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Should Never-Smokers at Increased Risk for Lung Cancer Be Screened?

      Introduction

      Lung cancer in never-smokers ranks among the 10 most common causes of death due to cancer worldwide and in the United States. However, it is unknown whether never-smokers at elevated risk for developing lung cancer may benefit from lung cancer screening.

      Methods

      The MIcrosimulation SCreening ANalysis (MISCAN)-Lung microsimulation model was used to assess the effects of lung cancer screening for simulated cohorts of never-smokers at different levels of relative risk (RR) for lung cancer compared with never-smokers at average risk. The benefits and harms of screening were estimated for each cohort and compared with those of a cohort of ever-smokers eligible for lung cancer screening according to the United States Preventive Services Task Force (USPSTF) criteria.

      Results

      The relative lung cancer mortality reduction in never-smokers was higher than the USPSTF eligible cohort (37% compared with 32%). However, the number of life-years gained per lung cancer death averted was lower (10.4 compared with 11.9) and the proportion of overdiagnosed cancers was higher (9.6% compared with 8.4%) for never-smokers compared with the USPSTF eligible cohort, as never-smokers are diagnosed at a later age. The estimated number of screens per lung cancer death averted ranged from 6162 for never-smokers at average risk to 151 for never-smokers with an RR of 35 compared with 353 for the USPSTF eligible cohort.

      Conclusions

      Never-smokers with RRs of 15 to 35 have similar to better trade-offs between benefits and harms compared with ever-smokers recommended for lung cancer screening by the USPSTF guidelines. For most never-smokers, lung cancer screening is not beneficial.

      Key Words

      Although smoking is considered a main risk factor for developing lung cancer, 10% to 25% of all lung cancers occur in never-smokers.
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      Lung cancer in never-smokers is a significant public health problem, as it ranks among the 10 most common causes of death due to cancer worldwide and in the United States.
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      The United States Preventive Services Task Force (USPSTF) recently published the recommendation to implement annual lung cancer screening for ever-smokers aged 55 to 80 years who have smoked at least 30 pack-years and, if quit smoking, quit less than 15 years ago.
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      Other organizations have recommended screening using the NLST eligibility criteria or variations thereof.
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      Lung cancer screening.
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      To our knowledge, no organization currently recommends lung cancer screening for never-smokers.
      Some lung cancer screening studies have included never-smokers, but these studies used chest radiography or were single-arm studies.
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      Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography.
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      Mass screening for lung cancer with mobile spiral computed tomography scanner.
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      Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial.
      A survey on attitudes toward lung cancer screening in the United States showed that a large proportion of never-smokers were willing to consider lung cancer screening, even though few believed that they were at risk for developing lung cancer.
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      • Bradford D
      Attitudes towards screening for lung cancer among smokers and their non-smoking counterparts.
      In addition to tobacco smoking, various risk factors for developing lung cancer have been identified for ever- and never-smokers, such as environmental tobacco smoke (e.g., “second-hand smoking”), exposure to carcinogens (e.g., asbestos, radon gas, and ionizing radiation), and genetic susceptibility.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
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      • Meza R
      • Jeon J
      • Moolgavkar SH
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
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      • Morin F
      • Souquet PJ
      Lung cancer in never smokers–a review.
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      • Govindan R
      Lung cancer in never smokers: a review.
      A number of risk models incorporate these and other risk factors to identify ever- and never-smokers at elevated levels of risk.
      • Tammemagi CM
      • Pinsky PF
      • Caporaso NE
      • et al.
      Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation.
      • Spitz MR
      • Hong WK
      • Amos CI
      • et al.
      A risk model for prediction of lung cancer.
      • Raji OY
      • Duffy SW
      • Agbaje OF
      • et al.
      Predictive accuracy of the Liverpool Lung Project risk model for stratifying patients for computed tomography screening for lung cancer: a case-control and cohort validation study.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • El-Zein RA
      • Lopez MS
      • D’Amelio AM
      • et al.
      The cytokinesis blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model.
      Recent studies have identified subpopulations within the NLST who were at a higher level of risk for developing lung cancer compared with the average population of the trial.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • Kovalchik SA
      • Tammemagi M
      • Berg CD
      • et al.
      Targeting of low-dose CT screening according to the risk of lung-cancer death.
      • Tammemägi MC
      • Katki HA
      • Hocking WG
      • et al.
      Selection criteria for lung-cancer screening.
      Screening was more effective for these subpopulations, which indicates that screening recommendations based on an individual's risk could lead to more effective screening programs.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • Kovalchik SA
      • Tammemagi M
      • Berg CD
      • et al.
      Targeting of low-dose CT screening according to the risk of lung-cancer death.
      • Tammemägi MC
      • Katki HA
      • Hocking WG
      • et al.
      Selection criteria for lung-cancer screening.
      Therefore, some researchers argue that lung cancer screening may be recommended for never-smokers, provided that they have a high risk for developing lung cancer.
      • Baldwin DR
      • Duffy SW
      • Wald NJ
      • Page R
      • Hansell DM
      • Field JK
      UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer.
      However, the long-term benefits and harms of implementing a lung cancer screening program for never-smokers are unknown. The USPSTF recommendations were in part based on modeling analyses, which investigated the trade-offs between the long-term benefits and harms of different screening policies for ever-smokers.
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      This study aims to investigate the trade-offs between the benefits and harms of lung cancer screening for never-smokers at different levels of risk.

      MATERIALS AND METHODS

      MISCAN-Lung

      The MIcrosimulation SCreening ANalysis (MISCAN)-Lung model is used in this investigation. MISCAN-Lung has been calibrated to the NLST, the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial (PLCO), and data from the Surveillance, Epidemiology and End Results (SEER) Program, from which it derived information on the preclinical duration of lung cancer and CT screening effectiveness.
      • ten Haaf K
      • van Rosmalen J
      • de Koning HJ
      Lung cancer detectability by test, histology, stage and gender: estimates from the NLST and the PLCO trials.
      • Meza R
      • ten Haaf K
      • Kong CY
      • et al.
      Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.
      Lung cancer incidence and mortality in never-smokers in the PLCO were among the calibration targets of the model.
      • ten Haaf K
      • van Rosmalen J
      • de Koning HJ
      Lung cancer detectability by test, histology, stage and gender: estimates from the NLST and the PLCO trials.
      • Meza R
      • ten Haaf K
      • Kong CY
      • et al.
      Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.
      MISCAN-Lung aided in informing the USPSTF on their recommendations for lung cancer screening.
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      • McMahon PM
      • Meza R
      • Plevritis SK
      • et al.
      Comparing benefits from many possible computed tomography lung cancer screening programs: extrapolating from the National Lung Screening Trial using comparative modeling.

      Histologic Types

      There are indications that smoking behavior affects not only a person's risk of developing lung cancer but also the histologic type that develops.
      • Kenfield SA
      • Wei EK
      • Stampfer MJ
      • Rosner BA
      • Colditz GA
      Comparison of aspects of smoking among the four histological types of lung cancer.
      • Haiman CA
      • Stram DO
      • Wilkens LR
      • et al.
      Ethnic and racial differences in the smoking-related risk of lung cancer.
      This suggests that the distribution of histological types of lung cancer in never-smokers may differ from ever-smokers. Subramanian and Govindan
      • Subramanian J
      • Govindan R
      Lung cancer in never smokers: a review.
      provided an overview of the distribution of histological types of lung cancer in never-smokers across different studies. This overview was used to derive the distribution of histological types of lung cancer in never-smokers for this investigation, shown in Table 1.
      • Subramanian J
      • Govindan R
      Lung cancer in never smokers: a review.
      To our knowledge, little information is available on differences in the distribution of histological types of lung cancer in never-smokers between sexes. Therefore, we assumed that the distribution of histological types of lung cancer in never-smokers did not differ by sex.
      TABLE 1Histological Types Considered in MISCAN-Lung
      Histological Types Considered in MISCAN-LungProportions Considered in Never-Smokers (Both Sexes)Proportions Considered in Ever-Smokers (Men)Proportions Considered in Ever-Smokers (Women)
      Adenocarcinoma/large cell carcinoma/bronchioloalveolar carcinoma66.68%41.01%50.33%
      Squamous cell carcinoma13.68%25.22%15.78%
      Small-cell carcinoma2.53%13.75%13.26%
      Other non-small-cell carcinoma17.12%20.02%20.63%
      MISCAN, Microsimulation Screening Analysis model.

      Lung Cancer Survival

      It has been suggested that never-smokers may have a better response to certain treatments compared with ever-smokers, such as treatment with epidermal growth factor receptor inhibitors, which could lead to differences in survival.
      • Shepherd FA
      • Rodrigues Pereira J
      • Ciuleanu T
      • National Cancer Institute of Canada Clinical Trials Group
      • et al.
      Erlotinib in previously treated non-small-cell lung cancer.
      • Thatcher N
      • Chang A
      • Parikh P
      • et al.
      Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).
      Some studies suggest that never-smokers have a better survival compared with ever-smokers, whereas other studies indicate that no significant differences in survival exist.
      • Kawaguchi T
      • Matsumura A
      • Fukai S
      • et al.
      Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases.
      • Meguid RA
      • Hooker CM
      • Harris J
      • et al.
      Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers.
      • Subramanian J
      • Velcheti V
      • Gao F
      • Govindan R
      Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC).
      • Toh CK
      • Gao F
      • Lim WT
      • et al.
      Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.
      To our knowledge, no study provides detailed data on lung cancer survival for never-smokers by stage, histology, and sex.
      • Kawaguchi T
      • Matsumura A
      • Fukai S
      • et al.
      Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases.
      • Meguid RA
      • Hooker CM
      • Harris J
      • et al.
      Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers.
      • Subramanian J
      • Velcheti V
      • Gao F
      • Govindan R
      Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC).
      • Toh CK
      • Gao F
      • Lim WT
      • et al.
      Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.
      Therefore, survival data from SEER were used, which provides detailed information on survival by stage, histology, and sex for ever- and never-smokers combined.

      Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov). SEER*Stat Database: Incidence – SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2012 Sub (1973–2010 varying) – Linked To County Attributes – Total U.S., 1969–2011 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013, based on the November 2012 submission. Accessed March 29, 2014.

      Lung Carcinogenesis

      MISCAN-Lung uses the two-stage clonal expansion model (TSCE) to estimate a person's risk of developing lung cancer as a function of age and smoking history.
      • ten Haaf K
      • van Rosmalen J
      • de Koning HJ
      Lung cancer detectability by test, histology, stage and gender: estimates from the NLST and the PLCO trials.
      • Meza R
      • ten Haaf K
      • Kong CY
      • et al.
      Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.
      • Heidenreich WF
      • Luebeck EG
      • Moolgavkar SH
      Some properties of the hazard function of the two-mutation clonal expansion model.
      • Meza R
      • Hazelton WD
      • Colditz GA
      • Moolgavkar SH
      Analysis of lung cancer incidence in the Nurses’ Health and the Health Professionals’ Follow-Up Studies using a multistage carcinogenesis model.
      The TSCE has been used to investigate the age-specific incidence of lung cancer in never-smokers previously.
      • McCarthy WJ
      • Meza R
      • Jeon J
      • Moolgavkar SH
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
      • Meza R
      • Hazelton WD
      • Colditz GA
      • Moolgavkar SH
      Analysis of lung cancer incidence in the Nurses’ Health and the Health Professionals’ Follow-Up Studies using a multistage carcinogenesis model.
      • Hazelton WD
      • Clements MS
      • Moolgavkar SH
      Multistage carcinogenesis and lung cancer mortality in three cohorts.
      To assess whether MISCAN-Lung is suitable for investigating the effectiveness of lung cancer screening for never-smokers, the estimated age-group–specific mortality rates of lung cancer in never-smokers were compared with those reported by Thun et al.
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.

      Considered Levels of Relative Risk

      If lung cancer screening is to be considered for never-smokers, eligible individuals will need to be identified, for example, through the application of risk models. To our knowledge, the following lung cancer risk models consider never-smokers: the Spitz, PLCOm2011, PLCOm2014, and the Liverpool Lung Project (LLP) models.
      • Tammemagi CM
      • Pinsky PF
      • Caporaso NE
      • et al.
      Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation.
      • Spitz MR
      • Hong WK
      • Amos CI
      • et al.
      A risk model for prediction of lung cancer.
      • Raji OY
      • Duffy SW
      • Agbaje OF
      • et al.
      Predictive accuracy of the Liverpool Lung Project risk model for stratifying patients for computed tomography screening for lung cancer: a case-control and cohort validation study.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      The Spitz model incorporates environmental tobacco smoke exposure (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.20–2.69)) and a family history of any cancer in two or more first-degree relatives (OR, 2.00; 95% CI, 1.39–2.90).
      • Spitz MR
      • Hong WK
      • Amos CI
      • et al.
      A risk model for prediction of lung cancer.
      Spitz et al
      • Spitz MR
      • Hong WK
      • Amos CI
      • et al.
      A risk model for prediction of lung cancer.
      noted that the ORs of these variables closely approximated the relative risks (RRs). Thus, the Spitz model considers RRs up to 3.6. Recently, this model was extended to incorporate micronuclei in binucleated cells (BN-MN) (OR 16.72 per unit increase; 95% CI, 9.01–31.02) alongside environmental tobacco smoke exposure (OR, 1.12; 95% CI, 0.47–2.68) and a family history of cancer in two or more first-degree relatives (OR, 1.06; 95% CI, 0.47–2.43).
      • El-Zein RA
      • Lopez MS
      • D’Amelio AM
      • et al.
      The cytokinesis blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model.
      The average difference in BN-MN between cases and controls in the model's development and validation data sets was 1.78 to 1.79 units.
      • El-Zein RA
      • Lopez MS
      • D’Amelio AM
      • et al.
      The cytokinesis blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model.
      Assuming the ORs of the model variables closely approximate the RRs and an increase of 1.80 units of BN-MN compared with a never-smoker at average risk is considered, the model considers RRs up to at least 35.73 for never-smokers.
      The PLCOm2011 model was the first model based on data from PLCO to provide risk estimates for never-smokers.
      • Tammemagi CM
      • Pinsky PF
      • Caporaso NE
      • et al.
      Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation.
      Recently, an updated version of this model (PLCOm2014) was published that incorporates five risk factors (excluding age and race) for never-smokers: education (OR 0.92 per one of six levels change; 95% CI, 0.87–0.96), body mass index (BMI) (OR 0.97 per one unit change; 95% CI, 0.95–0.99), chronic obstructive pulmonary disease (OR, 1.41; 95% CI, 1.15–1.73), a personal history of cancer (OR, 1.62; 95% CI, 1.22–2.16), and a family history of lung cancer (OR, 1.80; 95% CI, 1.48–2.18).
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      The calculator provided by the authors was used to verify that the ORs closely approximate the RRs (available at http://www.brocku.ca/lung-cancer-risk-calculator). A BMI of 18 is the lowest for which the model is valid and assuming the base BMI and education levels are similar to those in the PLCOm2012 model (a BMI of 27 and “some college education”), implies that the PLCOm2014 model considers RRs up to 6.98 (disregarding age and race).
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • Tammemägi MC
      • Katki HA
      • Hocking WG
      • et al.
      Selection criteria for lung-cancer screening.
      The LLP model incorporates four risk factors for never-smokers: a history of pneumonia (OR, 1.83; 95% CI, 1.26–2.64), asbestos exposure (OR, 1.89; 95% CI, 1.35–2.62), a history of cancer (OR, 1.96; 95% CI, 1.22–3.14), and a family history of lung cancer (OR, 2.02 for age of onset <60; 95% CI, 1.18–3.45; and 1.18 for age of onset ≥60; 95% CI, 0.79–1.76).
      • Raji OY
      • Duffy SW
      • Agbaje OF
      • et al.
      Predictive accuracy of the Liverpool Lung Project risk model for stratifying patients for computed tomography screening for lung cancer: a case-control and cohort validation study.
      The model was replicated in R software (version 3.0.1) and analyses indicate that the ORs of the risk factors closely approximate the RRs. Thus, the LLP model considers RRs up to 13.69.
      Therefore, cohorts of never-smokers with the following levels of RR will be simulated: 1, 2, 5, 10, 15, 20, and 35. For cohorts with RRs higher than 1, the hazard function of the TSCE at each age was multiplied by the considered level of RR.
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      In addition, a “USPSTF eligible” cohort is simulated composed of individuals who would be eligible for at least one screening at some point in their life according to the USPSTF recommendations. The Smoking History Generator developed by the National Cancer Institute was used to generate the probability of death from causes other than lung cancer by smoking behavior (including never smoking).
      • Jeon J
      • Meza R
      • Krapcho M
      • Clarke LD
      • Byrne J
      • Levy DT
      Chapter 5: Actual and counterfactual smoking prevalence rates in the U.S. population via microsimulation.
      • Rosenberg MA
      • Feuer EJ
      • Yu B
      • et al.
      Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.
      • Holford TR
      • Levy DT
      • McKay LA
      • et al.
      Patterns of birth cohort-specific smoking histories, 1965-2009.

      Considered Screening Programs, Benefits, and Harms

      The investigated cohorts are assumed to be born in 1950 and followed from ages 45 to 90 years, similar to de Koning et al.
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      To allow comparison with the screening policy recommended by the USPSTF, never-smokers are assumed to be screened annually from ages 55 to 80 years with a perfect adherence to screening. The investigated benefits and harms of lung cancer screening include the relative reduction in lung cancer mortality, the number of life-years gained, and overdiagnosis.

      RESULTS

      The age-group–specific lung cancer mortality rates for never-smoking men and women estimated by MISCAN-Lung were compared with those reported by Thun et al
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      (Table S13 in their report), in Figure 1A and B, respectively. Overall, the model reproduced the reported age-group-specific lung cancer mortality rates well for both sexes but somewhat overestimated the lung cancer mortality rate for ages 75 to 79 years.
      Figure thumbnail gr1
      FIGURE 1A, Observed and estimated lung cancer death rates in never-smoking men. Adapted from Thun et al.
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      Error bars denote 95% confidence intervals for the incidence rate difference. B, Observed and estimated lung cancer death rates in never-smoking women. Adapted from Thun et al.
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      Error bars denote 95% confidence intervals for the incidence rate difference.
      Table 2 shows the benefits of lung cancer screening for the investigated cohorts. The proportion of lung cancers detected at an early stage was higher for never-smokers compared with the USPSTF eligible cohort (65.8–65.9% of all cases compared with 59.4%). This may be a result of the higher proportion of adenocarcinomas in never-smokers (see Table 1), which have a longer preclinical sojourn time and are more likely to be detected at an early stage by CT screening compared with other histologies.
      • ten Haaf K
      • van Rosmalen J
      • de Koning HJ
      Lung cancer detectability by test, histology, stage and gender: estimates from the NLST and the PLCO trials.
      As a result of the larger proportion of lung cancers detected at an early stage, the relative reduction in lung cancer mortality was higher for never-smokers compared with the USPSTF eligible cohort: 37.0% to 37.3% compared with 32.7%. However, the number of lung cancer deaths averted (per 100,000) was lower for most cohorts of never-smokers, ranging from 354 deaths averted for never-smokers at average risk to 12,509 for never-smokers with an RR of 35 compared with 4305 for the USPSTF eligible cohort. The same holds for the number of life-years gained (per 100,000), which ranged from 3669 for never-smokers at average risk to 129,509 for never-smokers with an RR of 35 compared with 51,035 for the USPSTF eligible cohort.
      TABLE 2Benefits of Screening
      ScenarioLung Cancers Detected at an Early Stage (Stage I-II) (%)Lung Cancer Mortality Reduction (%)Absolute Number of Lung Cancer Deaths Averted per 100,000Life-Years Gained per 100,000Life-Years Gained per Lung Cancer Death AvertedScreens per Life-Year GainedScreens per Lung Cancer Death Averted
      USPSTF (ever eligible only)59.432.74,30551,03511.930353
      Never-smokers at average risk65.837.13543,66910.45946,162
      Never-smokers at two times average risk65.937.07067,33210.42963,075
      Never-smokers at five times average risk65.837.01,76418,35910.41171,216
      Never-smokers at 10 times average risk65.837.13,54136,80910.457593
      Never-smokers at 15 times average risk65.837.15,32255,24710.437387
      Never-smokers at 20 times average risk65.837.17,11873,89210.427283
      Never-smokers at 35 times average risk65.937.312,509129,78610.415151
      USPSTF, United States Preventive Services Task Force.
      The number of lung cancer deaths averted and life-years gained for never-smokers with an RR of 15 were higher compared with the USPSTF cohort. However, because of the high number of screens, the number of screens per life-year gained and the number of screens per lung cancer death averted were still higher compared with the USPSTF cohort. However, screening never-smokers with an RR of 20 leads to a slightly lower number of screens per life-year gained and a much lower number of screens per lung cancer death averted compared with the USPSTF cohort.
      Table 3 shows the harms of lung cancer screening for the investigated cohorts. The number of screens (per 100,000) was much greater for the USPSTF eligible and never-smoker cohorts compared with the 1950 cohort examined in de Koning et al,
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      as in the latter cohort only 19.3% of the cohort received at least one screen. The number of screens was higher for the never-smoker cohorts compared with the USPSTF eligible cohort: approximately 1.8 to 2.1 million screens compared with 1.5 million screens. This is because of two reasons: first, never-smokers live longer compared with ever-smokers and will be able to attend more screenings during their lifetime.
      • Rosenberg MA
      • Feuer EJ
      • Yu B
      • et al.
      Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.
      • Thun MJ
      • Carter BD
      • Feskanich D
      • et al.
      50-year trends in smoking-related mortality in the United States.
      Second, the USPSTF criteria indicate that ever-smokers may not be eligible for screening at the earliest starting age, as some current, continuing smokers may not reach the minimum number of pack-years at age 55 but at a later age. In addition, eligible former smokers may not complete the full screening program because of becoming ineligible by reaching the maximum years since cessation. As a result, the average number of screening examinations per person screened was higher for the cohorts of never-smokers compared with the USPSTF eligible cohort (20–22 compared with 16). As the never-smoker cohorts receive a higher number of screening examinations and are diagnosed at a later age (when no screening occurs), the proportion of overdiagnosis was higher compared with the USPSTF eligible cohort (9.5–9.6% of all screen-detected cases compared with 8.4%).
      TABLE 3Harms of Screening
      ScenarioScreens per 100,000CT Examinations per 100,000 (Includes Screenings)Average Screening Examinations per Person ScreenedPercentage of Lung Cancers OverdiagnosedPercentage of Screen-Detected Lung Cancers Overdiagnosed
      USPSTF (ever eligible only)1,520,6321,776,04616.24.68.4
      Never-smokers at average risk2,179,1732,544,60522.55.29.5
      Never-smokers at two times average risk2,170,5442,534,53222.55.29.6
      Never-smokers at five times average risk2,144,6012,504,24922.25.39.6
      Never-smokers at 10 times average risk2,101,2482,453,64521.95.39.6
      Never-smokers at 15 times average risk2,057,7452,402,86521.55.39.6
      Never-smokers at 20 times average risk2,014,1182,351,94021.15.39.6
      Never-smokers at 35 times average risk1,882,7212,198,56219.95.39.6
      USPSTF, United States Preventive Services Task Force.

      DISCUSSION

      Suggestions to recommend lung cancer screening based on an individual's risk and the growing awareness of lung cancer in never-smokers have raised the question of whether never-smokers at high risk for lung cancer should be screened.
      • Parkin DM
      • Bray F
      • Ferlay J
      • Pisani P
      Global cancer statistics, 2002.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
      • Thun MJ
      • Henley SJ
      • Burns D
      • Jemal A
      • Shanks TG
      • Calle EE
      Lung cancer death rates in lifelong nonsmokers.
      • Oken MM
      • Hocking WG
      • Kvale PA
      • PLCO Project Team
      • et al.
      Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial.
      • McCarthy WJ
      • Meza R
      • Jeon J
      • Moolgavkar SH
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • Tammemägi MC
      • Katki HA
      • Hocking WG
      • et al.
      Selection criteria for lung-cancer screening.
      • Haiman CA
      • Stram DO
      • Wilkens LR
      • et al.
      Ethnic and racial differences in the smoking-related risk of lung cancer.
      • Kawaguchi T
      • Matsumura A
      • Fukai S
      • et al.
      Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases.
      • Subramanian J
      • Velcheti V
      • Gao F
      • Govindan R
      Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC).
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      • Wakelee HA
      • Chang ET
      • Gomez SL
      • et al.
      Lung cancer incidence in never smokers.
      Our study is the first to provide indications whether never-smokers may benefit from lung cancer screening through quantifying the benefits and harms of screening never-smokers at different levels of risk.
      Screening never-smokers at average risk or an RR of 2 compared with average risk has unfavorable trade-offs between benefits and harms, requiring 3000 to 6000 screens to prevent one death. However, the trade-off for never-smokers with an RR of 5 is more favorable than breast cancer screening: 1216 screens per death averted compared with 1558 (Model E in Mandelblatt et al
      • Mandelblatt JS
      • Cronin KA
      • Bailey S
      • Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network
      • et al.
      Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms.
      ); however, the number of screens per life-year gained is less favorable: 117 compared with 91. Never-smokers with an RR of 10 have more favorable trade-offs in deaths prevented and life-years gained per screen compared with breast cancer screening but less favorable compared with ever-smokers for whom the USPSTF recommends screening.
      • de Koning HJ
      • Meza R
      • Plevritis SK
      • et al.
      Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.
      • Mandelblatt JS
      • Cronin KA
      • Bailey S
      • Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network
      • et al.
      Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms.
      However, never-smokers with an RR of 15 to 35 have similar to more favorable trade-offs between the benefits and the harms compared with smokers for whom the USPSTF recommends screening.
      Lung cancer screening for never-smokers may lead to a higher relative reduction in lung cancer mortality compared with screening ever-smokers. However, although the cohorts of never-smokers have a higher relative reduction in lung cancer mortality compared with the USPSTF eligible cohort, the increase in number of life-years gained is less than one would anticipate. For example, the number of lung cancer deaths averted for never-smokers with an RR of 15 was 23.62% higher compared with the USPSTF eligible cohort, whereas the number of life-years gained was only 8.25% higher (Table 2). This can be explained by the lower number of life-years gained per lung cancer death averted, which was 11.9 years for the USPSTF eligible cohort compared with 10.4 for the never-smoker cohorts. This may seem counterintuitive, as ever-smokers have a higher all-cause mortality compared with never-smokers but can be explained through the differences in the average age of lung cancer diagnosis and average age of death between these groups.
      • Rosenberg MA
      • Feuer EJ
      • Yu B
      • et al.
      Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.
      • Thun MJ
      • Carter BD
      • Feskanich D
      • et al.
      50-year trends in smoking-related mortality in the United States.
      Supplementary Table 1 (in Supplemental Digital Content, http://links.lww.com/JTO/A851) shows the average age of lung cancer diagnosis (given that the cancer is diagnosed after age 45) and the average age of death (given that the person is alive at age 45 years) for the investigated cohorts. Supplementary Table 1 (in Supplemental Digital Content, http://links.lww.com/JTO/A851) indicates that persons in the USPSTF eligible cohort die younger compared with never-smokers because of the detrimental effects of smoking.
      • Rosenberg MA
      • Feuer EJ
      • Yu B
      • et al.
      Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.
      • Thun MJ
      • Carter BD
      • Feskanich D
      • et al.
      50-year trends in smoking-related mortality in the United States.
      However, because of the carcinogenic effects of smoking, patients in the USPSTF eligible cohort developed lung cancer at a younger age compared with never-smokers. In addition, the high proportion of adenocarcinoma in never-smokers, which have a longer preclinical sojourn time compared with other histologies, may further contribute to the later age of diagnosis.
      • ten Haaf K
      • van Rosmalen J
      • de Koning HJ
      Lung cancer detectability by test, histology, stage and gender: estimates from the NLST and the PLCO trials.
      Our investigation has some limitations. We assume that the preclinical duration of lung cancer in never-smokers is similar to that of ever-smokers, whereas there are indications that lung cancer biology may differ in never-smokers.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
      However, although the carcinogenesis process may differ in never-smokers, to our knowledge, there are no indications that differences in the preclinical duration of lung cancer exist between never- and ever-smokers.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
      Another limitation is that the investigated levels of RR are assumed to be constant over a person's life. Although the elevation in risk may be constant over a person's life for some risk factors, such as genetic susceptibility, this may not be the case for risk factors such as asbestos or radon exposure.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
      • McCarthy WJ
      • Meza R
      • Jeon J
      • Moolgavkar SH
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
      • Subramanian J
      • Govindan R
      Lung cancer in never smokers: a review.
      However, the benefits and harms of screening never-smokers at specific levels of RR are more easily interpreted by assuming that the RR is constant over a person's lifetime.
      Finally, although our research indicates at what level of risk for developing lung cancer never-smokers could benefit from lung cancer screening, our findings are based on model-based extrapolations. Further research is needed to accurately identify never-smokers at high risk for developing lung cancer, which would allow us to further validate our findings. However, although a number of risk factors for developing lung cancer in never-smokers have been identified, the etiology of lung cancer in never-smokers is not well understood.
      • Sun S
      • Schiller JH
      • Gazdar AF
      Lung cancer in never smokers—a different disease.
      • McCarthy WJ
      • Meza R
      • Jeon J
      • Moolgavkar SH
      Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.
      • Couraud S
      • Zalcman G
      • Milleron B
      • Morin F
      • Souquet PJ
      Lung cancer in never smokers–a review.
      • Subramanian J
      • Govindan R
      Lung cancer in never smokers: a review.
      • Wakelee HA
      • Chang ET
      • Gomez SL
      • et al.
      Lung cancer incidence in never smokers.
      Although lung cancer risk models for never-smokers exist, the performance of the majority of these models is limited.
      • Tammemagi CM
      • Pinsky PF
      • Caporaso NE
      • et al.
      Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation.
      • Spitz MR
      • Hong WK
      • Amos CI
      • et al.
      A risk model for prediction of lung cancer.
      • Raji OY
      • Duffy SW
      • Agbaje OF
      • et al.
      Predictive accuracy of the Liverpool Lung Project risk model for stratifying patients for computed tomography screening for lung cancer: a case-control and cohort validation study.
      • Brenner DR
      • Hung RJ
      • Tsao MS
      • et al.
      Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors.
      This is further demonstrated by comparing the risk of developing lung cancer for an average 67-year-old (the age between the USPSTF recommended screening ages of 55–80 years) never-smoker (by sex) for different time frames in MISCAN-Lung (Supplementary Table 2, Supplemental Digital Content, http://links.lww.com/JTO/A851) with those of the investigated risk models (Supplementary Table 3 in Supplemental Digital Content, http://links.lww.com/JTO/A851). Supplementary Table 3 (in Supplemental Digital Content, http://links.lww.com/JTO/A851) indicates that the investigated lung cancer risk models for never-smokers generally predict higher lung cancer risks compared with MISCAN-Lung. However, the age-group–specific lung cancer mortality rates for never-smoking men and women estimated by MISCAN-Lung are comparable with those reported by Thun et al
      • Thun MJ
      • Hannan LM
      • Adams-Campbell LL
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      (Table S13 in their report). This indicates that the majority of lung cancer risk models may overestimate the risk of lung cancer for never-smokers.
      Finally, the proportion of never-smokers with RRs of 15 compared with never-smokers at average risk is uncertain as information on many risk factors (and the joint distribution thereof) is scarcely available at the population level. The application of the PLCOm2014 model to the PLCO data set and the application of the LLP model for recruiting participants for the UK Lung Cancer Screening Trial (UKLS) may currently provide the best information on the expected levels of risk for never-smokers.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • McRonald FE
      • Yadegarfar G
      • Baldwin DR
      • et al.
      The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.
      The PLCOm2014 model suggests that the maximum observed risk in 65,711 never-smokers in the PLCO was 1.47% over a 6-year period.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      A white never-smoker attaining the highest level of RR (6.98, disregarding age and race) would not reach this level of risk until age 73 years (verified using the calculator provided by the authors, available at http://www.brocku.ca/lung-cancer-risk-calculator). The theoretical maximum possible 6-year risk of lung cancer for never-smokers in the PLCOm2014 model is 3.5%; however, the necessary combination of risk factors to achieve this level of risk is expected to be rare.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      The LLP model was used to recruit participants for the UKLS trial, including never-smokers.
      • McRonald FE
      • Yadegarfar G
      • Baldwin DR
      • et al.
      The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.
      Only four (0.04% of 10,697) never-smokers had a high LLP risk (a risk of 5% or higher over a 5-year period) and all were aged at least 73 years.
      • McRonald FE
      • Yadegarfar G
      • Baldwin DR
      • et al.
      The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.
      Analyses using the model (replicated in R software) suggest that both men and women can only achieve this absolute level of risk at this age at the highest level of RR (13.69).
      In conclusion, this study is the first to investigate the long-term benefits and harms of lung cancer screening for never-smokers. Screening never-smokers at high levels of elevated risk for developing lung cancer (RRs of 15 or higher compared with average risk) is indicated to have similar or better trade-offs between benefits and harms as the population for which the USPSTF recommends screening. However, most lung cancer risk models for never-smokers consider RRs of lower than 15 for never-smokers at elevated risk compared with never-smokers at average risk. In addition, the majority of lung cancer risk models for never-smokers may overestimate the average risk of never-smokers. Applications of lung cancer risk models to populations of never-smokers suggest that few never-smokers attain high levels of risk.
      • Tammemägi MC
      • Church TR
      • Hocking WG
      • et al.
      Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts.
      • McRonald FE
      • Yadegarfar G
      • Baldwin DR
      • et al.
      The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.
      Thus, few never-smokers are expected to attain RRs of 15 compared with never-smokers at average risk. Therefore, for most never-smokers, lung cancer screening is not beneficial.

      ACKNOWLEDGMENTS

      We thank M.C. Tammemägi for providing useful comments with regard to the PLCOm2011 and PLCOm2014 models. We thank our colleagues from the CISNET Lung working group (in particular J. Jeon) and F. van Hees (Department of Public Health, Erasmus MC) for providing useful comments.

      Supplementary Material

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