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

In 2021, the USPSTF recommends annual lung cancer screening with low-dose CT in adults who have quit within the past 15 years (USPSTF, Krist; 2021). Similar to the 2013 USPSTF recommendation, screening should be discontinued once a person has not smoked for 15 years (Moyer, USPSTF; 2014). Thus, in both 2013 (Moyer, USPSTF; 2014) and 2021 (USPSTF, Krist; 2021), the USPSTF recommends stopping lung screening once a person has not smoked for 15 years. We received public comments during the initial public comment period requesting removal of the eligibility criterion for the quit smoking history. We decided to assess whether the clinical studies had data on quit smoking history for former smokers who quit within the past 15 years to confirm the effectiveness of the current recommendation. We also assessed whether the clinical studies had data on quit smoking history for former smokers who quit smoking for at least 15 years or more to determine whether lung cancer mortality is reduced among those who received low-dose CT and had quit smoking for more than 15 years. If the data show the effectiveness of low-dose CT screening by reducing lung cancer deaths among persons who quit smoking for more than 15 years, then it might be plausible to consider eliminating the quit smoking criterion of quitting for the past 15 years since low dose CT would still be effective in reducing lung cancer deaths among those who quit smoking beyond 15 years ago.One study, the good quality NLST trial, included former smokers who had quit within the past 15 years, but excluded persons who had quit more than 15 years ago. For the extended follow up analysis of the NLST trial the quitting smoking history inclusion criterion was persons who had quit within the past 15 years (NLST, 2019) and so former smokers who had quit within the past 15 years, such as quitting 14 years ago, were included in the NLST trial. However, persons who had quit beyond 15 yearsago, such as someone who had quit 16 years ago, was not included in the NLST study. This eligibility criterion excludes persons who had quit more than 15 years ago. The NLST randomized high-risk current and former smokers to three annual screens with either low dose CT or chest radiography (CXR) in the United States (NLST, 2019). For the low dose CT arm (n = 26,722), 51.9% were former smokers (NLST Research Team, 2019). In the NLST study results, no data was shown on the number of years ofquitting smoking. The definition of former smokers was not provided in the publication.After a median of 12.3 years of follow-up, the overall NLST study results demonstrated a statistically significant reduction in lung cancer mortality (dilution-adjusted lung cancer mortality rate ratio = 0.89; 95% CI: 0.80-0.997; p = 0.043; NLST Research Team, 2019) in the low dose CT arm, which is also clinically significant. The dilution-adjusted lung cancer mortality rate ratio is a more appropriate outcome measure to use than an overall lung cancer mortality rate ratio because with follow-up now well beyond the period of trial screening, there is the potential, or even likelihood, of some dilution of the screening effect. Specifically, patients in whom cancer did not develop until after the last scheduled screen could not have benefited from the trial screenings; therefore, deaths in such patients would only serve to add noise to the estimates, roughly an equal number of deaths in each arm. Therefore, in analyzing these data, we employ various methods that attempt to control for a dilution effect, including examining the difference across arms in lung cancer deaths in addition to the rate ratio, and examining the rate ratio adjusted for dilution by considering time of diagnosis. This latter method, which is well known in the mammography screening trial literature, only includes those cancer deaths for which the corresponding time of cancer diagnosis is close enough to the end of protocol screening in the trial (NLST Research Team, 2019). There were no stratified analyses of the dilution-adjusted lung cancer mortality rate ratio by the number of years of quitting smoking subgroups shown in the NLST study results, such as quitting smoking beyond 15 years ago. The overall results of the NLST study show that the quitting smoking history criterion for persons who had quit within the past 15 years significantly reduces lung cancer mortality among those receiving low dose CT. However, the NLST study does not have lung cancer mortality data on persons who had quit beyond 15 years ago and thus, there is no evidence from the NLST trial that supports changing or extending the quit year history to quitting more than 15 years ago.All of the remaining low dose CT randomized controlled trials in our internal technology assessment did not include former smokers who had quit 11 to 15 years ago or who had quit beyond 15 years ago. In the good quality NELSON study, the eligibility criterion for quitting smoking history was former  smokers who had quit  10 years ago (de Koning, 2020). Former smokers who had quit smoking 11 years to 15 years ago were not included and those who had quit more than 15 years ago also were not included in the NELSON study population. Among the male participants in the screening group (n = 6,583) for the NELSON study, 1.7% (49/2,908) had a quit smoking history of > 10 years since cessation of smoking (de Koning, 2020). It is not likely that the NELSON study population included men with a quit smoking history of at least 15 years or more. Additionally, the eligibility criterion for quitting smoking history did not allow former smokers who had quit smoking 11 years to 15 years ago or more than 15 years ago to be included in the NELSON study. The NELSON study does not provide data for the discussion of the quit smoking eligibility criterion for quitting smoking within the past 15 years ago.For quitting smoking history in the ITALUNG study, former smokers who had quit more than 10 years ago were excluded (Paci, 2017).  This exclusion criterion suggests that former smokers who had quit smoking up to 10 years ago were included and that former smokers who had quit more than 10 years ago, such as those quitting 11 to 15 years ago or quitting more than 15 years ago, were excluded from the ITALUNG study. The DANTE study (Infante, 2015) defined the eligibility criterion for quitting smoking history as persons who had quit less than 10 years before recruitment (Infante, 2015). No data were shown in the DANTE study results on the distribution of quitting smoking history for persons who had quit less than 10 years before recruitment.  There were no stratified analyses of lung cancer mortality by quitting smoking history for persons who had quit less than 10 years before recruitment shown in the DANTE study results. Because the quit smoking history eligibility criterion included ex-smokers who had stopped smoking less than 10 years before the invitation to screening, the study population for the DANTE trial did not include ex-smokers who had quit within the past 11 to 15 years. Additionally, the DANTE study population did not include ex-smokers who had quit more than 15 years ago. Thus, the ITALUNG and the DANTE studies did not provide data regarding maintaining the quit smoking history eligibility criterion at quitting within the past 11 to 15 years, or quitting smoking beyond 15 years.In the LUSI study, eligibility criterion for quitting smoking history was defined as ex-smokers who had stopped smoking not more than 10 years before invitation to screening (Becker, 2020). Because the quit smoking history eligibility criterion was ex-smokers who had stopped smoking not more than 10 years before invitation to screening, the study population for the LUSI trial did not include ex-smokers who had quit within the past 11 to 15 years. Additionally, the LUSI study population didnot include ex-smokers who had quit more than 15 years ago. The MILD study (Pastorino, Silva, Sestini; 2019) defined the eligibility criterion for quitting smoking history as former smoker from < 10 years ago. In the intervention arm, smoking status for smokers was defined as former smokers or current smokers with 31.4% of the study population in the intervention arm reported as former smokers (Pastorino, Silva, Sestini; 2019). There were no data shown on the distribution of former smokers by quit history subgroup defined as number of years quitting smoking. There were no data shown on the number of individuals who quit smoking between 10 years and 15 years ago. There were no data shown on the number of individuals who quit smoking beyond 15 years ago. For the LSS study, the eligibility criterion for quit smoking history was a former smoker who quit within the last 10 years (Doroudi, 2018). There were no data shown on the number of years since quitting smoking for the study population in the LSS study results (Doroudi, 2018). In the DLCST trial, the inclusion criterion for quitting smoking history was if participants were former smokers, they had to have quit after the age of 50 years and within the previous 10 years (Wille, 2016). Because the DLCST, LSS. LUSI, and MILD studies did not include persons who quit smoking within the past 10 or 11 to 15 years or quit smoking beyond 15 years ago, the LSS, LUSI, and MILD study results did not contribute evidence to the discussion of quit smoking history criterion.In the UKLS study, ex-smokers were not defined. Among the 75,958 positive responders to the invitation letter to participate in the UKLS trial, 39.3% were ex-smokers. Among the 2,028 participants in the screening arm, 61.6% were ex-smokers (Field; May, 2016). No data on the number of years of quitting smoking was shown for the UKLS study. Because the UKLS study did not have the number of years of quitting smoking history, the UKLS study did not have data that pertains to the analysis of maintaining the quit smoking history criterion. There is no mention of a quit smoking history inclusion criterion in the methods of the secondary analysis of the COSMOS study (Rampinelli, 2017). Because there was no quit smoking history inclusion criterion and no data on lung cancer mortality, the secondary analysis of the COSMOS study did not contribute data to the evaluation of the quit smoking history eligibility criterion.Overall, there are no lung cancer screening trial data or evidence on adults quitting smoking beyond 15 years ago. Only one study, the NLST study, shows that the quitting smoking history eligibility criterion for persons who had quit within the past 15 years significantly reduces lung cancer mortality among those receiving low dose CT. There is no relevant published human clinical study literature regarding the use of low dose CT in persons who quit smoking beyond 15 years ago. There is insufficient evidence to determine if persons who quit smoking more than 15 years ago would benefit from low dose CT screening for lung cancer. Thus, 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 quit smoking within the past 15 years. However, we find the human clinical evidence is insufficient 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 quit smoking beyond 15 years ago. The study results do not show sufficient evidence to change, extend, or eliminate the eligibility criterion for the quit smoking history for lung cancer screening with low dose CT. Thus, we find that the evidence is sufficient to conclude that lung cancer screening is reasonable and necessary for Medicare beneficiaries with the specific eligibility criterion for having a history of quitting smoking within the last 15 years. The Medicare beneficiary eligibility criterion for history of quitting smoking will not be changed and will remain as quitting smoking within the last 15 years.In the 2021 USPSTF recommendation statement, [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 quit within the past 15 years. This eligibility criterion for quitting smoking that is under reconsideration aligns with the 2021 USPSTF recommendation statement on low dose CT.