NCA - Screening for Lung Cancer with Low Dose Computed Tomography (LDCT) (CAG-00439R) - Decision Memo

Over an average observation time of 8.8 years after randomization, modeling by sex, however, showed a statistically significant reduction in lung cancer mortality among women (HR [hazard ratio] = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT.. and this heterogeneity was close to statistical significance ([Pheterogeneity = 0.09) (Becker, 2020). There were no stratified analyses by smoking history for number of pack-years of smoking for lung cancer mortality in the LUSI study results. Because the smoking history eligibility criterion was defined as having at least 15 or 19 pack-years of smoking, it appears that the study population for the LUSI trial is likely to include smokers with a 20 to 25 pack-year smoking history. Thus, the LUSI study showed that low dose CT screening among persons with a 20 to 29 pack-year history reduces lung cancer mortality, especially among women.Several studies, the ITALUNG, the DANTE, and the DLCST studies, had data on smokers with a smoking history of at least 20 pack-years but did not show a statistically significant effect on lung cancer mortality. The ITALUNG study, one of several small European randomized controlled clinical trials of low dose CT, randomized eligible persons to receive an annual invitation for low dose CT screening for four years, the active group (n = 1,613), or to usual care, the control group, in three screening centers in Italy (Paci, 2017). The ITALUNG study (Paci, 2017) defined the enrollment eligibility criterion for smokers as a smoking history of at least 20 pack-years in the last 10 years (Paci, 2017). Persons with a 20 to 29 pack-year history of smoking were included in the ITALUNG study. In the active group that received low dose CT, the median pack-years of smoking was 40 pack-years. The active group consisted of 66% current smokers (Paci, 2017). There was no data shown on the distribution of the number of pack-years smoked in the ITALUNG study results. After a median follow up of 9.3 years, study results showed a non-significant reduction of 30% (RR = 0.70; 95% CI 0.47 to1.03; p = 0.07) for lung cancer mortality in the active LDCT group compared to the usual care control group (Paci, 2017). However, the study authors reported that none of these published outcome studies alone (DANTE, MILD, and DLCST), including the ITALUNG, has sufficient statistical power to detect a real benefit and, for specific analyses, as those assessing benefit for risk profile subgroups (Paci, 2017). In the ITALUNG study results, there were no stratified analyses by pack-year smoking history for lung cancer mortality. While the ITALUNG study included smokers with a smoking history of at least 20 pack-years, the results showed a non-statistically significant reduction for lung cancer mortality in the low dose CT intervention group compared to the control group.The DANTE study (Infante, 2015) defined the enrollment eligibility criterion for smokers of at least 20 pack-years, defined as 20+ pack-years (Infante, 2015). Persons with a 20 to 29 pack-year history of smoking were included in the DANTE study. In the low dose CT group, the mean pack-years was 47.3 (95% confidence interval 45.7 - 49.0) with a standard error of the mean of 0.8, and a median pack-years of 45.0 (interquartile range 28.5) (Infante, 2015). There was no stratified distribution of smoking history by number of pack-years subgroups shown in the DANTE baseline study results. For lung cancer mortality, the hazard ratio was 0.993 with a 95% CI of 0.688 to 1.433 (Infante, 2015). Lung cancer mortality did not differ significantly between the two arms of LDCT screening compared to annual clinical review (Infante, 2015). There were no stratified analyses of lung cancer mortality by pack-years of smoking history subgroup shown in the DANTE study results. The authors concluded that given the limited statistical power of the DANTE [Detection And screening of early lung cancer with Novel imaging TEchnology] trial, our data do not allow making a definitive statement about whether or not LDCT screening is effective in reducing lung cancer mortality (Infante, 2015). While the DANTE study included smokers with a smoking history of at least 20 pack-years, the results showed a non-statistically significant reduction for lung cancer mortality in the low dose CT intervention group compared to the control group.In the DLCST trial, the inclusion criterion for smoking history was a minimum of 20 pack-years of smoking (Wille, 2016). In the screening group (n = 2,052), the mean pack-years was 36.4  13.4 pack-years (standard deviation) (Wille, 2016). In the DLCST study, no difference between the low dose CT study group and the no screening control group in lung cancer mortality (hazard ratio = 1.03; 95% CI: 0.66  1.6; p = 0.888; Wille, 2016) was observed. The study results for lung cancer mortality were not stratified by the number of pack-years smoked for the subgroup of 20 to 29 pack-years smoked. The authors of the DLCST trial concluded that no statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial [NLST] (Wille, 2016). The study authors also reported that the study was underpowered, and the results of the DLCST do not allow us to make definitive conclusions about the efficacy of screening (Wille, 2016). While the DLCST study included persons with a 20+ pack-year history of smoking, the results did not show that low dose CT screening lowers lung cancer deaths more so than in a no screening group. However, the study authors reported that the DLCST study may be underpowered and have a sample size that is too small to show a significant difference in lung cancer mortality among those receiving LDCT compared to no screening.Thus, the ITALUNG, the DANTE, and the DLCST studies had data on smokers with a smoking history of 20 to 29 pack-years, but the results did not show that low dose CT screening had a significant effect on lung cancer mortality.One study, the COSMOS study, had data on smokers with a smoking history of 20 to 29 pack-years but the study results did not have data on lung cancer mortality. In the secondary analysis of the COSMOS study, the eligibility criterion for smoking history was  20 pack-years of smoking (Rampinelli, 2017). No data on lung cancer mortality was presented in the secondary analysis of the COSMOS trial study results. The secondary analysis of the COSMOS study did not contribute data to the evaluation of the pack-year smoking history eligibility criterion.Several low-dose CT studies, such as the NLST, the LSS, and the UKLS, did not have data on persons who had a 20 to 29 pack-year history of smoking. For the extended follow up analysis of the good quality NLST (National Lung Screening Trial) trial, the pack-year smoking history criterion was a minimum of 30 pack-years of cigarette smoking (NLST Research Team, 2019). This eligibility criterion excluded persons with a 20 to 29 pack-year smoking history from enrolling in the NLST trial. For the low dose CT arm (n = 26,722), 48.1% were current smokers and the median pack-years was 48 (25th/75th percentile: 39/66) (NLST Research Team, 2019). In the NLST study results, no data was shown on the number of pack-years of cigarette smoking. Current smokers were not defined in the Methods of the NLST study. Because the NLST study does not have data on smokers with a 20 to 29 pack-year history of cigarette smoking, the NLST study results do not address the potential change in the pack-year smoking history eligibility criterion.For the LSS study, the eligibility criterion for smoking history was a 30 pack-year history of cigarette smoking (Doroudi, 2018). There were no data shown on the number of pack-years smoked for the study population in the LSS study results (Doroudi, 2018). Because the LSS study did not include persons with a 20 to 29 pack-year smoking history, the LSS study results did not contribute evidence to the discussion of lowering the pack-year smoking history criterion. In the UKLS study, who were current smokers was not defined. Among the 75,958 positive responders to the invitation letter to participate in the UKLS trial, 14.7% were current smokers. Among the 2,028 participants in the screening arm, 38.3% were current smokers (Field; May, 2016). No data on the number of pack-years smoked by current smokers were shown in the UKLS study results. Combining current and ex-smokers, 93.4% had a smoking duration of 20+ years and 5.8% had a smoking duration of 10 - 19 years (Field; May, 2016). The UKLS study did not have data on lung cancer mortality (Field; May, 2016). None of the analyses were stratified by pack-years of smoking. Because the UKLS study did not have the number of pack-years smoking history, the UKLS study did not have data that would affect the Analysis of lowering the pack-years smoking history.Overall, based primarily on the MILD, NELSON, and LUSI study results, we find the human clinical evidence is sufficient to determine that screening for lung cancer with low dose CT is reasonable and necessary for the prevention or early detection of illness or disability for the population of persons who have a smoking history of 20 to 29 pack-years who are eligible for low dose CT. Given the limitations of the three studies lacking stratified analyses, the evidence from the overall results of the MILD, NELSON, and LUSI studies suggest a clinically significant lowering of lung cancer deaths among persons who had a 20 to 29 pack-year history of smoking who received low dose CT lung cancer screening compared to those who had no low dose CT screening. The evidence supports that lowering the eligibility criterion for smoking history for low dose CT screening from 30 pack-years to 20 pack-years will continue to show benefit by reducing lung cancer deaths among persons eligible for low dose CT screening. The study results show sufficient evidence to lower the smoking history criterion which would expand the population eligible for lung cancer screening with low dose CT. Thus, with these limitations, we find that the evidence is sufficient to conclude that this approach to broadening the recommended population for lung cancer screening is reasonable and necessary for the prevention or early detection of illness or disability among Medicare beneficiaries with the specific eligibility criterion for a smoking history of at least a 20 pack-years.In the 2021 USPSTF recommendation statement on lung cancer screening, [t]he USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) (USPSTF, Krist; 2021). The 2021 USPSTF lung cancer screening statement recommends annual lung cancer screening with low-dose CT for adults who have a 20 pack-year smoking history and currently smoke (USPSTF, Krist; 2021). This revised National Coverage Determination policy that lowers the smoking pack-year history eligibility criterion aligns with the 2021 USPSTF recommendation statement on pack-years smoking history.Among the societal organizations making recommendations for the selection of individuals for lung cancer screening, the American College of Chest Physicians (CHEST) has two recommendations. 1. For asymptomatic individuals age 55 to 77 who have smoked 30 pack- years or more and either continue to smoke or have quit within the past 15 years, we recommend that annual screening with low-dose CT should be offered. (Strong recommendation, moderate-quality evidence). 2. For asymptomatic individuals who do not meet the smoking and/or age criteria in Recommendation #1, are age 50 to 80, have smoked 20 pack-years or more and either continue to smoke or have quit within the past 15 years, we suggest that annual screening with low-dose CT should be offered. (Weak recommendation, moderate-quality evidence) (Mazzone, Panel Report 2021). Thus, for the smoking history for persons who smoked 20 to 29 pack-years, the American College of Chest Physicians guidelines only suggest low dose CT since this is a weak recommendation, and so it is not recommended since it is not a strong recommendation.