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

The evidence base for this reconsideration of low dose CT for lung cancer screening has a primary focus on randomized controlled clinical trials of the effect of screening with low dose CT on the outcome of lung cancer mortality. Ten randomized controlled clinical trials involving human subjects were included in the evidence: the Continuous Observation of Smoking Subjects trial (COSMOS; Rampinelli, 2017), the Danish Lung Cancer Screening Trial (DLCST; Wille, 2016), the Detection And screening of early lung cancer with Novel imaging Technology and molecular assays trial (DANTE; Infante, 2015), the Italian Lung Cancer Screening Trial (ITALUNG; Paci, 2017), the Lung Cancer Screening Intervention trial (LUSI; Becker, 2020), the Lung Screening Study (LSS; Doroudi, 2018), the Multicentric Italian Lung Detection study (MILD; Pastorino, Silva, Sestini, 2019), the National Lung Screening Trial (NLST; National Lung Screening Trial Research Team [NLST], 2019), the NederlandsLeuvens Longkanker Screenings Onderzoek trial (NELSON, which is the Dutch acronym; de Koning, 2020), and the United Kingdom Lung Cancer Screening pilot study trial (UKLS; Field; May, 2016). In subsequent discussions, each randomized controlled trial will be referred to by its acronym.Of the 10 randomized controlled trials that report on lung cancer mortality (Table 1), only the NLST and the NELSON trials were adequately powered to answer the question of whether a mortality benefit from screening with low dose CT can be achieved (USPSTF, Krist; 2021). None of the other trials were individually powered to adequately address a mortality benefit due to issues such as a smaller sample size or the screening of a lower risk group than the NLST. Among the 10 randomized trials, the NLST (n = 53,454) and NELSON (n = 15,792) studies were the largest randomized controlled trials. Compared to the evidence cited in the 2015 national coverage determination on low dose CT, four studies provided longer follow-up results for the Dutch Belgian NELSON, the Italian MILD, the German LUSI, and the United States NLST trials. For benefits of screening, the NLST demonstrated a reduction in lung cancer mortality and all-cause mortality with three rounds of annual low dose CT screening compared with chest radiography, and the NELSON trial demonstrated a reduction in lung cancer mortality with four rounds of LDCT screening with increasing intervals (Jonas, 2021). Results of the other trials [besides NLST and NELSON, such as LUSI and DLCST] were very imprecise and did not show statistically significant differences between groups for lung cancer mortality (Jonas, 2021). NLST and NELSON participants were younger, more highly educated, and less likely to be current smokers than the US screening-eligible population (Jonas, 2021). Thus, the general US population eligible for lung cancer screening may be less likely to benefit from early detection compared with NLST and NELSON participants because they face a high risk of death from competing causes, such as heart disease and stroke (Jonas, 2021).Modeling StudiesWhile simulation modeling can be valuable tools that contribute to our understanding of lung cancer screening with low dose CT, there are challenges, such as uncertainty inherent about modeling and variability in the results depending on the assumptions used, around the usefulness and applicability of modeling studies. Thus, modeling studies were not included in our internal technology systematic review of the published primary evidence involving human subjects for changes in the eligibility criteria for lung cancer screening with low dose CT.Meta-AnalysesFour meta-analyses by Huang et al. (2019), Sadate et al. (2020), Wang et al. (2018), and Yang et al. (2019) were not the focus of the evidence base for this reconsideration of low dose CT for lung cancer screening due to concerns over substantial clinical and methodological heterogeneity (Table 2). The trials of lung cancer screening differed in eligibility criteria, such as the inclusion criteria for age, pack-years of smoking history, and years since quitting smoking, as shown in Table 2 and Table 3. As such, the heterogeneity of the study designs and results should be considered when interpreting the collective study results. As an example, the meta-analysis by Wang et al. (2018) was excluded because the authors reported a high degree of heterogeneity across the four studies included in the meta-analysis, [t]he high level of heterogeneity between studies is a limitation to the ability to extrapolate results from this meta-analysis to the general population (Wang, 2018). The authors go on to state other limitations in that the trials varied in their enrollment criteria especially in the age of participants and level of tobacco exposure. They also varied in size; the largest study randomized more than 50,000 participants while the other three combined randomized fewer than 10,000. Also, the trials differed in their follow-up periods even among study arms as in the MILD trial. In addition, the smaller trials demonstrated heterogeneous study methods, selection criteria, and screening modalities. The study outcomes may also vary due to location, participant demographics, and differences in healthcare systems between the international locations of the trials. (Wang, 2018). The Huang (2019) study authors reported as a limitation that there are major geographic differences, particularly in Asia, where 60 to 80% of women with lung cancer are never-smokers. In Yang 2018 study , they enrolled fewer active smokers (21.5%) and males (46.8%) than other USA and European trials. Although smoking is the primary etiologic factor responsible for lung cancer, racial/ethnic and sex differences may exist. According data from WHO, age-standardized rate of current tobacco smoking among population aged 15 years were estimated 2.2% for female in South-East Asia. Whereas for female in Americas and Europe, the rate were [sic] 12.4 and 20.7%. Previous studies also indicated that lung cancer [sic] significantly associated with Asian non-smoking women (Huang, 2019).There was considerable variability in the definition of the inclusion criterion for age across the four meta-analyses. For the Huang (2019) meta-analysis, the lower age limit of the inclusion criterion for age of the nine trials ranged from 45 to 60 years; and for the Sadate (2020), Wang (2018), and Yang (2019) meta-analyses, the lower limit for age ranged from > 49 to 60 years. For the Huang (2019) meta-analysis, the upper age limit of the inclusion criterion for age of the nine trials ranged from 69 to 75 years; for the Sadate (2020) meta-analysis, the upper limit for age ranged from 69 to 74 years; and for the Wang (2018) and Yang (2019) meta- analyses, the upper age limit ranged from 70 to 74 years.The results of the four meta-analyses demonstrated heterogeneity in the effect of low dose CT on lung cancer mortality. For the Wang (2018) study, pooling data from the four studies showed no significant difference (odds ratio = 1.13, 95% CI: 0.78-1.64; I2> 87.2%, p < 0.01, with I2of 50-75% representing high heterogeneity among the studies; Wang, 2018) in lung cancer mortality between the LDCT screening group compared to other screening tools. The Yang (2019) meta-analysis results demonstrated that LDCT screening with up to 9.80 years of follow-up was associated with a statistically non-significant decrease in lung cancer mortality (pooled relative risk [RR] 0.94, 95% confidence interval [CI] 0.74 to 1.19; p = 0.62; Yang, 2019). A moderate level of heterogeneity was observed in the magnitude of effects (I2= 43.3%, p = 0.152; Yang, 2019). However, in the pooled analysis for the Huang (2019) study, low dose CT reduced lung cancer mortality (risk ratio 0.83, 95% CI 0.760.90, I2= 1%) with no heterogeneity observed in the meta-analysis (p = 0.43, I2= 1%; Huang, 2019). For the Sadate (2020) meta-analysis, a significant relative reduction of lung cancer-specific mortality of 17% (risk ratio [RR] = 0.83, 95% confidence interval [CI]: 0.76-0.91) was observed in the screening group compared with the control group. There was no heterogeneity in the data (I2= 0%, p = 0.67; Sadate, 2020). Median follow up ranged from three years to ten years. Thus, while the four meta-analyses, Huang (2019), Sadate (2020), Wang (2018), and Yang (2019), could contribute to improving our understanding of the effect of screening with low dose CT on lung cancer mortality, given the substantial clinical and methodological heterogeneity inherent in the meta- analyses, the four meta-analyses were not the focus of the evidence base for this reconsideration of low dose CT for lung cancer screening.Lowering Starting Age From 55 years to 50 yearsThe 2021 USPSTF recommendation on lung cancer screening recommends that people start screening at age 50 (USPSTF, Krist; 2021), rather than age 55 years. The previous 2013 USPSTF recommendation started screening with low dose CT at age 55 years (Moyer, USPSTF; 2014). To determine whether to lower the starting age for low dose CT screening from 55 years to 50 years, we will assess the human clinical evidence on low dose CT screening and its impact on lung cancer mortality among persons age 50 to 54 years.The study population for the NederlandsLeuvens Longkanker Screenings Onderzoek (NELSON) study, one of two high quality randomized controlled clinical trials of low dose CT with a large sample size, the other being the National Lung Screening Trial (NLST) study, enrolled individuals between 50- and 55- years-old (de Koning, 2020). The NELSON study was a Dutch Belgian lung cancer screening study that consisted of 13,195 men, which was the primary analysis, and 2,594 women, which was the subgroup analysis, between the ages of 50 and 74 years who were at high risk and were randomly assigned to undergo low-dose computed tomographic (LDCT) screening compared to no screening (de Koning, 2020). The subgroup of men aged 50 to 54 years consisted of 24.6% (1611/6560) of the screening group. Among men age 50 to 54 years at randomization, there was a non-statistically significant 15% reduction in lung cancer mortality, since the rate ratio for death from lung cancer at 10 years of follow up was 0.85 (95% confidence interval [CI], 0.48 to 1.50) in the screening group as compared with the control group (de Koning, 2020). There was a strong trend, though not a statistically significant one, of lower lung-cancer mortality among men age 50 to 54 years who underwent low dose CT screening compared to those who underwent no screening. However, the NELSON study reported a statistically significant 26% reduction in lung cancer mortality in men of all ages (risk ratio = 0.74, 95% CI: 0.600.91) (de Koning 2020). Additionally, for the overall results from the NELSON study, the cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group (de Koning, 2020). The authors concluded that for the overall results in the NELSON trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening (de Koning, 2020).