Increase in second primary lung cancers in a nation-wide cohort study from Sweden

Abstract

Background

We describe the occurrence of second primary lung cancers (SPLCs) and their determinant in Sweden.

Methods

Nation-wide cancer registry from years 1961 to 2021 identified a total of 853 SPLCs.

Results

The incidence of SPLCs increased almost linearly from 1980 onwards, equally for women and men and approximately equally after the four main histological types. SPLC included adenocarcinoma 63.9%, squamous cell carcinoma (SCC) 19.4%, small cell carcinoma 9.6% and large cell carcinoma 9.1%. The female cumulative probability (CumP) of SPLC after first adenocarcinoma in 10 years reached 0.019, after SCC 0.015 and after small and large cell carcinoma 0.008. The respective CumP for men was 0.013, 0.012, 0.002 and 0.005. While adenocarcinoma was often followed by second adenocarcinoma, after first non-adenocarcinoma SPLCs presented in diverse histologies. Relative risk of SPLC compared with first lung cancer was overall 3.59, higher for women (4.16) than for men (2.99) and approximately equally high after adenocarcinoma and SCC. In patients diagnosed before age 55 years, the relative risk was 6.68 for all, but after female adenocarcinoma it was 9.95 compared with 6.77 for males. The highest relative risks, up to 20-fold, were found after early onset female adenocarcinoma diagnosed after defined T stages.

Conclusions

Although SPLCs are still rare, their number is increasing rapidly and the relative risks compared with first lung cancer are substantial, qualifying selected groups of high-risk patients, such as patients with early onset adenocarcinoma for early detection by CT screening when/if such tests become available.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Second primary lung cancers (SPLCs) increase as a result of improving survival in first lung cancer.

WHAT THIS STUDY ADDS

• Novel data were provided on relative risk of SPLC, which was 4.16 for women and 2.99 for men, and as high as 10 after early-onset female adenocarcinoma.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Follow-up schemes of patients with lung cancer should consider risk-adjusted targeting.

Introduction

Survival has increased in lung cancer (LC) because of early diagnosis, improvements in treatment and changing histology towards the less fatal adenocarcinoma type.^{1 2} Cure fraction or long-term survivors for LC were 8% for men and 10% for women in Europe by year 2000.³ According to US data, cure rates depended on stage and histology, and by year 2015 the best cure fractions through 2020 were for adenocarcinoma stage I at 82%, decreasing to 6% for stage IV.⁴ A consequence of this positive development is an increasing likelihood that a patient will be diagnosed with an independent second primary LC (SPLC).^{5 6} For optimal treatment, such independent primaries need to be distinguished from metastasis of the initial primary LC (IPLC).⁶ To achieve this, commonly applied clinicohistological criteria (termed Martini-Melamed or MM criteria) define that between IPLC and SPLC: (1) histological types need to be different or one tumour is in situ LC, or (2) they may be the same histological type but diagnostic date of the second cancer needs to be at least 2 years later, or (3) they may be the same histological type without time limit as long as the two tumours are located in different lobes or sides of the lung with no involvement of lymphatics common to both and no evidence of extra pulmonary metastasis (see studies by Tian et al and Jensen et al^{5 6}). For confirmation of the independent origins of IPLC and SPLC laboratory techniques have recently been developed and increasingly applied.^5–7 These are used to establish clonal independence of SPLC by means of, for example, immunohistochemistry, genome sequencing, comparative genomic hybridisation or loss of heterozygosity analyses.^5–7

Many epidemiological studies on SPLC have been published despite relatively low survival of patients with LC.^{6 8 9} Cancer registry-based studies do not use the above clinicohistological (MM) criteria for SPLC but may use their own or some international criteria for classifying second cancers as independent primaries.^10–12 Many LC studies, including data on SPLC, covered in fact many types of second cancers with main focus on aetiology (rather than risk of SPLC), such as smoking.^13–15 Swedish and US registry/cohort-based studies focused on SPLCs only and showed that the relative risk for these exceeded that for IPLC.^{8 9 16 17} Aetiology of SPLCs may be shared by IPLC, including smoking, other environmental factors and hereditary predisposition, but also field cancerisation and treatment-related factors have been proposed as possible mechanisms for SPLC.^{5 6} The risk of SPLC has been reported to be equal between people who smoke and people who have never smoked, which could imply involvement of hereditary or other unknown factors.¹⁷ Two US studies reported on the variables that influenced the probability of SPLC, including age at diagnosis of IPLC (maximal at 60–64 years), histology (highest for adenocarcinoma) and stage (highest for local).^{16 18} When the risk factors were combined and divided into deciles, the incidence difference between the extremes was over fourfold.¹⁸ However, the risk stratification was heavily influenced by age of IPLC diagnosis (low risk for diagnosis below 45 and over 75 years, and advanced stages, particularly distant disease).¹⁸

We use data from the most recent update of the Swedish cancer registry (1961–2021) with a focus on a cohort of patients diagnosed with IPLC during 1993–2021. As background information about Swedish IPLC, squamous cell carcinoma (SCC) was the main histological type of male LC when it reached a maximal incidence in 1982, while for women adenocarcinoma was always the main histological type and the incidence peaked as late as in 2018.^{2 19} Here we estimate the risk of SPLC as cumulative proportion of patients developing SPLC by age, sex, histology and follow-up time. The data will guide thorax clinics to plan their follow-up schemes for SPLC in patients successfully treated for IPLC. The need to institute follow-up schemes for patients with LC at risk of SPLC is linked to a more public health-related ambition of screening healthy at-risk individuals using low-dose CT for which screening schemes are rolling out or planned in many countries.²⁰ The consequence will be an increasing proportion of patients with early-stage LC who need to be evaluated for risk of SPLC.

Methods

Data on LC occurrence were obtained from the Swedish cancer registry. LC was defined through ICD-7 code 1621, ‘LC specified as primary’. For any reported cancer, the cancer registry makes an effort to include only primary cancers and we thus presume that multiple LCs are independent primaries (8). Nevertheless, in order to exclude mix-up of notifications, we include only LCs diagnosed at least 1 month apart from each other. We additionally used the MM criteria for classifying LC cases as SPLC (see Introduction); however, only eight potential SPLCs were deleted because of these criteria, indicating careful definition of SPLC by the cancer registry (online supplemental table 1). The analyses considered patients born in Sweden, ensuring reliable tracking of patient cancer history.

In the Swedish cancer registry, 98% of cancers are histologically verified. Data content and quality of the cancer registry has been thoroughly reviewed.¹⁰ Data on the main histological types were available through the whole study period and include adenocarcinoma code 96, SCC (146), small cell carcinoma 186, large cell carcinoma 196 and bronchoalveolar cancer (BAC) 76. As BAC is considered part of adenocarcinoma, we combined it with the ‘adenocarcinoma’ category. The IPLC and SPLC definitions were restricted to the main four histologies. Data on tumour topography were available since 1993. Staging data (tumour, node, metastases (TNM), sixth edition to 2009 and then seventh edition) were almost complete after 2005 but mostly missing before 2004, and were not included in SPLC defining criteria. We use T and N stage data in analysis. Metastatic data were not analysed because of a total of 444 patients, only 35 were other than M0.

Statistical analysis

We analysed data in competing risk setting, where competing events included death, SPLC diagnosis and diagnosis of any LC not meeting criteria for SPLC. This was modified for SPLC-histology analysis, where cancers with different histologies represented competing risks, representing mutually exclusive events. The follow-up started 1 month after IPLC diagnosis and was terminated at the time of death, emigration, LC diagnosis or end of study (29 December 2021), whichever came earliest. Cumulative incidence function (CumP) of competing events was estimated by non-parametric Aalen-Johansen estimator, using cmprsk package in R.²¹

Incidence rates were calculated as numbers of cases/100 000 person-years at risk by calendar period. Standardised incidence ratios (SIRs) for SPLC were estimated for patients diagnosed with IPLC in 1993–2021, as number of observed SPLC cases divided by expected number of cases based on IPLC incidence in background population. The start and termination of follow-up were the same as in the cumulative probability analyses. The estimates were standardised by sex, age (5-year groups), calendar year (10-year periods), education (proxy for socioeconomic status) and area of residence (large cities, southern and northern Sweden). The standardisation should partially adjust for differences in smoking levels between patients with LC; our earlier studies have shown over twofold differences in LC incidence between female and male educational and social groups.^{22 23} We have recently published data on familial risk which could be identified for 15% of patients with LC in 1961–2021.²⁴ However, as the focus in the present paper is for the period 1993–2021, the proportion would be much smaller.

The 95% CIs for crude and standardised incidence rates were calculated by assuming that observed numbers of SPLCs follow a Poisson distribution. To control for potential non-Poissonian distribution of SPLCs, we have additionally estimated bootstrap 95% CI, where patients with IPLC were 1000 times sampled randomly with replacement to obtain 2.5th and 97.5th quantile of bootstrapped SIR distributions. We further report bootstrap-derived p values for testing the hypothesis that younger age groups are associated with higher marginal relative risk, calculated as p=(|SIR_Yboot−SIR_Oboot≤0|+1)/(B+1), where |SIR_Yboot−SIR_Oboot≤0| is number of non-positive samples in bootstrap distribution of differences between SIR values for younger and older age groups, respectively, and B=1000 is number of random samples. Bootstrapping was performed for patient subgroups in which age groups had sufficient case numbers to ensure stable estimates.

All statistical analyses and data visualisation were done using SAS (V.9.4) and R (V.4.4.0).

Results

Case numbers of IPLC and SPLC are shown for two calendar periods, 1993–2021 with most complete data (N for IPLC=67 000) and 1961–2021 with larger overall case number (n=105 000) (online supplemental table 2). In 1993–2021, case numbers for IPLCs were almost equal for women and men, but for SPLC, women clearly outnumbered men (59.5 vs 40.5%). Most SPLCs developed in patients initially diagnosed with adenocarcinoma (57.4%) and in patients who were 60–69 old at IPLC diagnosis (43.8%).

The incidence of SPLC after histology-specific IPLC is shown in figure 1 for period 1971–1980 to 2011–2021. On top, female and male rates increased sharply but did not differ; the increase in incidence was more than threefold in 30 years. No difference was noted between the incidence rates for SPLC after the four histological types of IPLC (CIs are given in the legend).

Figure 1. The incidence of SPLC after histology-specific IPLC from the period 1971–1980 to 2011–2021. On top (A), male and female rates (2011–2021 incidence (95% CI): females 641.3 (571.4 to 717.5), males 596.6 (515.6 to 686.8)). Incidence rates for SPLC after the four histological types of IPLC (B, 2011–2021: adenocarcinoma 593.3 (528.2 to 664.1), SCC 690.3 (568.4 to 830.6), small cell carcinoma 578.7 (381.4 to 842.0), large cell carcinoma 700.5 (531.9 to 905.6)). IPLC, initial primary lung cancer; SCC, squamous cell carcinoma; SPLC, second primary lung cancer.

Stage distributions of IPLC and SPLC are shown by T classification according to histology in online supplemental table 3. SPLCs diagnosed after adenocarcinoma were largely also adenocarcinomas, 84% for women and 68% for men. Adenocarcinoma as SPLC accounted for 63.6%, SCC for 18.2%, small cell for 9.5% and large cell for 8.7% of the four main histological types of SPLC. Adenocarcinomas dominated also after IPLC adenocarcinoma of T1 stage, accounting for 86% of all female and 69% of male second adenocarcinomas. For the other SPLC histologies, the stage distribution of the corresponding IPLC was more variable, and even T4 IPLC contributed over 10% of SPLCs. IPLC of SCC histology was followed by nearly equal numbers of SPLCs of adenocarcinoma and SCC histology in women, whereas in men second SCC dominated (SCC-adenocarcinoma 28%, SCC-SCC 43%). SPLCs after small cell carcinoma were mainly adenocarcinomas (42%, 38% in women, 50% in men) and SCCs (53%). SPLC after large cell carcinoma was mainly adenocarcinomas (54%), whereas SCCs accounted for 15%. Even though concordant adenocarcinoma was common in IPLC-SPLC sequence, discordant histology (113 vs 34) was three times more common than concordant histology when IPLC was not adenocarcinoma.

Incidence rates for male and female IPLC and estimated smoking prevalence, as cited by Lee et al, are shown in online supplemental figure 1A.²⁵ Male smoking prevalence started to decline already after 1950 and it reached 15% in 2005. LC incidence peaked at 30/100 000 in 1982 and declined to 16/100 000 in 2021. Female smoking prevalence increased sharply towards the early 1970s reaching the male prevalence at around 1990. Female incidence increased almost linearly until 2010, exceeding shortly thereafter male incidence. In online supplemental figure 1B only adenocarcinoma incidence is shown. The male rate increased relatively evenly to 9/100 000 in 2010 with a broad maximum. Female incidence shot up in the year 2000 towards a sharp maximum at 12/100 000 in 2016.

CumP for competing events after any IPLC was dominated by deaths (online supplemental figure 2). Men died in larger proportions than women (A and D); CumPs were 0.76 vs 0.68 in 2 years and 0.93 vs 0.88 in 10 years. In 336 months (28 years), female SPLC reached CumP of 0.021 (B) while the share of LC not meeting the criteria for SPLC was marginal (B); in panel C, CumP of 0.001 was reached in 12 months. CumP for SPLC in men reached 0.013 in 336 months (E) and 0.0009 in 12 months (F).

CumP in age-groups of any IPLC diagnosis is shown in online supplemental figure 3. By 10 years of follow-up, those diagnosed at age before 50 years reached a CumP of 0.007 (A), while those diagnosed at age 50–69 years reached CumP of 0.013 (B) and those diagnosed at a higher age reached CumP of 0.008 (C). The 10-year CumP for female SPLC increased from 0.009 to 0.016 (1.8-fold) between periods 1993–2004 and 2005–2021 (D, E). The increase in male CumP was larger, from 0.004 to 0.01 (2.5-fold) (F, G).

CumP of sex-and histology-specific SPLC since IPLC diagnosis is shown in figure 2. There was a large sex difference for adenocarcinoma, female CumP reaching close to 0.014 (over a maximum follow-up time of up to 28 years) while the male CumP converged to a maximum below 0.006. The CumP curves for SCC (0.004) and large cell carcinoma (0.0025) showed no sex difference, but the maximum for small cell carcinoma was higher for women (0.0021) than for men (0.0012).

Figure 2. Cumulative probability of histology-specific SPLC since start of follow-up in period 1993–2021. The shading shows 95% CIs. SCC, squamous cell carcinoma; SPLC, second primary lung cancer.

CumP for sex-specific SPLCs after histology-specific IPLC is shown in figure 3. Female CumP of SPLC in 10 years after first adenocarcinoma was 0.019, after SCC it was 0.015, after small cell carcinoma it was 0.008 and after large cell carcinoma it was also 0.008. The respective CumPs for men were 0.013, 0.012, 0.002 and 0.005.

Figure 3. Cumulative probability of histology-specific SPLC since start of follow-up in period 2005–2021 in females (upper row) and males (lower row). The shading shows 95% CIs. The broken line marks the probability at 120 months (10 years). SCC, squamous cell carcinoma; SPLC, second primary lung cancer.

CumP for SPLC in 10 years for combined T and N stages is shown in online supplemental table 4. Patients with N stage other than N1 were few, but these were associated with lower CumP. For example, female CumP was 0.055 for T1 N0, but it decreased to 0.039, 0.016 and 0.005 when N changed to N1, N2 and N3.

Relative risk (SIR) for a SPLC diagnosis, depending on histology of IPLC and age, is shown in table 1. For all patients with IPLC, and for those with adenocarcinoma and large cell carcinoma, the highest relative risk for having a SPLC was observed for patients below 60 years of age, while for SCC it was between ages 60–74 and for small cell carcinoma it was at age 75+ years. At an age below 60 years female risk after adenocarcinoma risk was 9.95 (male 6.77). Female risk after SCC before age 60 years was also substantial, 6.23. As explained in Methods, we wanted to control for potential non-Poissonian distribution of SPLCs; we thus additionally estimated bootstrap 95% CIs (online supplemental table 5). Bootstrapping was performed for patient subgroups in which age groups had sufficient case numbers to ensure stable estimates. The CIs were essentially identical between the two approaches.

Table 1. SIR of SPLC for patients diagnosed with IPLC during 1993–2021.

Histology IPLC	All ages		Age group
			<60		60–74		75+
	N	SIR 95% CI	N	SIR 95% CI	N	SIR 95% CI	N	SIR 95% CI
All LC	662	3.59 (3.32 to 3.87)	37	6.68 (4.71 to 9.21)	375	3.88 (3.50 to 4.29)	250	3.04 (2.68 to 3.44)
Adenocarcinoma	380	3.70 (3.34 to 4.10)	28	9.18 (6.10 to 13.27)	209	3.84 (3.34 to 4.40)	143	3.17 (2.67 to 3.73)
SCC	167	3.60 (3.07 to 4.18)	3	3.31 (0.68 to 9.66)	94	4.20 (3.39 to 5.14)	70	3.02 (2.36 to 3.82)
Small cell	40	3.05 (2.18 to 4.15)	2	2.89 (0.35 to 10.43)	21	2.67 (1.65 to 4.09)	17	3.72 (2.17 to 5.95)
Large cell	75	3.36 (2.64 to 4.21)	4	4.51 (1.23 to 11.54)	51	4.23 (3.15 to 5.56)	20	2.13 (1.30 to 3.30)
Females
All LC	394	4.16 (3.76 to 4.59)	30	7.72 (5.21 to 11.02)	236	4.32 (3.79 to 4.91)	128	3.53 (2.95 to 4.20)
Adenocarcinoma	245	4.05 (3.56 to 4.59)	23	9.95 (6.31 to 14.94)	48	4.26 (3.60 to 5.00)	74	3.16 (2.48 to 3.97)
SCC	80	4.85 (3.84 to 6.03)	3	6.23 (1.28 to 18.20)	44	5.00 (3.63 to 6.71)	33	4.57 (3.15 to 6.42)
Males
All LC	268	2.99 (2.64 to 3.37)	7	4.24 (1.71 to 8.74)	139	3.30 (2.78 to 3.90)	122	2.65 (2.20 to 3.17)
Adenocarcinoma	135	3.21 (2.69 to 3.80)	5	6.77 (2.20 to 15.81)	61	3.06 (2.38 to 3.99)	69	3.18 (2.47 to 4.02)
SCC	87	2.91 (2.33 to 3.59)		.	50	3.68 (2.73 to 4.85)	37	2.32 (1.64 to 3.20)

Reference rate corresponds to IPLC incidence in background population.

IPLC, initial primary lung cancer; LC, lung cancer; SCC, squamous cell carcinoma; SIR, standardised incidence ratio; SPLC, second primary lung cancer.

We further assessed relative risks for SPLC conferred after various T stages at IPLC diagnosis among women (table 2). After any IPLC, relative risks were highest before age 60 years but case numbers were few compared with age group 60–74 years for which SIRs declined from 5.91 for T1 to 1.29 for T4. Female SIRs after T1 IPLC adenocarcinoma were 13.62 (n=8) and 21.09 after T3 (n=3). The largest case numbers were for T1 at age group 60–74 years (n=83, SIR 5.99) and at age 75+ years (n=44, SIR 4.43).

Table 2. SIR for SPLC in female patients diagnosed with IPLC by age and T stage of IPLC.

Age group	T1		T stage of IPLC				T4
			T2		T3
	N	SIR 95% CI	N	SIR 95% CI	N	SIR 95% CI	N	SIR 95% CI
Females—all LC
<60	8	10.98 (4.74 to 21.63)	5	6.30 (2.04 to 14.69)	3	12.53 (2.58 to 36.62)	2	3.7 (0.45 to 13.38)
60–74	106	5.91 (4.84 to 7.15)	49	3.76 (2.78 to 4.97)	10	2.30 (1.10 to 4.23)	11	1.29 (0.64 to 2.31)
75+	63	4.70 (3.61 to 6.02)	27	3.11 (2.05 to 4.52)	5	1.81 (0.59 to 4.23)	8	1.71 (0.74 to 3.37)
Females—adenocarcinoma
<60	8	13.62 (5.88 to 26.84)	2	3.87 (0.47 to 13.96)	3	21.09 (4.35 to 61.63)	2	7.59 (0.92 to 27.41)
60–74	83	5.99 (4.77 to 7.42)	26	3.16 (2.07 to 4.64)	5	2.00 (0.65 to 4.67)	1	0.23 (0.01 to 1.3)
75+	44	4.43 (3.22 to 5.95)	13	2.36 (1.26 to 4.03)	2	1.29 (0.16 to 4.67)	1	0.4 (0.01 to 2.24)

Subset of 1993–2021 cohort with available staging data.

IPLC, initial primary lung cancer; SIR, standardised incidence ratio; SPLC, second primary lung cancer; T, tumour.

Discussion

Using Swedish nation-wide cancer data we could identify 853 SPLCs from four histological types of IPLC that passed the MM criteria for SPLC.⁶ The incidence in SPLCs increased more than threefold in 30 years (figure 1). The overall relative risk of SPLC diagnosis was 3.59, higher for women (4.16) than for men (2.99) and approximately equally high after adenocarcinoma and SCC. Case numbers of SPLCs diagnosed before age 60 were only 5% of all, but the relative risk was high, 6.68. The risk conferred after female adenocarcinoma in this age group was 9.95 (males 6.77). Risks were exquisitely high, 13.62 and 21.09 after rare female adenocarcinomas of stages T1 and T3 at age before 60 years. The current relative risk of SPLC of 3.59 is relatively high compared with other common cancers such as colon, breast, kidney and bladder cancers, for which the relative risks of second (concordant) primary cancers typically vary between 2.0 and 3.0.^{11 26} However, higher risks have been reported for skin cancers and virally predisposed cancers.^{26 27}

When we followed the incidence of SPLC from years 1971–1980 onwards, we observed an identical increase among women and men and after the four main histological types of IPLC. Data from the US Surveillance, Epidemiology and End Results database showed similar results with larger case numbers from years 1992 to 2007.¹⁶ In the present study, the histological distribution of SPLC in 1993–2021 was adenocarcinoma 63.6%, SCC for 18.2%, small cell for 9.5% and large cell for 8.7%, which deviated only with a few % units from the US distribution for which data on large cell carcinoma were lacking.¹⁶

In pair-wise analysis, the present data showed that SPLCs diagnosed after adenocarcinoma were largely also adenocarcinomas and more than half of these originated from IPLC cases of T1 stage without much sex difference. T1 prominence was not true for the other SPLC histologist, and over 10% of any histological types of SPLC were diagnosed in T4 patients. IPLC of SCC histology was followed by a comparable number of SPLCs of adenocarcinoma and SCC histology in women, but in men, second SCC dominated (SCC-adenocarcinoma 28%, SCC-SCC 43%). SPLCs after small cell carcinoma were mainly adenocarcinomas (42%) and SCCs (53%). After large cell carcinoma, they were mainly adenocarcinomas (54%) and diverse other histologies. Thus, when IPLC presented with non-adenocarcinoma histology, three times more SPLCs were of discordant histology from IPLC, which is another piece of evidence for the cases being independent SPLCs; recurrences from the IPLC should be dominated by the same histology.

The probability of SPLCs was dominated by female adenocarcinoma (CumP 0.014) while the male maximum remained close to 0.006 and female and male SCC reached 0.004 (figure 2). 5-year relative survival in LC has also doubled in this period in Sweden; however, somewhat more for women than for men.²⁸ In order to understand the CumP curves for histology-specific SPLCs, we need to consider also the background incidence in IPLC. We checked the web site of the Swedish cancer registry that the incidence difference in period 2005–2021 was quite large in favour of adenocarcinoma versus SCC (approximate world standardised rates/100 000 were for women 9.8 vs 2.4 and for men 7.7 vs 4.3) (https://sdb.socialstyrelsen.se/if_can/val.aspx). 5-year relative survival for female adenocarcinoma in Sweden has been clearly better than that for SCC; for 2012 the difference was about 27 vs 20%.²⁹ For male survival, there was no difference, both about 17%.²⁹ For small cell carcinoma, survival was clearly lower, 8% for women and 5% for men. Thus, the large excess of female SPLC adenocarcinoma (figure 2) is likely to be the sum result of high incidence and survival of IPLC adenocarcinoma and high proportion of female SPLC adenocarcinoma (81%, male 71%) after first adenocarcinoma (online supplemental table 2). For men, the difference in CumP between adenocarcinoma and SCC was smaller as the IPLC incidence in these cancers differed far less than that for women and survival was equal (see above). Female survival exceeds male survival not only in LC but in many other cancers which may imply that some sex-related biological or social factors, including alertness about early signs of cancer, play a role.^{2 30}

The limitations of the present study include low case numbers, particularly after the rarer histological types of IPLC and in men. As a national study spanning a long calendar period, we are lacking individual smoking data as well as treatment details for IPLC. During the current period, the incidence of LC has changed extensively as shown in online supplemental figure 1 and elsewhere.^{28 31} The rapid increase among women who smoke in the late 1960s appeared to boost the steep increase in adenocarcinoma 30 years later, which contributed to the epochal crossing of female and male LC incidence rates.¹⁹ In spite of the declining male smoking prevalence since 1960 and female prevalence since 1990 among LCs diagnosed in Sweden in 2023, only 16% of women and 11% of men were people who do not smoke (https://cancercentrum.se/globalassets/cancerdiagnoser/lunga-och-lungsack/kvalitetsregister/rapport/20241105_nlcr_nationell_rapport2023.pdf). Even though the identity of SPLC is likely to be correct, as the cases passed the MM criteria, the results are not informative of the detailed aetiology of SPLCs.

In conclusion, we could describe a vastly increasing incidence in SPLCs in Sweden which was dominated by female adenocarcinoma reaching CumP of 0.014 compared with male adenocarcinoma of 0.006. CumP of SPLC increased past 10 years of IPLC diagnosis. Relative risk for any SPLC was 3.59 and it was highest of 9.95 after female adenocarcinoma diagnosed before age 60 years. Several LC CT-based screening studies and some randomised trials have shown incidence and mortality reduction among high-risk populations as reviewed.^{5 6 20 32} The application and funding of CT screening to population screening of risk groups are being discussed, and some European professional organisations have collected a comprehensive background data bank on the theme European Respiratory Society (ERS)/European Society of Radiology (ESR) factsheet. These are beyond our scope, but we believe that the present study may help to define potential target populations for such studies when launched.^32–34 Although we lack individual smoking data, the overwhelming proportion of Swedish patients with LC have a smoking history. Based on the relative risks of SPLC, the target population should be adenocarcinoma patients diagnosed before age 60 years.

Data availability statement

Data are available upon reasonable request.