Our study provides empirical evidence for the potential utility of targeting smokers at highest risk for lung cancer for low-dose CT screening. The number of CT-prevented lung-cancer deaths strongly increased with an increase in the prescreening risk of death from lung cancer. Consequently, the number of participants who would need to be screened to prevent one lung-cancer death decreased from 5276 among the 20% of participants at lowest risk to 161 among the 20% of those at highest risk. Also, the number of participants with false positive results on screening per CT-prevented lung-cancer death decreased from 1648 among the 20% of participants at lowest risk to 65 among the 20% of those at highest risk.
In our study, the overall relative reduction of 20% in the rate of lung-cancer death among participants in the CT group, as compared with the radiography group, did not differ significantly across risk quintiles. Nevertheless, owing to an increase in the risk of lung-cancer death across risk quintiles, the constant 20% reduction in death rate translated into a significant increase in the total number of CT-prevented lung-cancer deaths across risk quintiles. A similar phenomenon was observed for the number of stage I lung cancers, as well as the number of false positive results across risk quintiles. These observations underscore the importance of absolute measures (e.g., risk differences and counts) over relative measures (e.g., ratios) for evaluating the public health benefits of screening interventions.
Although there is currently a consensus among published screening guidelines on recommending low-dose CT screening for patients who meet the NLST entry criteria,29
some experts have speculated that further refinement of selection criteria may be appropriate.4,15
Our results confirm that tailoring of low-dose CT screening to a patient's predicted risk of lung-cancer death could narrow the NLST-eligible population without a loss in the potential public health benefits of screening or a disproportionate increase in the potential harms. For example, we found that restricting screening to the 60% of participants at highest risk for death from lung cancer within 5 years (>0.85%), as compared with the entire CT group, captured 88% of CT-preventable lung-cancer deaths, reduced the number of participants who would need to be screened to prevent one lung-cancer death from 302 to 161, and reduced the number of false positive results per CT-prevented lung-cancer death from 108 to 65. In contrast, the 20% of participants at lowest risk for lung-cancer death accounted for almost none of the CT-prevented lung-cancer deaths. These observations argue for the use of individualized risk assessment of lung-cancer death instead of the NLST entry criteria to increase the efficiency of low-dose CT screening.
Furthermore, a risk-based strategy for low-dose CT screening could provide a rational, empirical framework for the inclusion of NLST-ineligible smokers at high risk for lung-cancer death. However, such a strategy would depend on the generalizability of the benefits and harms of screening that were observed in NLST participants, as compared with NLST-ineligible persons at similar risk, for whom there are no empirical data.30,31
Risk-based low-dose CT screening could be based on a patient's risk of either lung-cancer incidence or lung-cancer death. We focused on the risk of lung-cancer death because the primary benefit of low-dose CT screening is the prevention of lung-cancer death. Yet, given the high case fatality rate for lung cancer, prediction models for lung-cancer incidence and death are likely to have similar discriminatory ability. Indeed, we found similar trends in the number of CT-prevented lung-cancer deaths across risk quintiles that were defined according to the risk of lung-cancer death and the risk of lung-cancer incidence. Thus, although there is evidence to support the use of risk assessment for screening selection, further study of the comparative performance of available tools for assessing lung-cancer risk is needed to determine which tool to recommend for risk-based screening strategies.
Our findings need to be interpreted within the context of low-dose CT screening in the NLST. This limits extrapolation of our results to alternative screening and follow-up schedules. Furthermore, beyond false positive results, we did not consider other potential harms of low-dose CT screening, such as the psychological burden of false positive results, complications with invasive follow-up procedures, and radiation-induced cancers.32
In addition, our assessment of the efficacy of low-dose CT screening in patients with coexisting pulmonary conditions had limited power. Thus, additional study of the benefits and risks of low-dose CT screening in the presence of coexisting pulmonary conditions is needed.
Our results have public health implications. In 2011, there were 8.9 million NLST-eligible and 20.3 million NLST-ineligible smokers between the ages of 55 to 74 years and 94 million current and former smokers of all ages in the United States.33
Since the publication of the NLST findings, a key question has been which of these smokers should be targeted for low-dose CT screening. Our observation that both the potential benefits and harms of such screening strongly depend on a patient's risk of lung-cancer death underscores the potential utility of risk-based low-dose CT screening. Our estimates of the expected benefits and potential harms of such screening across risk groups provide the empirical framework for evaluating the cost-effectiveness of low-dose CT screening, investigating optimal risk cutoffs for screening, and communicating the potential benefits and harms of such screening tailored to each patient's individual risk.