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

The limitations in the subgroup analysis of men aged 50 to 54 years in the NELSON trial are that there was a small number of outcome events, such that 25 persons died of lung cancer in the screening arm compared to 31 persons in the control arm. Changes in these numbers can lead to a wide variation in the effect size under investigation in the clinical trial, which is the effect of low dose CT screening on lung cancer deaths. Additionally, the confidence interval (95% confidence interval [CI], 0.48 to 1.50) for the rate ratio of 0.85 appears to be wide and includes 1 or null effect, indicating a small sample size, a p-value greater than 0.05, and less confidence in this estimate of the true rate ratio. Moreover, the small number of events means that the likelihood of detecting any effect size by the clinical trial would probably be small, and as a result, a larger sample size would be needed to detect a small effect size, meaning that a large sample size would be needed to detect a small change in lung cancer deaths due to the effect of low dose CT screening on lung cancer deaths when compared to no screening. Additionally, the NELSON study authors reported that the NELSON trial was not powered to show a possible favorable difference in all-cause mortality (expected within the range of 2.5%), because it would have required unrealistic sample sizes (de Koning, 2020). Given the small number of lung cancer deaths, a small effect size, and wide confidence intervals, the NELSON study was likely underpowered for the subgroup analysis among age 50 to 54. The sample size was likely too small to show a difference in lung cancer mortality for those who had low dose CT screening compared to those with no screening. Thus, the NELSON study results suggest a clinically significant trend of decreasing lung cancer deaths, though not statistically significant, among men 50- to 54- years-old who received low dose CT lung cancer screening compared to those who had no screening. In contrast, the overall results from the NELSON study had a statistically significant cumulative lowering in lung cancer deaths among all men and women in the study.While the main study population for the NELSON study (de Koning, 2020) consisted of men, two studies, the NELSON and the LUSI studies, had evidence for women on the effect of low dose CT screening on lung cancer mortality. In the NELSON study, women consisted of 16.7% (1,317/7,900) of the screening group (de Koning, 2020). However, the age distribution of the women in the screening group was not shown in the study results, so it is not possible to determine how many women in the screening group were aged 50- to 54-years-old though this age group of women was included in the NELSON study. Among women in the NELSON study, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up indicating no observed difference in lung cancer mortality comparing those women who underwent LDCT to those who had no screening (de Koning, 2020). The NELSON study did not have any age-stratified results for the women in the study population. Thus, there was a strong trend, though not a statistically significant one, of lung-cancer mortality being 33% lower among women who underwent low dose CT screening compared to those who underwent no screening.Similar to the subgroup age-stratified analysis for men, it is likely that the NELSON study was underpowered to find an effect of low dose CT screening on lung cancer mortality among women. There was a small number of outcome events, such that 25 women died of lung cancer in the screening arm compared to 36 persons in the control arm. Changes in these numbers can lead to a wide variation in the effect size under investigation in the clinical trial, which is the effect of low dose CT screening on lung cancer deaths. Additionally, the confidence interval (95% confidence interval [CI], 0.38 to 1.14) for the rate ratio of 0.67 appears to be wide and includes 1 or null effect, indicating a small sample size, a p-value greater than 0.05, and less confidence in this estimate of the true rate ratio. The small number of events means that the likelihood of detecting any effect size by the clinical trial would probably be small, thus a larger sample size would be needed to detect a small effect size, meaning that a large sample size would be needed to detect a small change in lung cancer deaths due to the effect of low dose CT screening on lung cancer deaths when compared to no screening. The NELSON study authors concluded that trial data suggest greater benefits in women than in men, but in a subgroup with a relatively low number of women. More research is required in women, as well as in other subgroups (de Koning, 2020).While the main study population for the NELSON study (de Koning, 2020) consisted of men and had a subsample of women, the LUSI study (Becker, 2020) had a large enough study population for a stratified analysis specific to women. The German Lung cancer Screening Intervention (LUSI) was a randomized trial among 4,052 long-term smokers 5069 years of age, recruited from the general population, comparing five annual rounds of low dose CT screening (screening arm; n = 2,029 participants) with a control arm without screening who received usual care (n = 2,023) (Becker, 2020). In the intervention arm, 49.9% (714/2,029) were women and there were 942 men and women age 50-to 54 years (46.4%; 942/2029; Becker, 2020). However, there were no age distribution categories for women in the study results, so it is not known how many women in the study were age 50 to 54 years though they were part of the inclusion criteria for age. Among the lung cancer deaths, 4 women died of lung cancer in the low dose CT arm compared to 13 women in the control arm. Over an average observation time of 8.8 years after randomization, the hazard ratio [HR] for lung cancer mortality was 0.74 (95% CI: 0.461.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.100.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.541.61], p = 0.81) screened by LDCT, and when testing for interaction by gender, this heterogeneity was close to statistical significance (Pheterogeneity = 0.09) (Becker, 2020). The results of the LUSI study showed a significant benefit for lung-cancer mortality in the small subgroup of women across all age groups between the ages of 50 and 69 years who were invited to undergo screening. The authors concluded that the an intriguing observation in LUSI is the apparent heterogeneity (although only borderline significant, Pheterogeneity = 0.09) in the effect of LDCT screening on lung cancer mortality by sex, suggesting a mortality reduction among the women only, and go on to report that the findings from LUSI are in line with those from other trials, including NLST [National Lung Screening Trial], that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men (Becker, 2020).The LUSI study authors report that this gender heterogeneity could be the result of different relative counts of lung tumor [histologic] subtypes occurring in men and women, but that the numbers of cancer deaths in LUSI were too small to examine whether the apparent heterogeneity in relative mortality hazards for men and women could be explained by differences in tumor histology, or whether it could have been entirely due to chance (Becker, 2020).Two small European studies of low dose CT, the MILD and DLCST studies, included persons 49 to 54 years in its study population. The Multicentric Italian Lung Detection (MILD) trial prospectively randomized 4,099 participants aged from 49 to 75 years, to a screening arm (n = 2,376), with further randomization to annual (low dose CT every 12 months, n = 1,190) or biennial (low dose CT every 24 months, n = 1,186) low dose CT for a median period of 6 years, or control arm (n = 1,723) without intervention (Pastorino, Silva; Prolonged, July, 2019). In the intervention arm, 32.5% (773/2,376) were below age 55 years and 31.6% (750/2,376) were women (Pastorino, Silva; Prolonged, July, 2019).However, there were no data that showed the number of women or men in the 50 to 54-year-old category. The low dose CT arm showed a statistically significant 39% reduced risk of lung cancer mortality at 10 years (adjusted hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.390.95; p = 0.02) compared with the control arm for all men and women included in the MILD study (Pastorino, Silva; Prolonged, July, 2019). The Cox model analysis was adjusted for gender, age, and pack-years. However, there were no stratified analyses by specific age subgroup, such as age 50 to 54 years, or gender category for lung cancer mortality. The authors concluded that the long-term results of the MILD trial show a statistically significant and clinically relevant 39% reduction of LC mortality at 10 years in the LDCT arm (Pastorino, Silva; Prolonged, July, 2019). However, no data was shown on the magnitude of the statistically significant reduction in lung cancer deaths among men and women age 50- to 54-years-old even though that age group consisted of 32.5% of the study population.The Danish Lung Cancer Screening Trial (DLCST) was a prospective, randomized screening trial comparing annual low-dose CT screening with no screening that enrolled a total of 4,104 men and women aged 5070 years (Wille, 2016). The mean age of the screening group at randomization was 57.9  standard deviation of 4.8 and 56% were men (Wille, 2016). The frequency of persons in the 50-to 54-year-old age group was not shown, though the lower limit of the inclusion criteria included persons equal to or greater than 50 years-old. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.661.6; P = 0.888) with a mean of 9.47 person-years of follow up was observed (Wille, 2016). No age specific stratified subgroup analyses for lung cancer mortality were shown. For study limitations, the authors reported that the reason that we did not see a difference in mortality may be small numbers; however, it may also be due to differences in inclusion criteria. The risk of lung cancer was probably lower in the DLCST cohort because participants were younger (5070 years of age), had smoked less (lower limit was 20 pack-years),  (Wille, 2016).Additionally, the authors reported that the annual incidence of lung cancer in our control group was only half what we expected (i.e., 0.27% instead of 0.50%); thus, the study was underpowered, and concluded that the limited statistical power of this trial does not allow a conclusive statement about the efficacy of lung cancer screening but go on to say that nevertheless, our results support risk stratification with a focus on age, smoking history, and obstructive lung disease when selecting candidates for lung cancer screening (Wille, 2016). Thus, the DLCST study (Wille, 2016) did not show age-specific subgroup data on the effect of low dose CT screening on lung cancer deaths among 50- to 54-year-old persons, even though the inclusion criteria for age included persons greater than or equal to age 50 years, and the DLCST study results did not show a statistically significant lowering of lung cancer mortality in the low dose CT group.