PURPOSE: There is widespread acceptance that screening for lung cancer is not indicated, to our knowledge, because no randomized trial has demonstrated a reduction in mortality as a result of screening. The objectives of this work are to review prospective studies on lung cancer screening and to analyze the extent to which known biases may have influenced observed results. BACKGROUND: Four randomized controlled trials have been conducted. The Memorial-Sloan Kettering and Johns Hopkins Lung Projects compared annual chest radiographs (CXRs) in a control group with CXRs and sputum cytologic findings in an experimental group. Although both studies failed to demonstrate any difference in outcome by the addition of cytologic study to CXR, long-term survival in both studies was approximately three times that predicted by other data. Accordingly, these results are at least consistent with the hypothesis that the screening CXRs may have improved survival. Two randomized trials, the Mayo Lung Project and the Czechoslovak study, compared regular and frequent rescreening CXRs in an experimental group with sporadic and/or infrequent rescreening in a control group. RESULTS: Both the Mayo and Czech studies demonstrated a striking advantage for screening with respect to stage distribution, resectability, survival, and fatality. Nevertheless, mortality was somewhat higher in the screened groups in both studies. Survival and fatality comparisons in randomized trials can be confounded by overdiagnosis bias, lead-time bias, and length bias, while mortality is not subject to these biases. Accordingly, it is believed that a mortality reduction represents the strongest evidence for screening efficacy. Mortality is directly proportional to cumulative incidence. In both the Mayo and Czech studies, incidence of lung cancer was higher in the screened group. The higher cumulative incidence (which in the Mayo Lung Project was statistically significant) made possible the discordant findings of superior survival/fatality and inferior mortality in the screened populations. Overdiagnosis has been widely accepted to account for the "missing cases" in the control populations in the Mayo and Czech studies. However, epidemiologic and autopsy evidence as well as an outcome analysis of unresected early-stage screen-detected lung cancer demonstrates that screening does not lead to the overdiagnosis of lung cancer. Similarly, lead-time bias and length bias cannot account for the outcome differences in the Mayo Lung Project or Czech study. If survival and fatality comparisons (which suggest a striking benefit from screening) are not biased, then mortality comparisons (which suggest no benefit) cannot accurately reflect lung cancer death rates in these trials. Population heterogeneity may provide an explanation for how outcome differences may have been misrepresented by mortality comparisons in these two trials, as well as other large population-based randomized studies. CONCLUSIONS: Periodic screening CXRs lead to clinically meaningful improvements in stage distribution, resectability, survival, and fatality in lung cancer. Mortality reductions have not been demonstrated, but mortality did not accurately reflect lung cancer death rates in the Mayo Lung Project and Czechoslovak study. Accordingly, reconsideration of the desirability of periodic CXR screening may be appropriate for individuals at high risk of lung cancer.
PURPOSE: There is widespread acceptance that screening for lung cancer is not indicated, to our knowledge, because no randomized trial has demonstrated a reduction in mortality as a result of screening. The objectives of this work are to review prospective studies on lung cancer screening and to analyze the extent to which known biases may have influenced observed results. BACKGROUND: Four randomized controlled trials have been conducted. The Memorial-Sloan Kettering and Johns Hopkins Lung Projects compared annual chest radiographs (CXRs) in a control group with CXRs and sputum cytologic findings in an experimental group. Although both studies failed to demonstrate any difference in outcome by the addition of cytologic study to CXR, long-term survival in both studies was approximately three times that predicted by other data. Accordingly, these results are at least consistent with the hypothesis that the screening CXRs may have improved survival. Two randomized trials, the Mayo Lung Project and the Czechoslovak study, compared regular and frequent rescreening CXRs in an experimental group with sporadic and/or infrequent rescreening in a control group. RESULTS: Both the Mayo and Czech studies demonstrated a striking advantage for screening with respect to stage distribution, resectability, survival, and fatality. Nevertheless, mortality was somewhat higher in the screened groups in both studies. Survival and fatality comparisons in randomized trials can be confounded by overdiagnosis bias, lead-time bias, and length bias, while mortality is not subject to these biases. Accordingly, it is believed that a mortality reduction represents the strongest evidence for screening efficacy. Mortality is directly proportional to cumulative incidence. In both the Mayo and Czech studies, incidence of lung cancer was higher in the screened group. The higher cumulative incidence (which in the Mayo Lung Project was statistically significant) made possible the discordant findings of superior survival/fatality and inferior mortality in the screened populations. Overdiagnosis has been widely accepted to account for the "missing cases" in the control populations in the Mayo and Czech studies. However, epidemiologic and autopsy evidence as well as an outcome analysis of unresected early-stage screen-detected lung cancer demonstrates that screening does not lead to the overdiagnosis of lung cancer. Similarly, lead-time bias and length bias cannot account for the outcome differences in the Mayo Lung Project or Czech study. If survival and fatality comparisons (which suggest a striking benefit from screening) are not biased, then mortality comparisons (which suggest no benefit) cannot accurately reflect lung cancer death rates in these trials. Population heterogeneity may provide an explanation for how outcome differences may have been misrepresented by mortality comparisons in these two trials, as well as other large population-based randomized studies. CONCLUSIONS: Periodic screening CXRs lead to clinically meaningful improvements in stage distribution, resectability, survival, and fatality in lung cancer. Mortality reductions have not been demonstrated, but mortality did not accurately reflect lung cancer death rates in the Mayo Lung Project and Czechoslovak study. Accordingly, reconsideration of the desirability of periodic CXR screening may be appropriate for individuals at high risk of lung cancer.