compared with never-smokers, were 25, 14.5, and 4.4, respectively, based on person-year incidence rates. The relative risks are generally concordant with, perhaps a bit higher than, those observed in nonscreening populations (29
). These findings suggested that screening with CXR did not preferentially detect lung cancers in never-smokers. In contrast, there was some evidence that screening with low-dose CT scans preferentially detected cancers, perhaps overdiagnosed, in never-smokers. In a mass screening program with CT in Japan (32
), the detection rate in women never-smokers (45/10
000) was essentially equivalent to that in male smokers (49/10
000), but there were too few women smokers and male never-smokers to make direct within-gender comparisons.
The limitations of the PLCO lung cancer screening study are an underrepresentation of Black race and Hispanic ethnicity, limited availability of occupational and environmental exposure data, and the fact that the trial population represents a higher socioeconomic status than the general population based on educational level, which may limit the ability to apply these results to the general population.
The strengths of the PLCO Lung Cancer Screening Trial include the large sample size, inclusion of women and never-smokers, excellent long-term follow-up of participants, and availability of the biorepository. In summary, the results of this study showed that PLCO has maintained excellent participant compliance and continues to robustly detect lung cancers at later screening rounds and that these screen-detected cancers at later rounds have a similar favorable stage distribution as those detected at baseline. A determination of whether early detection with CXR will translate into a mortality benefit of screening awaits the final PLCO results, which based on design assumptions are anticipated in 2015. In addition, the National Lung Screening Trial, a randomized trial comparing low-dose CT with CXR, is ongoing in the United States (33
), and results from the PLCO trial will be critical to interpretation of that study.