The National Lung Screening Trial: Results Stratified by Demographics, Smoking History and Lung Cancer Histology

Abstract

Background

The National Lung Screening Trial (NLST), which compared lung cancer screening with low-dose CT (LDCT) versus chest radiograph (CXR), demonstrated a statistically significant mortality benefit of LDCT screening. We performed a post-hoc analysis to examine whether the benefit was affected by various baseline factors, including age, gender and smoking status, and whether it differed by histology.

Methods

Lung cancer death rates were computed as events over person years of observation; the mortality risk ratio (RR) was defined as the lung cancer death rate in the LDCT versus CXR arm. Poisson regression was used to test for interactions of gender, age (<65 versus 65+) and smoking status (current versus former) with trial arm. Mortality risk ratios were also computed for specific lung cancer histologies.

Results

The overall mortality RR was 0.92 in men and 0.73 in women, with a p-value for interaction of 0.08. RRs were similar for subjects under age 65 (0.82) versus 65+ (0.87), and for current (0.81) versus former smokers (0.91). By histology, mortality RRs were 0.75 for adenocarcinoma, 0.71 for all non small cell lung cancer (NSCLC) except squamous, 1.23 for squamous cell carcinoma, and 0.90 for small cell carcinoma. RRs were similar for men and women for non-squamous NSCLC, 0.71 and 0.70, respectively; women had lower RRs for small cell and squamous cell carcinoma.

Conclusions

LDCT benefit did not vary substantially by age or smoking status; there was weak evidence of differential benefit by gender. Differential benefit across lung cancer histologies may exist.

Introduction

The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality for annual screening over three years with low dose computed tomography (LDCT) compared to chest radiography (CXR)¹. The eligibility criteria for NLST included an age range of 55–74 and a smoking history of at least 30 pack years, with either current smoking status or having quit within the past 15 years; both men and women were included.

The NLST results prompted a discussion of how, and in which population groups, LDCT screening might be implemented in the U.S.^2–4 Addressing this question requires understanding how LDCT screening performed in various subgroups within NLST. Such subgroups include men and women, younger (below age 65) and older subjects, and current and former smokers. Although NLST was powered to find a statistically significant difference in lung cancer for the entire NLST population, there might be differences in LDCT benefit between subgroups.

For some lung cancer histologies, specifically small cell carcinoma, LDCT screening may not be effective^5–6. It is also possible that effectiveness of LDCT screening may differ among the histologies comprising non-small cell lung carcinoma (NSCLC). Again, although NLST was not powered to find significant mortality differences for specific histologies, trends can be examined, including differential survival rates across arms as well as mortality risk ratios. Note the analysis of LDCT effectiveness by histology differs fundamentally from analyses of effectiveness by demographics or smoking history. In the latter, pre-defined subsets of the population may be identified and targeted to preferentially receive (or not receive) LDCT screening based on relative effectiveness; in contrast, for histology, it is not known a-priori what histology subjects will be diagnosed with. However, it is clearly an important scientific question whether LDCT screening is differentially effective by histology.. Similar analyses of efficacy of screening tests for different disease histologies or subtypes provided insight about the differential ability of Pap smears to detect squamous versus adenomatous lesions of the cervix⁷.

In this manuscript we report mortality risk ratios (LDCT versus CXR arm) for various NLST population subgroups to examine whether they might vary according to sex, age or smoking status. In addition, we examine mortality rates and survival rates across trial arms for specific lung cancer histologies, including small cell carcinoma, adenocarcinoma and squamous cell carcinoma.

Methods

The NLST protocol has been described previously⁸. Briefly, NLST randomized subjects aged 55–74 to LDCT or CXR in a 1:1 ratio. Eligibility criteria included a 30+ pack year history of cigarette smoking and current smoking status or having quit within the past 15 years. Subjects were enrolled at 33 U.S. screening centers during 2002–2004 and a received either LDCT or CXR screens at baseline and then annually for two more years. An LDCT scan that revealed a non-calcified nodule ≥4 mm or a chest radiograph that revealed any non-calcified nodule or mass was categorized as a positive screen. Diagnostic follow-up of positive screens was directed by subjects’ individual health care providers; NLST provided guidelines but no specific approach was mandated.

Incident cancers were tracked through follow-up of positive screens and annual status update questionnaires. Deaths were tracked through the annual questionnaires as well as through national death index (NDI) searches. Death certificates were obtained and an independent blinded review process for cause of death was conducted on deaths possibly due to lung cancer. Medical records, including pathology and tumor staging reports, were obtained for all suspected lung cancers and NLST coders abstracted lung cancer characteristics, including stage and histology (ICD-O-3 classification). The histological classifications shown here are the same as reported in primary NLST outcome paper; since diagnosis and treatment in NLST was performed outside of the auspices of the trial, histology was determined as part of routine patient care at the numerous clinical centers where NLST subjects were evaluated.

Statistical Methods

Subjects were followed for incident lung cancers and deaths through 12/31/2009. Incidence and mortality rates were calculated as number of events divided by person years (PY) of follow-up; risk ratios (RRs) for the LDCT versus the CXR arm were computed as the ratio of rates in the two arms.

In the primary NLST outcome paper, the final result for lung cancer deaths was derived using an event cutoff date of January 15^th, 2009, whereas results for incident lung cancers and total deaths were derived using the December 31, 2009 cutoff¹. The earlier date for lung cancer deaths was employed to allow adequate time for these events to undergo endpoint verification. With time passed since that publication, the endpoint verification process has been extended to cover deaths through 12/31/2009, with 98% of all lung cancer deaths endpoint verified. Therefore, for this analysis, we utilized all lung cancer deaths through December 31, 2009, resulting in some estimates here differing from those in the primary outcome paper due.

To examine interactions of the mortality RR (lung cancer and overall) with the major covariates of sex, age at randomization (< 65 vs ≥65), and baseline smoking status (current vs. former), we utilized Poisson regression with a log link. PY of follow-up for each subject were computed as the time from randomization to either death, loss to follow-up or 12/31/2009, whichever came first.

Mortality RRs for each histology were computed by treating deaths from other lung cancer histologies as other-cause mortality. We utilized Kaplan-Meier curves to examine survival for specific histologies. Survival curves were generated both from the time of randomization and from the time of diagnosis; using randomization as the start time eliminates bias due to differential lead time across study arms (note, however, that it does not remove the bias related to overdiagnosis in one arm relative to the other). Confidence intervals on differences in RRs by histology were computed using bootstrapping.

For a global test of whether LDCT efficacy differed among histologies, we assumed outcomes in each trial arm were governed by a multinomial distribution, where the outcomes were lung cancer death of a given histology or no lung cancer death. We used the likelihood ratio test to compare the model with a single common RR (for LDCT versus CXR arm) across histologies to a saturated model with a fitted RR for each histology, with the histologies being squamous cell carcinoma, NSCLC excluding squamous cell, small cell, and other/unknown.

A potential bias in the analysis of histology-specific mortality RRs (and histology-specific survival) derives from the classification of NSCLC-NOS (not otherwise specified). In distinguishing between NSCLC histologic classifications, e.g., between adenocarcinoma and squamous cell carcinoma, NSCLC-NOS constitutes missing data since the specific subtype of NSCLC is unknown⁹. Due to the differential rate of NSCLC-NOS by arm, bias could result for specific NSCLC sub-types. To adjust for this bias, we performed simulations (n=1000) where, for each simulation, NSCLC-NOS cases were randomly assigned to squamous cell carcinoma (or non-squamous NSCLC) according to the percentage of squamous cell, 33.5%, among the cases with known NSCLC sub-types (bronchioloalveolar carcinoma (BAC) was excluded for this purpose since it is very different from other NSCLC, having substantially higher survival and overdiagnosis rates with LDCT). We then averaged over the simulations (N=1000) to obtain adjusted mortality RRs and adjusted survival rates by NSCLC sub-type (squamous and non-squamous NSCLC).

Results

Table 1 displays the number of enrolled subjects, by trial arm, for the major baseline covariates (sex, age, smoking status), as well as incident lung cancer counts and rates. A total of 59% of participants were male, 27% were aged 65+ at enrollment, and 48% were current smokers. Among men and women, the proportions that were current smokers and that were age 65+ were similar (e.g., 47% of men and 50% of women were current smokers; data not shown in table).

Table 1.

Lung cancer incidence by trial arm and major covariates

	Arm	Total Enrolled	# Incident Lung Cancers	Incidence Rate (per 100,000 PY)	Incidence RR (95% CI) 1
Subset		N
All	LDCT	26722	1089	662	-
All	CXR	26730	969	588	-
		N(% within arm)
Women	LDCT	10953 (41)	434	638	Referent
Men	LDCT	15769 (59)	655	678	1.06 (0.94–1.20)
Women	CXR	10969 (41)	395	580	Referent
Men	CXR	15761 (59)	574	594	1.02 (0.90–1.16)
Age < 65	LDCT	19612 (73)	620	508	Referent
Age ≥ 65	LDCT	7110 (27)	469	1100	2.16 (1.92–2.44)
Age < 65	CXR	19622 (73)	549	450	Referent
Age ≥ 65	CXR	7108 (27)	420	981	2.18 (1.93–2.49)
Former Smoker	LDCT	13862 (52)	452	522	Referent
Current Smoker	LDCT	12860 (48)	637	816	1.56 (1.39–1.76)
Former Smoker	CXR	13830 (52)	365	421	Referent
Current Smoker	CXR	12900 (48)	604	773	1.84 (1.62–2.09)

¹. Risk Ratio across covariate categories within trial arm (e.g., for men versus women within the LDCT arm).

Lung cancer incidence rates were similar between men and women within each arm. Incidence RRs were about 2.2 in each arm for those aged 65+ as compared to those under 65; for current smokers (as compared to former smokers) the incidence RR was 1.56 in the LDCT arm and 1.84 in the CXR arm.

Mortality results are displayed in Table 2. Our updated analysis (using the later 12/31/2009 cutoff) continued to show an overall reduction in lung cancer mortality (RR=0.84, 95% CI: 0.75 to 0.95). For sex by study arm, there was a borderline significant interaction (p=0.08), with the mortality RR for women, 0.73, more protective than that for men, RR=0.92. For both age and smoking status, there were no significant interactions for the lung cancer mortality RR, with p-values for interaction above p=0.40. For all-cause mortality there was no suggestion of interaction of the mortality RR with any of the three major covariates (p-value for interaction range 0.61–0.84).

Table 2.

Lung Cancer and Overall Mortality Rates by Major Covariates, with Interaction Analysis

	Arm	# Lung Cancer Deaths | Death Rate 1	Risk Ratio 2	p-value for interaction3	# Total Deaths | Death Rate 1	Risk Ratio 2	p-value for interaction3
Subset
All	LDCT	469 | 280	0.84		1912 | 1141	0.931
All	CXR	552 | 332	Referent		2039 |1225	Referent
Women	LDCT	158 | 228	0.73		574 |828	0.921
Women	CXR	215 | 312	Referent		619 |899	Referent
Men	LDCT	311 | 316	0.92		1338 |1361	0.936
Men	CXR	337 | 345	Referent	0.08	1420 | 1454	Referent	0.84
Age < 65	LDCT	253 | 205	0.82		1059 | 856	0.942
Age < 65	CXR	307 | 250	Referent		1117 | 909	Referent
Age >=65	LDCT	216 | 491	0.87		853 | 1943	0.918
Age >=65	CXR	245 | 562	Referent	0.60	922 | 2116	Referent	0.67
Current Smoker	LDCT	294 | 369	0.81		1146 |1437	0.944
Current Smoker	CXR	360 | 455	Referent		1206 | 1523	Referent
Former Smoker	LDCT	175 | 199	0.91		766 | 872	0.914
Former Smoker	CXR	192 | 220	Referent	0.40	833 | 954	Referent	0.61

¹. Per 100,000 PY.

². Risk ratio of LDCT versus CXR arm within covariate category.

³. Interaction of Risk Ratio with given covariate.

Table 3 summarizes lung cancer cases and deaths by arm according to histology. Adenocarcinoma comprised about 30% of lung cancer deaths in each arm (29% CT, 33% CXR) and small cell about 20% in each arm. Squamous cell carcinoma comprised 22% of CT arm and 15% of CXR arm deaths, while NSCLC-NOS comprised 10% of CT arm and 14% of CXR arm deaths.

Table 3.

Lung Cancer Cases and Deaths by Histology

Arm	CT	CXR	CT	CXR
Histology	Cases	Cases	Lung Cancer Deaths	Lung Cancer Deaths	Lung Cancer Mortality RR (95% CI)
	N (%)	N(%)	N(%)	N(%)
Bronchioloalveolar Carcinoma (BAC)	111 (10)	36 (4)	13 (3)	10 (2)	1.3 (0.58–2.9)
Adenocarcinoma	389 (35)	337 (34)	136 (29)	181 (33)	0.75 (0.60–0.94)
Large Cell	40 (4)	44 (4)	17 (4)	24 (4)	0.71 (0.38–1.3)
NSCLC-other 1	48 (4)	49 (5)	25 (5)	34 (6)	0.74 (0.44–1.2)
NSCLC-NOS	89 (8)	113 (11)	45 (10)	76 (14)	0.59 (0.41–0.86)
All NSCLC minus Squamous (excl BAC)	566 (51)	543 (55)	223 (48)	315 (57)	0.71 (0.60–0.84)
Squamous Cell	249 (22)	214 (22)	102 (22)	83 (15)	1.23 (0.92–1.64)
Small Cell	143 (13)	163 (16)	102 (22)	113 (20)	0.90 (0.69–1.18)
Carcinoid	6 (0.5)	3 (0.3)	1 (0.2)	0
Unknown	34 (3)	34 (3)	28 (6)	31 (6)	0.90 (0.54–1.5)
All	1109	993	469	552	0.84 (0.75–0.95)

¹. Excludes adenocarinoma, large cell, squamous cell, BAC and NSCLC-NOS.

Observed mortality RRs (LDCT versus CXR arm) were 0.75 (95% CI: 0.60–0.94) for adenocarcinoma, 1.23 (95% CI 0.92–1.23) for squamous cell carcinoma and 0.90 (95% CI: 0.69–1.18) for small cell carcinoma. For all NSCLC except squamous cell (and excluding BAC), the mortality RR was 0.71 (95% CI: 0.60–0.84); this RR was significantly different than the RR for squamous cell carcinoma (95% CI of log ratio of RRs, 0.18–0.83). The global test of differential LDCT efficacy showed that the null hypothesis of equal RRs across histologies was rejected at the p=0.01 level, as compared to the alternative hypothesis of separate RRs for the major histologies (squamous cell, NSCLC excluding squamous cell, small cell, and other).

Survival rates by arm and histology are displayed in Table 4. Analyzed by time from randomization, 3 and 6 year survival rates (lung cancer specific) among adenocarcinoma cases were significantly greater in the LDCT (89.4% and 71.6%, respectively) than in the CXR arm (81.9% and 54.5%). Survival rates were similar for all non-squamous NSCLC as for adenocarcinoma. In contrast, for squamous cell, survival was similar between arms; 3 and 6 year survival rates (from randomization) were 88.7% and 66.6%, respectively, in the LDCT versus 89.3% and 65.7%, respectively, in the CXR arm. NSCLC-NOS had worse survival than either squamous cell carcinoma or adenocarcinoma, irrespective of study arm. The above results for both survival and mortality did not adjust for the bias due to the imbalance in NSCLC-NOS between arms (24 more cases in the CXR arm). After adjustment, which apportioned the NSCLC-NOS cases between squamous and non-squamous NSCLC, the (estimated) numbers of deaths from squamous cell carcinoma was increased to 116.7 (LDCT) and 108.5 (CXR), as compared to the original counts of 102 (LDCT) and 83 (CXR), decreasing the mortality RR for squamous cell carcinoma to 1.08 (95% CI: 0.86–1.31) from the original 1.23. For non-squamous NSCLC, the adjusted mortality RR changed only slightly, to 0.72 from the original (unadjusted) 0.71. The RR for squamous cell carcinoma remained significantly greater than that for non-squamous NSCLC in the adjusted analysis (95% CI of log ratio of RRs, 0.14–0.65). For the adjusted analysis of survival (from randomization), survival rates for squamous cell were still similar across arms, if slightly better for LDCT, with 3 and 6 year survival rates of 87.8% and 65.4%, respectively, versus 87.1% and 61.7% for the CXR arm. For all non-squamous NSCLC, (adjusted) 3 and 6 year survival rates were 87.3% and 67.8% for LDCT versus 79.2% and 49.4% for CXR.

Table 4.

Lung Cancer Specific Survival by Histology and Study Arm

		LDCT Arm	CXR Arm	p-value (difference between arms)
		Survival Rate 2	Survival Rate 2
Histologic Type	Start of follow-up for analysis 1	3 years | 6 years	3 years|6 years
Adenocarcinoma	Diagnosis	69.7 | 59.1	43.5 |33.2	<0.0001
	Randomization	89.4|71.6	81.9| 54.5	< 0.0001
NSCLC-NOS	Diagnosis	46.1|43.8	29.5|24.4	0.004
	Randomization	80.9|55.4	75.0|39.5	0.034
All NSCLC minus squamous (excl BAC)	Diagnosis	64.4 | 54.3	38.4| 30.7	<0.0001
	Randomization	87.0 | 67.2	79.1|49.1	<0.0001
Squamous Cell	Diagnosis	59.5|50.7	58.6|48.5	0.82
	Randomization	88.7|66.6	89.3|65.7	0.68
		1 yr| 3yrs|6 yrs	1 yr| 3yrs|6 yrs
Small Cell	Diagnosis	56.2|15.8|14.4	49.9|21.3|11.5	0.72
	Randomization	97.9|76.2|39.1	95.7|77.2|37.8	0.80

¹. Start of follow-up for survival analysis – either date of diagnosis or date of NLST randomization.

². Lung cancer specific survival.

Table 5 shows lung cancer deaths by gender, histology and study arm. For adenocarcinoma, and more broadly non-squamous cell NSCLC, the mortality RRs were essentially equivalent for men and women; 0.71 for men versus 0.70 for women for non-squamous cell NSCLC. Mortality RRs were greater for men than women for both small cell carcinoma (1.10 for men versus 0.67 for women) and squamous cell carcinoma (1.31 for men versus 1.04 for women).

Table 5.

Lung Cancer Deaths by Gender, Histology and Arm

	Men			Women
	LDCT	CXR	Mortality RR (95% CI)	LDCT	CXR	Mortality RR (95% CI)
Histologic Type	N(%)
BAC	10 (3)	6 (2)	1.7 (0.6–4.4)	3	4	0.75 (0.2–3.0)
Adenocarcinoma	85 (27)	111 (33)	0.77 (0.6–1.02)	51	70	0.73 (0.51–1.05)
Large Cell	11 (3)	18 (5)	0.61 (0.3–1.3)	6	6	1.0 (0.3–3.0)
NSCLC-other 1	15 (5)	21 (6)	0.71 (0.4–1.4)	10	13	0.77 (0.4–1.7)
NSCLC-NOS	26 (8)	42 (12)	0.62 (0.4–1.01)	19	34	0.56 (0.3–0.98)
All NSCLC minus squamous (excl BAC)	137 (44)	192 (57)	0.71 (0.6–0.9)	86	123	0.70 (0.5–0.9)
Squamous Cell	77 (25)	59 (18)	1.31 (0.9–1.8)	25 (16)	24 (11)	1.04 (0.6–1.8)
Small Cell	68 (22)	62 (18)	1.10 (0.8–1.6)	34	51 (24)	0.67 (0.4–1.03)
Carcinoid	1 (0.3)	0		0	0
Unknown	13 (4)	7 (2)	1.9 (0.8–4.5)	14	10	1.4 (0.6–3.1)
All except small cell and squamous cell	166 (53)	216 (64)	0.77 (0.6–0.9)	99	140	0.71 (0.5–0.9)
All except small cell	243 (78)	275 (82)	0.88 (0.7–1.05)	124	164	0.76 (0.6–0.96)
All	311	337	0.92 (0.8–1.08)	158	215	0.73 (0.6–0.9)

¹. Excludes Adenocarinoma, Large Cell, Squamous Cell, BAC and NSCLC-NOS.

Discussion

In this post-hoc analysis of the NLST mortality results according to the major demographic and smoking behavior covariates, we found no evidence of an interaction of the all-cause mortality risk ratio (LDCT versus CXR arm) by age, sex or smoking status. For the lung cancer specific mortality risk ratio, which was the primary outcome for the trial, we found no evidence of an interaction by age or smoking status; however, a borderline significant interaction by sex was observed, with women having a more protective effect of LDCT than men.

With respect to histology, we found differences in the mortality effect of LDCT screening by histologic subtypes in our exploratory analysis. For adenocarcinoma, and more broadly all NSCLC combined excluding squamous cell, the mortality RRs were significantly below 1, 0.75 and 0.71, respectively, showing a substantial LDCT screening benefit. In contrast, for squamous cell carcinoma, mortality rates were higher in the LDCT arm, with an RR=1.23 (95% CI 0.92–1.64), which decreased modestly to 1.08 (95% CI 0.86–1.31) when adjusting for the potential bias associated with the NSCLC-NOS classification. While the lower 95% CI for the squamous cell mortality RR is consistent with a modest 10–15% benefit of LDCT screening, it should also be noted that the RR for all NSCLC excluding squamous cell (as well as for adenocarcinoma alone) was statistically significantly less than that for squamous cell carcinoma.

In our analysis we separated out BAC from the adenocarcinoma cases, not including deaths from BAC in the adenocarcinoma relative risk estimate. However, after the NLST was completed, a new histologic classification scheme for adenocarcinoma was unveiled that eliminates the category of BAC and replaces it with adenocarcinoma in situ, minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma¹⁰. For a subset of the NLST BAC cases, tissue specimens were retrospectively collected and a centralized pathology was performed utilizing the new classification scheme. Of the subset re-analyzed, all of the fatal cases in each arm were classified as invasive adenocarcinoma. Based on these results, and the fact that adenocarcinoma in-situ and MIA cases are typically indolent, it is likely that most or all of the deaths in originally classified BAC cases were actually from invasive adenocarcinoma. If we thus add all the BAC deaths (13 in the LDCT and 10 in the CXR arm) to the adenocarcinoma category, the RR for adenocarcinoma would only increase slightly, from 0.75 to 0.78.

With relatively small numbers of deaths when broken down by histologic sub-type, the mortality RR could be influenced by a chance imbalance in the numbers of incident cancers across arms. For that reason, and to compare with observational studies in the literature, we also analyzed lung cancer survival by histology. To control for lead-time bias, we computed survival from randomization as well as from diagnosis. We found that squamous cell carcinoma cases did not have better survival in the LDCT than the CXR arm, in contrast to the findings for adenocarcinoma. This provides further evidence that LDCT screening in NLST was not effective for squamous cell carcinoma. In contrast to the survival findings here, a Japanese study demonstrated that both adenocarcinomas and squamous cell carcinomas had significantly greater survival when detected by CT than CXR⁵. Note this study did not adjust for lead time bias; however, in our analysis, even when analyzed from time of diagnosis, squamous cell survival was no better in the LDCT than the CXR arm. Other studies examining volume doubling time (VDT) have generally found that VDTs were significantly shorter (indicating faster growth) for squamous cell carcinomas than for adenocarcinomas^11–12. These findings are consistent with a smaller benefit of LDCT screening for squamous cell as compared to adenocarcinoma, since the window for screening effectiveness could thus be shorter for squamous cell carcinoma.

It has generally been assumed that small cell carcinoma is not amenable to LDCT screening, due to its aggressive natural history and early metastases^5–6. Here the data were consistent with this assumption, with an RR not significantly different from 1 (RR=0.9, 95% CI 0.69–1.18) and no survival advantage for LDCT versus CXR arm cases.

The analysis of mortality by histology sheds light on the possible greater benefit of LDCT screening in women versus men. For adenocarcinoma, the histology with the strongest case for a benefit of LDCT screening, the mortality RR was essentially the same for men as for women (RR=0.77 and 0.73, respectively), as it was for all NSCLC excluding squamous. The greater benefit for women comes almost exclusively from small cell and squamous cell carcinomas. If screening is ineffective for small cell, then the variations across arm and gender in small cell deaths may simply be chance occurrences, which should be ignored when evaluating the relative benefit of LDCT screening in men and women; RRs for men and women for all lung cancer excluding small cell were 0.88 versus 0.76, as compared to 0.92 versus 0.73 for all lung cancer, a smaller differential. To the extent that screening for squamous cell carcinoma is also ineffective, then the same would go for these deaths; excluding both squamous and small cell deaths gave similar RRs of 0.77 for men and 0.71 for women. Therefore, the true difference in LDCT screening effectiveness by gender, if one exists at all, is likely smaller than that observed in NLST. Note that if screening were more effective for adenocarcinoma than for squamous cell carcinoma, then the fact that squamous cell carcinoma is relatively less prevalent in women than men would logically lead to the mortality benefit for all lung cancer being greater in women than in men. However, an analysis based on the NLST data shows that this effectiveness difference would probably be slight. Using the observed LDCT mortality RR for NSCLC excepting squamous cell of 0.71, assuming true RRs of 1.0 for squamous cell and small cell, and given the histology distribution in NLST (CXR arm) of 64% non-squamous NSCLC in women versus 58% in men, the mortality RR (for all lung cancer) would be 0.81 in women and 0.83 in men, a quite modest differential.

As described above, in this analysis we utilized a later cutoff date for lung cancer deaths than did the primary outcome paper, resulting in the overall lung cancer RR increasing from 0.80 to 0.84¹. The effect of using the later cutoff can also be examined in terms of other summary measures of screening efficacy, such as the number needed to screen with LDCT to prevent one lung cancer death (NNS) and the absolute difference in lung cancer death rates across arms. The NNS provides a rough measure of the harms-benefit tradeoff of screening, while the absolute difference in death rates provides a more direct measure (than the risk ratio) of an individual’s potential gain from screening. The NNS changed little, from 307 using the original (earlier) cutoff to 322 using the later cutoff date (note an NNS of 320 was reported in the primary outcome paper; this was computed among those receiving at least one screen, whereas the numbers here reflect an intent-to-screen analysis). The difference in death rates across arms decreased modestly, from 62/100,000 PY originally to 52/100,000 PY. Therefore, the same qualitative conclusions about the efficacy of LDCT screening can be made based on the later as compared to the earlier data.

An analysis conducted using the earlier cutoff date and also employing weights (rising linearly from time 0 to 4 years after randomization and flat thereafter), as was done in the primary outcome paper¹ did not change our finding of no statistically significant interaction between randomization arm and any of the three major subgroups.

The question addressed here of whether the mortality RR differs according to sex, age or smoking status is different from that of whether there is a differential harms-benefit trade-off of LDCT screening according to these characteristics⁴. For example, if the mortality RR is similar for current versus former smokers, then the NNS would be greater for former smokers because the underlying death rates are lower. Although the observed RR was 0.81 for current and 0.91 for former smokers, the lack of a significant p-value for interaction leads to an assumption of equivalent RRs. With an (assumed) common RR of 0.84, the NNS would be 462 for former smokers versus 230 for current smokers, based on an approximately two fold higher background lung cancer death rate for current versus former smokers in NLST. Thus, even with similar mortality RRs, differences in underlying death rates between population subgroups can modify the harms-benefit tradeoff of screening.

Conclusion

LDCT benefit did not vary substantially by age or smoking status; there was weak evidence of differential benefit by gender. Differential benefit across lung cancer histologies may exist.