All-Cause Mortality in Randomized Trials of Cancer Screening

BACKGROUND: The most widely accepted end point in randomized cancer screening trials is disease-specific mortality. The validity of this end point, however, rests on the assumption that cause of death can be determined accurately. An alternative end point is all-cause mortality, which depends only on the accurate ascertainment of deaths and when they occur. We compared disease-specific and all-cause mortality in published randomized cancer-screening trials to indirectly assess the validity of the disease-specific mortality end point. METHODS: We examined all 12 published randomized trials of cancer screening for which both end points were available (seven of mammography, three of fecal occult blood detection, and two of chest x-ray screening for lung cancer). For each randomized trial, we subtracted disease-specific mortality observed in the screened group from that observed in the control group and all-cause mortality in the screened group from that in the control group. We then compared the differences in these two mortality measures. RESULTS: In five of the 12 trials, differences in the two mortality rates went in opposite directions, suggesting opposite effects of screening. In four of these five trials, disease-specific mortality was lower in the screened group than in the control group, whereas all-cause mortality was the same or higher. In two of the remaining seven trials, the mortality rate differences were in the same direction but their magnitudes were inconsistent; i.e., the difference in all-cause mortality exceeded the disease-specific mortality in the control group. Thus, results of seven of the 12 trials were inconsistent in their direction or magnitude. CONCLUSION: Major inconsistencies were identified in disease-specific and all-cause mortality end points in randomized cancer screening trials. Because all-cause mortality is not affected by bias in classifying the cause of death, it should be examined when interpreting the results of randomized cancer-screening trials.