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Lung Screening Benefits and Challenges: A Review of The Data and Outline for Implementation

Open AccessPublished:November 11, 2020DOI:https://doi.org/10.1016/j.jtho.2020.10.127

      Abstract

      Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for almost a fifth of all cancer-related deaths. Annual computed tomographic lung cancer screening (CTLS) detects lung cancer at earlier stages and reduces lung cancer-related mortality among high-risk individuals. Many medical organizations, including the U.S. Preventive Services Task Force, recommend annual CTLS in high-risk populations. However, fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening. In large part, this is owing to delayed implementation of CTLS in many countries throughout the world. Factors contributing to low uptake in countries with longstanding CTLS endorsement, such as the United States, include lack of patient and clinician awareness of current recommendations in favor of CTLS and clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and cost. This review of the literature serves to address these concerns by evaluating the potential risks and benefits of CTLS. Review of key components of a lung screening program, along with an updated shared decision aid, provides guidance for program development and optimization. Review of studies evaluating the population considered “high-risk” is included as this may affect future guidelines within the United States and other countries considering lung screening implementation.

      Keywords

      Introduction

      Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for 1.76 million deaths in 2018 (18% of all cancer-related deaths).
      International Agency for Research on Cancer, World Health Organization
      Cancer fact sheet: all cancers.
      Every year, at least twice as many people die from lung cancer as from other common malignancies, including colorectal, stomach, liver, and breast cancer.
      International Agency for Research on Cancer, World Health Organization
      Cancer fact sheet: all cancers.
      Approximately 8 million people in the United States alone are eligible for computed tomographic lung cancer screening (CTLS),
      • Pham D.
      • Bhandari S.
      • Oechsli M.
      • Pinkston C.M.
      • Kloecker G.H.
      Lung cancer screening rates: data from the lung cancer screening registry.
      but in 2018, only 4% of eligible Americans were screened. If all high-risk individuals in the United States were screened, an estimated 48,000 lung cancer deaths could be prevented, a number that exceeds the total number of lives lost owing to breast cancer in the United States each year.
      International Agency for Research on Cancer, World Health Organization
      Breast.
      Furthermore, lung cancer is the most frequently fatal cancer in the European Union, causing more than 266,000 deaths yearly (21% of all cancer-related deaths).
      In this review of CTLS, we evaluate the potential risks and benefits in the current context, review perceived barriers to implementation, discuss key issues, and components of successful screening programs, review risk models, and provide a shared decision-making graphic for clinical use.

      Lung Screening Trials: Examining the Evidence

      Annual CTLS detects lung cancer at earlier stages than chest radiography (CXR) and leads to a reduction in lung cancer mortality in individuals at high risk for the disease. First suggested by the International Early Lung Cancer Action Program,
      • Henschke C.I.
      • McCauley D.I.
      • Yankelevitz D.F.
      • et al.
      Early lung cancer action project: overall design and findings from baseline screening.
      ,
      • Henschke C.I.
      • Yankelevitz D.F.
      • et al.
      International Early Lung Cancer Action Program Investigators
      Survival of patients with stage I lung cancer detected on CT screening.
      a reduction in lung cancer mortality was confirmed by the National Lung Screening Trial (NLST), a U.S. multicenter, randomized controlled trial that enrolled more than 53,000 people and was halted early after detecting a significant 20% improvement (p = 0.004) in lung cancer mortality and a 6.7% improvement in overall mortality in individuals undergoing CTLS compared with those undergoing CXR.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      The NLST evaluated CTLS at baseline and annually for the following 2 years without a defined algorithm to guide management of abnormal screens and was not designed to evaluate the degree of benefit achieved by a prolonged screening program. However, an extended analysis of the NLST revealed that improvement in lung cancer specific mortality persisted up to 12.8 years.
      National Lung Screening Trial Research Team
      Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial.
      Since the publication of the NLST in 2011, several other trials/analyses have evaluated the impact of CLTS (the key characteristics and main findings of the trials are summarized in Table 1
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ,
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Baseline characteristics of participants in the randomized National Lung Screening Trial.
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      • Huang K.L.
      • Wang S.Y.
      • Lu W.C.
      • Chang Y.H.
      • Su J.
      • Lu Y.T.
      Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      • De Koning H.
      • Van Der Aalst C.
      • Ten Haaf K.
      • Oudkerk M.
      PL02.05 Effects of volume CT lung cancer screening: mortality results of the NELSON randomised-controlled population based trial.
      • Pastorino U.
      • Rossi M.
      • Rosato V.
      • et al.
      Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial.
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      • Paci E.
      • Puliti D.
      • Lopes Pegna A.
      • et al.
      Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.
      • Puliti D.
      • Mascalchi M.
      • Carozzi F.M.
      • et al.
      Decreased cardiovascular mortality in the ITALUNG lung cancer screening trial: analysis of underlying factors.
      • Lopes Pegna A.
      • Picozzi G.
      • Falaschi F.
      • et al.
      Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.
      • Wille M.M.
      • Dirksen A.
      • Ashraf H.
      • et al.
      Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling.
      • Pedersen J.H.
      • Ashraf H.
      • Dirksen A.
      • et al.
      The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round.
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      UK lung cancer RCT pilot screening trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      The UK lung cancer screening trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.
      • Infante M.
      • Lutman F.R.
      • Cavuto S.
      • et al.
      Lung cancer screening with spiral CT: baseline results of the randomized Dante trial.
      • Infante M.
      • Cavuto S.
      • Lutman F.R.
      • et al.
      Long-term follow-up results of the DANTE trial, a randomized study of lung cancer screening with spiral computed tomography.
      • Becker N.
      • Motsch E.
      • Trotter A.
      • et al.
      Lung cancer mortality reduction by LDCT screening—results from the randomized German LUSI trial.
      ). Succeeding trials compared CTLS with a standard of care (no screening; Table 1). The Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON) randomized high-risk individuals to CTLS versus observation. CTLS was performed at 0, 1, 3, and 5.5 years.
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      The trial involved more than 15,000 people aged 50–75 years with a high tobacco intake (≥15 cigarettes per d for ≥25 y or ≥10 cigarettes per d for ≥30 y; individuals who currently smoke or who quit ≤10 y previously).
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      ,
      • Huang K.L.
      • Wang S.Y.
      • Lu W.C.
      • Chang Y.H.
      • Su J.
      • Lu Y.T.
      Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.
      Approximately 84% were male individuals.
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      In men, after 10 years of follow-up, the cumulative rate ratio for death owing to lung cancer between the CTLS arm and the control arm was 0.76 (95% confidence interval [CI]: 0.61–0.94; p = 0.01), representing a 24% reduction in lung cancer-related death in the CTLS arm. In women, the reduction in lung cancer-specific mortality was much greater. The benefit in both sexes persisted at 11 years. Among screened male participants, lung cancers were at stages I to II in 138 (68%) of 203 screen-detected lung cancers. In the same group, non–screen-detected lung cancers were at stages I to II in only 30 (21%) of 141 cases.
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      The non–screen-detected cases were diagnosed on imaging unrelated to the screening schedule, occurring either between scheduled screening studies or after the last scheduled negative screening study, at 5.5 years of the 10-year study. The NLST reported similar trends; 70% of screen-detected lung cancer cases in the CTLS group were in early stage, compared with 37% of non–screen-detected cases largely during follow-up after the 3 rounds of screening.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      This suggests that ongoing regular screening, rather than years of follow-up without screening, would likely reveal an even greater difference in stage of diagnosis compared with the control arm with potential additional relative decrease in lung cancer mortality.
      Table 1Selected Lung Cancer Screening Studies
      Study CharacteristicsNLST
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ,
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Baseline characteristics of participants in the randomized National Lung Screening Trial.
      NELSON
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      • Huang K.L.
      • Wang S.Y.
      • Lu W.C.
      • Chang Y.H.
      • Su J.
      • Lu Y.T.
      Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      • De Koning H.
      • Van Der Aalst C.
      • Ten Haaf K.
      • Oudkerk M.
      PL02.05 Effects of volume CT lung cancer screening: mortality results of the NELSON randomised-controlled population based trial.
      MILD
      • Pastorino U.
      • Rossi M.
      • Rosato V.
      • et al.
      Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial.
      ,
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      ITALUNG
      • Huang K.L.
      • Wang S.Y.
      • Lu W.C.
      • Chang Y.H.
      • Su J.
      • Lu Y.T.
      Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.
      ,
      • Paci E.
      • Puliti D.
      • Lopes Pegna A.
      • et al.
      Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.
      • Puliti D.
      • Mascalchi M.
      • Carozzi F.M.
      • et al.
      Decreased cardiovascular mortality in the ITALUNG lung cancer screening trial: analysis of underlying factors.
      • Lopes Pegna A.
      • Picozzi G.
      • Falaschi F.
      • et al.
      Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.
      DLCST
      • Huang K.L.
      • Wang S.Y.
      • Lu W.C.
      • Chang Y.H.
      • Su J.
      • Lu Y.T.
      Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis.
      ,
      • Wille M.M.
      • Dirksen A.
      • Ashraf H.
      • et al.
      Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling.
      ,
      • Pedersen J.H.
      • Ashraf H.
      • Dirksen A.
      • et al.
      The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round.
      UKLS
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      UK lung cancer RCT pilot screening trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.
      ,
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      The UK lung cancer screening trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.
      DANTE
      • Infante M.
      • Lutman F.R.
      • Cavuto S.
      • et al.
      Lung cancer screening with spiral CT: baseline results of the randomized Dante trial.
      ,
      • Infante M.
      • Cavuto S.
      • Lutman F.R.
      • et al.
      Long-term follow-up results of the DANTE trial, a randomized study of lung cancer screening with spiral computed tomography.
      LUSI
      • Becker N.
      • Motsch E.
      • Trotter A.
      • et al.
      Lung cancer mortality reduction by LDCT screening—results from the randomized German LUSI trial.
      Study design
       Randomized, Y/NYYYYYYYY
       Screening interval, y11; 2; 2.51 or 2 (rand)110/0.25/111
       Number of screens, n345 annual/3 biennial451
      Repeated only if category 2 nodule or above detected in initial screen.
      55
       Overall follow-up, y7.410108.5 (median)10108.35 (median)8.8 (median)
       ComparatorCXRNo screeningNo screeningNo screeningNo screeningNo screeningNo screeningNo screening
       Inclusion criteria
      DLCST also specified: FEV1 at least 30% of predicted; able to climb two flights of stairs (total of 36 steps) without pausing.
      Pack-years≥30≥15/d
      Cigarettes per day.
      for >25y OR >10/d
      Cigarettes per day.
      for >30y
      ≥20≥20≥20NA
      Inclusion based on risk model (led to inclusion of two individuals who had never smoked).
      ≥20≥15/d for V25y or ≥10/d for ≥30y
      FS
      People who used to smoke were also required to meet the pack-year criterion.
      : abstinence, y
      ≤15<10<10<10≤10 (age >50 y)<10<10
      Age, y55–7450–7549–75; no cancer in <5 y55–6950–7050–75Males, 60–74
      Patients
       Total randomized, n53,452
      • Cressman S.
      • Lam S.
      • Tammemagi M.C.
      • et al.
      Resource utilization and costs during the initial years of lung cancer screening with computed tomography in Canada.
      13,195
      Primary analysis (male patients only).
      409932064104405524504052
       CTLS arm, n26,7226583
      Primary analysis (male patients only).
      2376161320522028
      1994 underwent CT screening.
      12642029
       Age, y61±5
      Mean ± SD.
      CTLS: 58 (55–63)
      Primary analysis (male patients only).
      ,
      Median (IQR).


      C: 58 (54–63)
      Primary analysis (male patients only).
      ,
      Median (IQR).
      Intr: 58

      C: 57 (NR)
      Median (IQR).
      60.9±4
      Mean ± SD.
      57.9±5
      Mean ± SD.
      CTLS: 67.1±4.1

      C: 66.9±4.1
      Mean ± SD.
      64 (5)
      Median (IQR).
      CTLS: 55
      Median (IQR).


      C: 55
      Median (IQR).
       Age range, y55–74CTLS: 46–76
      Primary analysis (male patients only).


      C: 34–89
      Primary analysis (male patients only).
      49–7555–6950–7050–7560–7450–69
       Males, %
      Data revealed are the average percentage between the treatment arms or the percentages for the treatment and control arms (as reported in each article).
      59.0100
      Primary analysis (male patients only).
      68.4/63.364.755.2∼75100CTLS: 50.1

      C: 49.9
       Smoking history
      Pack-years48 (27)
      Median (IQR).
      CTLS: 38 (30–50)
      Primary analysis (male patients only).
      ,
      Median (IQR).


      C: 38 (30–50)
      Primary analysis (male patients only).
      ,
      Median (IQR).
      39/38 (NR)
      Median (IQR).
      40 (NR)
      Median (IQR).
      S: 36.4±13.4
      Mean ± SD.


      C: 35.9±13.4
      NR45 (30)
      Median (IQR).
      NR
      Currently smoke, %48.2CTLS: 55.5
      Primary analysis (male patients only).


      C: 54.8
      Primary analysis (male patients only).
      68.6/89.764.876.138.756.9CTLS: 50.2

      C: 49.8
      Key outcomes
       Primary outcome20% ↓ in LC-related mortality24% ↓ in LC-related mortality (10 y)
      Primary analysis (male patients only).
      39% ↓ in LC-related mortality (10 y)17% ↓ in LC-related mortality;

      30% reduction in overall mortality
      No statistically significant effect on LC-related mortalityLC prevalence 1.7% at baselineNo statistically significant effect on LC-related mortalityNo statistically significant effect on LC-related mortality
       Mortality, %
      General: CTLS/C13.0/14.0
      Deaths per 1000 person-years.
      13.9 / 13.76
      Primary analysis (male patients only).
      ,
      Deaths per 1000 person-years.
      5.8/6.29.5/11.48.0/7.9NR14.2/14.8HR: 0.99 (95% CI: 0.79–1.25) p = 0.95
      Lung-cancer: CTLS/C2.5/3.1
      Deaths per 1000 person-years.
      2.5 / 3.3
      Deaths per 1000 person-years.
      1.7/2.32.7/3.80.2/0.2NR4.7/4.6HR: 0.74 (95% CI: 0.46–1.19) p = 0.21
       Lung cancers detected, n

      CTLS/C
      1701/ 1681
      National Lung Screening Trial Research Team
      Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial.
      203/304
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      98/60
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      67/71
      • Paci E.
      • Puliti D.
      • Lopes Pegna A.
      • et al.
      Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.
      100/53
      • Wille M.M.
      • Dirksen A.
      • Ashraf H.
      • et al.
      Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling.
      42/NR
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      UK lung cancer RCT pilot screening trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.
      104/72
      • Infante M.
      • Cavuto S.
      • Lutman F.R.
      • et al.
      Long-term follow-up results of the DANTE trial, a randomized study of lung cancer screening with spiral computed tomography.
      85/67
      • Becker N.
      • Motsch E.
      • Trotter A.
      • et al.
      Lung cancer mortality reduction by LDCT screening—results from the randomized German LUSI trial.
       Stage, n (%)
      Stage I: CTLS/C673 (40)/462 (27)119 (59)/41 (14)
      Primary analysis (male patients only).
      49 (50)/13 (22)24 (36)/ 8 (11)50 (50)/8 (15)28 (67)/NR47 (45)/16 (22)48 (57)/6 (9)
      Stage II: CTLS/C145 (9)/153 (9)19 (9)/30 (10)
      Primary analysis (male patients only).
      4 (4)/5 (8)5 (8)/5 (7)4 (4)/2 (4)8 (19)/NR7 (7)/5 (7)7(8)/9(13)
      Stage III: CTLS/C298 (18)/321 (19)33 (16)/77 (25)
      Primary analysis (male patients only).
      16 (16)/10 (17)9 (13)/8 (11)23 (23)/9 (17)3 (7)/NR17 (16)/12 (17)12 (14)/21 (31)
      Stage IV: CTLS/C468 (28)/597 (36)19 (9)/139 (46)
      Primary analysis (male patients only).
      29 (30)/32 (53)24 (36)/35 (49)23 (23)/32 (60)3 (7)/NR26 (25)/33 (46)17 (20)/30 (45)
      Unknown stage: CTLS/C112 (7)/ 143 (9)
      Occult: CTLS = 5, C = 4.
      13 (6)/17(6)0(−)/0(−)5 (8)/15 (21)0 (-)/2 (4)0 (-)/NR7 (7)/6 (8)1 (1)/1 (2)
      C, control; CI, confidence interval; CS, people who currently smoke; CT, computed tomography; CTLS, computed tomographic lung screening; CXR, chest radiography; DANTE, Detection And screening of early lung cancer with Novel imaging TEchnology; DLCST, Danish Lung Cancer Screening Trial; FS, people who used to smoke; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; IQR, interquartile range; ITALUNG, Italian Lung Cancer Screening Trial; LC, lung cancer; LUSI, German Lung cancer Screening Intervention; MILD, Multicentric Italian Lung Detection; NELSON, Dutch-Belgian Randomized Lung Cancer Screening Trial; NLST, National Lung Screening Trial; NR, not reported; rand, randomized; UKLS, UK lung cancer screening trial.
      a Repeated only if category 2 nodule or above detected in initial screen.
      b DLCST also specified: FEV1 at least 30% of predicted; able to climb two flights of stairs (total of 36 steps) without pausing.
      c Cigarettes per day.
      d Inclusion based on risk model (led to inclusion of two individuals who had never smoked).
      e People who used to smoke were also required to meet the pack-year criterion.
      f Primary analysis (male patients only).
      g 1994 underwent CT screening.
      h Mean ± SD.
      i Median (IQR).
      j Data revealed are the average percentage between the treatment arms or the percentages for the treatment and control arms (as reported in each article).
      k Deaths per 1000 person-years.
      l Occult: CTLS = 5, C = 4.
      The Multicentric Italian Lung Detection study was conducted for 10 years and provided insight into the benefit of more prolonged consistent screening. This trial was initially designed to compare annual versus biennial CTLS versus no intervention.
      • Pastorino U.
      • Rossi M.
      • Rosato V.
      • et al.
      Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial.
      The results revealed a 39% improvement in the risk of lung cancer-related mortality at 10 years in the two CTLS arms (pooled together), compared with the control arm (hazard ratio [HR]: 0.61; 95% CI: 0.39–0.95).
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      The magnitude of benefit increased when restricted to outcomes occurring after the fifth year of screening, leading to a 58% reduction in the risk of lung cancer-related mortality (HR: 0.42; 95% CI: 0.22–0.79).
      • Pastorino U.
      • Silva M.
      • Sestini S.
      • et al.
      Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.
      When pooled with the Multicentric Italian Lung Detection trial, the Detection And screening of early lung cancer with Novel imaging TEchnology trial revealed a benefit in lung cancer overall mortality with CTLS, compared with no screening
      • Infante M.
      • Sestini S.
      • Galeone C.
      • et al.
      Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials.
      ; similar findings were also found in the Italian Lung Cancer Screening Trial.
      • Paci E.
      • Puliti D.
      • Lopes Pegna A.
      • et al.
      Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.
      Although the Danish Lung Cancer Screening Trial did not reveal a benefit of screening on lung cancer mortality versus the control arm, the results were calculated after only 5 years of follow-up with only 2000 subjects per arm, limiting the power of the study to find a mortality benefit.
      • Wille M.M.
      • Dirksen A.
      • Ashraf H.
      • et al.
      Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling.
      Finally, findings from the German Lung cancer Screening Intervention trial were in line with those from other trials, including the NLST and NELSON, suggesting a stronger reduction in lung cancer mortality after CTLS among women, compared with men.
      • Becker N.
      • Motsch E.
      • Trotter A.
      • et al.
      Lung cancer mortality reduction by LDCT screening—results from the randomized German LUSI trial.
      The accumulation of data and experience with CTLS exceed those of other routine cancer screenings and have led to important insights that further guide CTLS implementation and future studies for ongoing improvements.

      Current Guidelines and Recommendations on CTLS

      In December 2013, the U.S. Preventive Services Task Force (USPSTF) released their initial recommendation for lung screening. Most U.S. programs conducting CTLS at that time had adopted either the NLST– or the National Comprehensive Cancer Network (NCCN)–positive solid pulmonary nodule size thresholds of greater than or equal to 4 mm in a maximum (NLST) or mean (NCCN) diameter. In 2014, the NCCN and Lung-RADS increased the size threshold at which a solid pulmonary nodule would trigger a positive CTLS examination designation to greater than or equal to 6 mm in mean diameter, after research by multiple organizations revealed a considerable increase in positive predictive value and a minimal increase in false-negative examinations at this larger threshold size.
      American College of Radiology
      Lung CT Screening Reporting & Data System. Lung-RADS® Version 1.1. Assessment categories release date; 2019.
      • Callister M.E.
      • Baldwin D.R.
      • Akram A.R.
      • et al.
      British Thoracic Society guidelines for the investigation and management of pulmonary nodules.
      • MacMahon H.
      • Naidich D.P.
      • Goo J.M.
      • et al.
      Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017.
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Lung cancer screening.
      • Yip R.
      • Henschke C.I.
      • Yankelevitz D.F.
      • Smith J.P.
      CT screening for lung cancer: alternative definitions of positive test result based on the national lung screening trial and international early lung cancer action program databases.
      In current clinical practice, analysis of the performance of CTLS should reflect this established positive size threshold when using two-dimensional measurements.
      Many medical organizations recommend annual CTLS in populations at high risk of lung cancer. Table 2
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Lung cancer screening.
      ,
      American Academy of Family Physicians
      Clinical preventive service recommendation. Lung cancer.
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      • Mazzone P.J.
      • Silvestri G.A.
      • Patel S.
      • et al.
      Screening for lung cancer: CHEST guideline and expert panel report.
      • Wender R.
      • Fontham E.T.
      • Barrera E.J.
      • et al.
      American Cancer Society lung cancer screening guidelines.
      • Wiener R.S.
      • Gould M.K.
      • Arenberg D.A.
      • et al.
      An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice.
      Centers for Medicare & Medicaid Services
      Decision memo for screening for lung cancer with low dose computed tomography (LDCT) (CAG-00439N).
      • Roberts H.
      • Walker-Dilks C.
      • Sivjee K.
      • et al.
      Screening high-risk populations for lung cancer: guideline recommendations.
      Cancer Care Ontario. Guideline and Advice
      Frequently asked questions for healthcare providers: lung cancer screening in Ontario for people at high risk.
      • Kauczor H.U.
      • Bonomo L.
      • Gaga M.
      • et al.
      ESR/ERS white paper on lung cancer screening.
      Japan Radiology Society, Japanese College of Radiology
      The Japanese imaging guideline 2013.
      • Lee J.
      • Lim J.
      • Kim Y.
      • et al.
      Development of protocol for Korean lung cancer screening project (K-LUCAS) to evaluate effectiveness and feasibility to implement national cancer screening program.
      • Couraud S.
      • Cortot A.B.
      • Greillier L.
      • et al.
      From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the French InterGroup (IFCT) and the Groupe d’Oncologie De Langue Francaise (GOLF).
      • Tanner N.T.
      • Silvestri G.A.
      Shared decision-making and lung cancer screening: let’s get the conversation started.
      American Thoracic Society, American Lung Association
      Lung cancer screening. Implementation guide.
      summarizes the published guidelines. Although there are some minor variations between the definitions of “high-risk,” the criteria used are generally driven by age and smoking history.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      More recent CTLS studies have included individuals with less tobacco exposure, and consequently, adjustment to the recommendations may follow. We review the topic of “high-risk” in another section. Guidelines are yet to be published in People’s Republic of China, but thoughtful consideration specific to the population is underway.
      • Cheng Y.I.
      • Davies M.P.A.
      • Liu D.
      • Li W.
      • Field J.K.
      Implementation planning for lung cancer screening in China.
      Additional guidelines on CTLS are available, including the European Society for Medical Oncology,
      • Postmus P.E.
      • Kerr K.M.
      • Oudkerk M.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      the European Society of Thoracic Surgeons
      • Pedersen J.H.
      • Rzyman W.
      • Veronesi G.
      • et al.
      Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe.
      recommendations, and the European position statement on lung cancer screening.
      • Oudkerk M.
      • Devaraj A.
      • Vliegenthart R.
      • et al.
      European position statement on lung cancer screening.
      Table 2Recommended Eligibility Criteria for CTLS in Patients at High Risk of LC
      GuidelineCriteria for Patients to be Considered for CTLS
      YearAge, yPack-Years, yTime Since Stopped Smoking, yComments
      AAFP
      American Academy of Family Physicians
      Clinical preventive service recommendation. Lung cancer.
      2013Insufficient evidenceEligibility criteria were based on one study (NLST); shared decision-making was recommended instead
      AATS tier 1
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      201255-79
      AATS tier 2
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      201250–79Must have additional risk (≥5%) of developing lung cancer within 5 y (e.g., previous cancer, genetics)
      AATS tier 2 (alternative)
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      2012AnyAny/noneAny/noneLung cancer survivors with no evidence of disease for 4 y
      ACCP
      • Mazzone P.J.
      • Silvestri G.A.
      • Patel S.
      • et al.
      Screening for lung cancer: CHEST guideline and expert panel report.
      201855–77≥30≤15Evidence-based smoking cessation treatments are recommended
      ACS
      • Wender R.
      • Fontham E.T.
      • Barrera E.J.
      • et al.
      American Cancer Society lung cancer screening guidelines.
      201355–74≥30≤15“Apparently healthy”
      ALA202055-80≥30≤15
      ASCO/ATS
      • Wiener R.S.
      • Gould M.K.
      • Arenberg D.A.
      • et al.
      An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice.
      201555–74≥30≤15
      CMS
      Centers for Medicare & Medicaid Services
      Decision memo for screening for lung cancer with low dose computed tomography (LDCT) (CAG-00439N).
      201555–77≥30≤15Offered to asymptomatic Medicare beneficiaries if they agree to receive counseling and participate in shared decision-making before screening
      CCO
      • Roberts H.
      • Walker-Dilks C.
      • Sivjee K.
      • et al.
      Screening high-risk populations for lung cancer: guideline recommendations.
      ,
      Cancer Care Ontario. Guideline and Advice
      Frequently asked questions for healthcare providers: lung cancer screening in Ontario for people at high risk.
      201355–74≥30≤15Patients must be “disease-free” at time of screening
      ESR/ERS
      • Kauczor H.U.
      • Bonomo L.
      • Gaga M.
      • et al.
      ESR/ERS white paper on lung cancer screening.
      201555–80≥30≤15
      Japanese Imaging Guidelines
      Japan Radiology Society, Japanese College of Radiology
      The Japanese imaging guideline 2013.
      2013≥50Brinkman index ≥ 600
      K-LUCAS (NCCK)
      • Lee J.
      • Lim J.
      • Kim Y.
      • et al.
      Development of protocol for Korean lung cancer screening project (K-LUCAS) to evaluate effectiveness and feasibility to implement national cancer screening program.
      201855–74≥30≤15
      NCCN Cat 1
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Lung cancer screening.
      201755–74≥30<15
      NCCN Cat 2
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Lung cancer screening.
      2017≥50≥20Must have additional risk factor
      Cancer history, family history of lung cancer in first-degree relative, COPD or pulmonary fibrosis, radon exposure, or occupational exposure.


      Alternatively, consider those with ≥1.3% threshold of lung cancer in a 6-year time frame, based on the PLCOm2012 model
      French (SPLF, IFCT, SIT)
      • Couraud S.
      • Cortot A.B.
      • Greillier L.
      • et al.
      From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the French InterGroup (IFCT) and the Groupe d’Oncologie De Langue Francaise (GOLF).
      201255–74≥30<15Currently being revised. Likely to use NELSON entry criteria (50–75 y old; 10 cig × 30 y or 15 cig × 25 y; former <15 y)
      USPSTF201355–80≥30≤15
      Note: The table was adapted from the ATS & ALA Lung screening implementation guide.
      American Thoracic Society, American Lung Association
      Lung cancer screening. Implementation guide.
      AAFP, American Association of Family Physicians; AATS, American Association of Thoracic Surgery; ACCP, American College of Chest Physicians; ACS, American Cancer Society; ALA, American Lung Association; ASCO, American Society of Clinical Oncology; ATS, American Thoracic Society; Cig, cigarettes; CMS, Centers for Medicare & Medicaid Services; CCO, Cancer Care Ontario; COPD, chronic obstructive pulmonary disease; CTLS, computed tomographic lung screening; ERS, European Respiratory Society; ESR, European Society of Radiology; IFCT, The French Cooperative Thoracic Intergroup, K-LUCAS, Korean Lung Cancer Screening Project; LC, lung cancer; NCCN, National Comprehensive Cancer Network; NCCK, National Cancer Center, Korea; NELSON, Dutch-Belgian Randomized Lung Cancer Screening Trial; NLST, National Lung Screening Trial; SITC, Society for the Immunotherapy for Cancer; SPLF, Société de Pneumologie de Langue Française; USPSTF, U.S. Preventive Services Task Force.
      a Cancer history, family history of lung cancer in first-degree relative, COPD or pulmonary fibrosis, radon exposure, or occupational exposure.

      Perceived Barriers to the Implementation of CTLS Screening for the Prevention of Lung Cancer

      After publication of the NLST,
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      guidelines in the United States were updated to recommend CTLS in a high-risk population. Despite these longstanding recommendations, rates of screening implementation and uptake in the United States have been limited.
      • Li J.
      • Chung S.
      • Wei E.K.
      • Luft H.S.
      New recommendation and coverage of low-dose computed tomography for lung cancer screening: uptake has increased but is still low.
      • Jemal A.
      • Fedewa S.A.
      Lung cancer screening with low-dose computed tomography in the United States—2010 to 2015.
      • Zahnd W.E.
      • Eberth J.M.
      Lung cancer screening utilization: a behavioral risk factor surveillance system analysis.
      • Nishi S.
      • Zhou J.
      • Kuo Y.F.
      • Goodwin J.S.
      Use of lung cancer screening with low-dose computed tomography in the Medicare population.
      A number of factors may contribute to the low uptake of CTLS (Table 3), including a lack of patient and clinician awareness of the mortality benefit of CTLS, clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and overtreatment, health system resource utilization, and cost-effectiveness.
      • Wang G.X.
      • Baggett T.P.
      • Pandharipande P.V.
      • et al.
      Barriers to lung cancer screening engagement from the patient and provider perspective.
      • Ersek J.L.
      • Eberth J.M.
      • McDonnell K.K.
      • et al.
      Knowledge of, attitudes toward, and use of low-dose computed tomography for lung cancer screening among family physicians.
      • Raz D.J.
      • Wu G.X.
      • Consunji M.
      • et al.
      The effect of primary care physician knowledge of lung cancer screening guidelines on perceptions and utilization of low-dose computed tomography.
      In addition, stigma against individuals who smoke and nihilism about lung cancer outcomes may bias both clinicians and patients.
      • Hamann H.A.
      • Ver Hoeve E.S.
      • Carter-Harris L.
      • Studts J.L.
      • Ostroff J.S.
      Multilevel opportunities to address lung cancer stigma across the cancer control continuum.
      Most often, cancer screening occurs after a discussion with a primary care provider (PCP), and patients cite their PCP’s advice as important to their decision-making. It is therefore important for PCPs to understand the benefits and risks of CTLS and the appropriate screening criteria.
      • Peterson E.B.
      • Ostroff J.S.
      • DuHamel K.N.
      • et al.
      Impact of provider-patient communication on cancer screening adherence: a systematic review.
      Lack of CLTS knowledge may prevent PCPs from engaging in shared decision making (SDM) conversations with their patients.
      • Lewis J.A.
      • Chen H.
      • Weaver K.E.
      • et al.
      Low provider knowledge is associated with less evidence-based lung cancer screening.
      A recent study reported that PCPs who are less familiar with the qualifying CTLS criteria had 2.7 times higher odds of ordering CXR than CTLS.
      • Lewis J.A.
      • Chen H.
      • Weaver K.E.
      • et al.
      Low provider knowledge is associated with less evidence-based lung cancer screening.
      The Centers for Medicare & Medicaid Services (CMS) requires the use of a formal decision aid as part of CTLS SDM.
      Centers for Medicare & Medicaid Services
      Decision memo for screening for lung cancer with low dose computed tomography (LDCT) (CAG-00439N).
      An accurate decision aid that is understandable to the general public is critical, and we provide an updated decision aid for use in clinics (Fig. 1
      • McKee B.J.
      • Regis S.
      • Borondy-Kitts A.K.
      • et al.
      NCCN guidelines as a model of extended criteria for lung cancer screening.
      ,
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      ).
      Table 3Common perceived Barriers to Lung Cancer Screening
      Perceived barrierComments
      Unwanted consequences of radiation exposure

      Risk of radiation seems nonexistent or too low to be measurable

      No reported cases of radiation-induced malignancy
      False-positive findings/overdiagnosis

      False-positive findings occur less frequently than those that have been reported

      “False discovery” has been misinterpreted/misreported as “false-positive”

      No difference in rates of diagnosis between CTLS and chest radiography groups; suggests that overdiagnosis is not a major concern
      Unnecessary invasive procedures

      Low numbers of resections of benign nodules

      Need to consider balance between resection of benign nodules and watching lung cancer progress without action

      Implementing a standardized system reduces the number of unnecessary interventions
      CTLS, computed tomographic lung screening.
      Figure thumbnail gr1
      Figure 1Updated decision aid to support shared decision-making in clinical practice. (A) Lung screening outcomes per 100 high-risk individuals during full duration of screening eligibility. A scan result leading to at least a recommendation for follow-up imaging occurs in approximately 13% of baseline scans and 6% of yearly follow-up scans.
      • McKee B.J.
      • Regis S.
      • Borondy-Kitts A.K.
      • et al.
      NCCN guidelines as a model of extended criteria for lung cancer screening.
      (B) Five-year survival of all patients with lung cancer, by stage at diagnosis (not specific to screening).
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      (C) Overall survival of all patients with lung cancer, by clinical stage (eighth edition of the TNM classification) at diagnosis (not specific to screening). Figure adapted from Goldstraw P. et al. J Thorac Oncol. 2016;11:39–51.
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      Stage of lung cancer at diagnosis, diagnosed within (D) and outside of (E) CTLS programs. CTLS, computed tomographic lung screening.
      Although clinicians may have concerns about the level of radiation associated with CTLS, this risk appears minimal in the CTLS setting. According to the Health Physics Society, the risk of radiation in the diagnostic realm (<100 mSv) is either too low to measure or nonexistent.
      Health Physics Society
      Radiation risk in perspective. Position statement of the Health Physics Society.
      Although current guidelines recommend a computed tomography (CT) dose index (CTDlvol) of less than or equal to 3 mGy for standard-sized patients,
      American Association of Physicists in Medicine
      Lung cancer screening CT protocols version 5.1. Lung cancer screening CT.
      an achievable dose for CTLS in clinical practice is less than half of this level.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      In addition, screening currently occurs in populations aged from 50/55 to 80 years in which any risk of radiation-induced cancer is less of a concern. Clinicians should consult their local guidelines for further information on radiation exposure.
      • Oudkerk M.
      • Devaraj A.
      • Vliegenthart R.
      • et al.
      European position statement on lung cancer screening.
      ,
      European Society for Medical Oncology
      ESMO clinical practice guidelines: lung and chest tumours.
      The false-positive rate of screening examinations is a critical metric in assessing test effectiveness and should be part of every SDM discussion. The NLST reported that 24.2% of CTLS examinations performed were positive for a nodule greater than or equal to 4 mm in maximum diameter, resulting in a false-positive rate of 23.3%. Unfortunately, many subsequent publications describing the NLST results have misreported the 96.4% NLST false-discovery rate (the percent of positive examinations which is false-positive) as the false-positive rate.
      • Aberle D.R.
      • Adams A.M.
      • et al.
      National Lung Screening Trial Research Team
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      A reanalysis of the NSLT using greater than or equal to 6 mm mean diameter-positive solid nodule size threshold yielded a marked decrease in the false-positive rate to approximately 13% at baseline and 5% for subsequent annual screening examinations,
      • Pinsky P.F.
      • Gierada D.S.
      • Black W.
      • et al.
      Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment.
      which is similar to the false-positive rate of mammography.
      • Seely J.M.
      • Alhassan T.
      Screening for breast cancer in 2018-what should we be doing today?.
      ,
      • Christiansen C.L.
      • Wang F.
      • Barton M.B.
      • et al.
      Predicting the cumulative risk of false-positive mammograms.
      In many cases, a positive CTLS examination is followed by a repeat scan in 3 to 6 months; if stable, this interval follow-up examination will be considered negative, and an annual CTLS examination will be performed 12 months after.
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Lung cancer screening.
      The NELSON protocol reported fewer false positives by including an “indeterminate” classification for certain nodules that required a repeat CT scan to monitor for changes in size before defining the final screening test outcome
      • van Klaveren R.J.
      • Oudkerk M.
      • Prokop M.
      • et al.
      Management of lung nodules detected by volume CT scanning.
      rather than classifying them as positive in the baseline examination. The U.K. Lung Cancer Screening trial (UKLS) investigators suggest that making the distinction between findings that require CT follow-up from findings that require referral for consideration of more invasive work-up may be meaningful for the patient’s perspective.
      Following standardized reporting algorithms, such as International Early Lung Cancer Action Program, NELSON, NCCN protocol, and Lung-RADS, invasive procedures are limited to a subset of the most suspicious findings. It is important for all screening programs to use a standardized system to reduce the number of unnecessary interventions. Although low in numbers, resection of benign nodules does occur. It is important to balance the risk of resecting benign nodules and watching suspected lung cancer progress without action.
      • McKee B.J.
      • Regis S.M.
      • McKee A.B.
      • Flacke S.
      • Wald C.
      Performance of ACR Lung-RADS in a clinical CT lung screening program.
      Distinguishing benign or indolent nodules from malignant nodules is an important area of ongoing research.
      Although overdiagnosis was regarded as a concern after initial NLST estimate of 18%, recent analyses have indicated that overdiagnosis (and therefore overtreatment) may not be a substantial problem for CTLS. Follow-up data from the NLST revealed that there was no significant difference (rate ratio = 1.01) in diagnosed lung cancer between the CTLS and CXR groups with follow-up periods up to 11 years.
      National Lung Screening Trial Research Team
      Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial.
      CTLS seems to be cost-effective in health care systems in which it was assessed and compares well with other routine cancer screenings, including colorectal, breast, and cervical cancers.
      • Pyenson B.S.
      • Sander M.S.
      • Jiang Y.
      • Kahn H.
      • Mulshine J.L.
      An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost.
      ,
      • Black W.C.
      • Gareen I.F.
      • Soneji S.S.
      • et al.
      Cost-effectiveness of CT screening in the National Lung Screening Trial.
      An economic evaluation of the Manchester Lung Health Check pilot found that CTLS represents a cost-effective use of NHS resources.
      • Hinde S.
      • Crilly T.
      • Balata H.
      • et al.
      The cost-effectiveness of the Manchester “lung health checks”, a community-based lung cancer low-dose CT screening pilot.
      The cancer detection rate (CDR) was approximately 3%, and the cost-effectiveness ratio was approximately £10,000 per Quality-Adjusted Life Year,
      • Hinde S.
      • Crilly T.
      • Balata H.
      • et al.
      The cost-effectiveness of the Manchester “lung health checks”, a community-based lung cancer low-dose CT screening pilot.
      which is substantially less than the $81,000 per Quality-Adjusted Life Year calculated from the NLST.
      • Black W.C.
      • Gareen I.F.
      • Soneji S.S.
      • et al.
      Cost-effectiveness of CT screening in the National Lung Screening Trial.
      These findings have been supported by cost data from CTLS trials.
      • Claxton K.
      • Martin S.
      • Soares M.
      • et al.
      Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold.
      For example, the PanCan screening study (Canada; CDR = 4% over 18 mo) reported that treating lung cancer with curative surgery is more cost-effective than treating late-stage lung cancer.
      • Cressman S.
      • Lam S.
      • Tammemagi M.C.
      • et al.
      Resource utilization and costs during the initial years of lung cancer screening with computed tomography in Canada.
      Sex and socioeconomic status may affect access to CTLS. A recent analysis revealed that patients in the CTLS programs tend to have relatively high socioeconomic status and are mostly male individuals,
      • Schütte S.
      • Dietrich D.
      • Montet X.
      • Flahault A.
      Participation in lung cancer screening programs: are there gender and social differences? A systematic review.
      highlighting the need for strategies that focus on better engaging women and people with low-economic status at high-risk for lung cancer.
      • Schütte S.
      • Dietrich D.
      • Montet X.
      • Flahault A.
      Participation in lung cancer screening programs: are there gender and social differences? A systematic review.
      In addition to limited access, some populations, including women and black men, have a higher risk of lung cancer after adjusting for other risk factors including age and smoking exposure. Therefore, some individuals that fail to meet CTLS eligibility criteria carry a higher risk of lung cancer than those who qualify.
      • Borondy Kitts A.K.
      The patient perspective on lung cancer screening and health disparities.
      The perception of risk and concerns about developing lung cancer varies with age, race, and health insurance status, which should be considered in efforts to improve participation rates.
      • Chalian H.
      • Khoshpouri P.
      • Assari S.
      Demographic, social, and behavioral determinants of lung cancer perceived risk and worries in a national sample of American adults; does lung cancer risk matter?.
      In the United States, despite the proven effectiveness of CTLS, established reimbursement, and years of near universal support from governmental agencies and medical societies, uptake remains low. To increase CTLS utilization, widespread awareness and education campaigns are needed to improve clinician engagement. Educational interventions should focus on appropriate CTLS settings and eligibility criteria. Engaging underserved at-risk populations is important as CTLS programs are initiated, to avoid increasing the considerable disparities that have been inherent within health care systems.

      Key Issues and Components of Successful Lung Screening Programs

      Implementation of a CTLS program requires several foundational elements
      • Moffat J.
      • Hiom S.
      • Kumar H.S.
      • Baldwin D.R.
      Lung cancer screening—gaining consensus on next steps - proceedings of a closed workshop in the UK.
      that cover the entire CTLS pathway, from identification of the target population to treatment and follow-up. This begins with accurate selection of the people at high risk for lung cancer who would benefit from CTLS (section 5). Essential core elements of a CTLS program include a program navigator and a reliable database for nodule/patient monitoring.
      American Thoracic Society, American Lung Association
      Lung cancer screening. Implementation guide.
      ,
      • Darling G.
      • Tammemagi M.
      • Schmidt H.
      • et al.
      Organized lung cancer screening pilot: informing a province-wide program in Ontario, Canada [e-pub ahead of print]. Ann Thorac Surg.
      A multidisciplinary steering committee facilitates the management of a program that involves multiple specialties. Other aspects for particular attention include the following.

      Participation

      Participation requires a robust system to identify individuals for CTLS and to track participants over years of follow-up. In the United States, identification of individuals is generally accomplished by PCPs. The internal CTLS program infrastructure is of paramount importance to support PCPs and other ordering providers. Primary care representation on hospital CTLS steering committees is crucial to help identify workflow issues and system tools that may affect enrollment. Some more centralized health care systems around the world allow for systematized identification of individuals for CTLS. Attention to optimizing the involvement of all high-risk populations is of particular importance to prevent disparities. Smoking is increasingly concentrated in disadvantaged populations, including those living below the poverty level, those with disabilities, and those experiencing psychosocial distress.
      • Jamal A.
      • Phillips E.
      • Gentzke A.S.
      • et al.
      Current cigarette smoking among adults—United States, 2016.
      These populations often distrust the medical community and face structural challenges that reduce access to care. They often experience stigma and implicit bias, both as people who smoke and related to their disability, race/ethnicity, and socioeconomic situation.
      • Borondy Kitts A.K.
      The patient perspective on lung cancer screening and health disparities.
      Partnering with community leaders and community health workers, along with developing empathetic, culturally appropriate outreach initiatives is essential to avoid exacerbating existing care access disparities. Some programs offer CTLS within a broader lung health-check framework. This may enhance participation because those involved feel that they are doing something positive about their health. It also reduces the focus on lung cancer, which may be alienating, and allows clinicians to capitalize on clinic attendance by identifying and acting on unmet health needs.
      • Moffat J.
      • Hiom S.
      • Kumar H.S.
      • Baldwin D.R.
      Lung cancer screening—gaining consensus on next steps - proceedings of a closed workshop in the UK.

      Shared Decision-Making

      SDM is an important component of any medical decision. In the United States, formal SDM, including use of a decision aid, is required by CMS to order CTLS. This CMS requirement for SDM is unique to CTLS and a potential barrier to screening uptake if overly cumbersome or misrepresenting the balance of risks and benefits. We provide an updated decision aid (Fig. 1) for use in clinical practice and encourage clinicians to print this for practical use during SDM discussions in clinic. This decision aid provides the background to allow for more effective discussion of patient preferences, because it incorporates the full duration of screening eligibility (as opposed to a certain number of screenings in a clinical trial setting). The components of the decision aid are organized to guide counseling of patients on risks versus benefits of lung screening, starting with the likelihood of diagnosis of lung cancer and risk of an unnecessary invasive procedure. This is followed by the implications of early detection, staging, and mortality for those who develop lung cancer. The first aspect of SDM for patients to consider is the risk-benefit ratio of CTLS. In Figure 1A, we outline the likelihood of diagnosis of lung cancer and the risk of an unnecessary invasive procedure from CTLS over the years of recommended screening. The likelihood of developing lung cancer in the CTLS-eligible population may be as high as 10% to 16%.
      • Peto R.
      • Darby S.
      • Deo H.
      • Silcocks P.
      • Whitley E.
      • Doll R.
      Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies.
      Our decision aid conservatively estimates the risk at 10%. A 5-year survival chart (Fig. 1B) and survival curves (0–72 mo) by stage (Fig. 1C) provide context for the graphic revealing stage of diagnosis within a CTLS program (Fig. 1D) compared with diagnosis outside of a CTLS program (Fig. 1E). The larger randomized studies on lung screening each incorporate a limited number of scans followed by years without scans, during which higher numbers of later-stage lung cancer are diagnosed. Baseline scans also include a higher number of later-stage diagnoses than the following yearly scans. The stage breakdown in the figure is a representation of the experience of the authors with mature lung screening programs. This decision aid will remain accurate after the USPSTF has finalized its updated lung screening recommendations, because the lung cancer risk ratio will not substantially change in a younger population with less smoking history (start age of 50 y, with at least 20 pack years).

      Standardized Radiology Reporting

      Standardized radiology reporting is important to ensure pathway management of findings. In the absence of a standardized reporting system, management of nodules can be inconsistent, leading to overmanagement of benign nodules and potential for delays in the diagnosis of suspicious findings. An understanding of the currently available classification systems is important for the development and management of screening guidelines, but excessive focus on the pros and cons of the different management systems may prove to be a barrier to implementation. In the United States, nodule size and growth assessment rely on two-dimensional measurements (Table 1), whereas in parts of Europe, semiautomatically measured volume and volume-doubling time may be the preferred approach.
      • Oudkerk M.
      • Devaraj A.
      • Vliegenthart R.
      • et al.
      European position statement on lung cancer screening.
      It is undoubtable that reporting systems will evolve as CTLS understanding improves. Nevertheless, it is likely more important to follow an established guideline consistently than to delay implementation of a CTLS program owing to concerns about which guideline to follow.

      Care Escalation Pathways

      Care escalation pathways are required for all suspicious findings. Nodule clinics staffed by pulmonologists and/or thoracic surgeons, with input from radiology, are helpful and can reduce the burden on the ordering PCP, who may be less well-equipped to determine when biopsy or other intervention is indicated. Guidelines highlight when care escalation is recommended.
      • Walker B.L.
      • Williamson C.
      • Regis S.M.
      • et al.
      Surgical outcomes in a large, clinical, low-dose computed tomographic lung cancer screening program.
      ,
      • Crosbie P.A.
      • Balata H.
      • Evison M.
      • et al.
      Second round results from the Manchester “Lung Health Check” community-based targeted lung cancer screening pilot.
      Various guidelines/reporting systems use different CTLS overall examination assessment terminology (e.g., reports of “indeterminate” examinations in patients in the European NELSON trial correlate somewhat with Lung-RADS 3 “positive” and certain Lung-RADS 4A “suspicious” findings in the most typically used U.S. system). In either scenario, follow-up with a nodule specialist is critical for all “suspicious” findings to determine if intervention is indicated. The crucial consideration is the potential impact on the patient; an “indeterminate” Lung-RADS 3 classification generally implies a short interval repeat CTLS examination, whereas a “suspicious” classification implies the potential need for invasive interventions.
      On the basis of our experience, reliable, standardized reporting systems should identify fewer than 8% of examinations per round of CTLS that warrant care escalation. Reasonable efforts should be made to avoid intervention for nonmalignant findings. An aggressive approach designed to eliminate delays in diagnosing lung cancer carries some risk of unnecessary intervention. A robust database for tracking nodules and outcomes can provide internal data necessary for individual clinicians and programs to monitor outcomes and rates of interventions for malignant or benign nodules. Like all types of clinical care, experience improves the process and the outcomes.

      Significant Incidental Findings

      Significant Incidental findings lack a consensus definition. Widespread adoption of a standard definition would enhance the development of management guidelines. Some centers consider a “significant incidental finding” to be any new or unknown unexpected finding that warrants some form of clinical or imaging evaluation before the next scheduled CTLS examination. Emphysema and coronary artery calcifications are highly prevalent in the CTLS-eligible population. In this regard, they are not unexpected and therefore are not classified as “significant incidental findings”. Instead, they are expected findings on CTLS examinations that should be reported and managed accordingly. In contrast, an unknown breast, renal, or liver mass without benign radiographic features would qualify as a “significant incidental finding” requiring urgent targeted clinical/imaging assessment.

      Smoking Cessation Counseling

      Smoking cessation counseling is an important aspect of CTLS. Higher levels of sustained quit rates have been noted in CTLS programs relative to the general smoking population.
      • Pedersen J.H.
      • Tonnesen P.
      • Ashraf H.
      Smoking cessation and lung cancer screening.
      CTLS provides multiple opportunities to counsel and provide advice on quitting for patients who smoke. Studies have revealed that even a brief three-minute intervention on cessation can increase quit rates.
      US Preventive Services Task Force
      Counseling and interventions to prevent tobacco use and tobacco-caused disease in adults and pregnant women: U.S. Preventive Services Task Force reaffirmation recommendation statement.
      In just one year of CTLS program enrollment, there are up to six opportunities for smoking cessation advice/counseling.
      • McKee B.J.
      • McKee A.B.
      • Kitts A.B.
      • Regis S.M.
      • Wald C.
      Low-dose computed tomography screening for lung cancer in a clinical setting: essential elements of a screening program.
      In fact, one study of smoking cessation in a clinical CTLS program found that the longer a person was in a screening program, the more likely they were to quit smoking.
      • Borondy Kitts A.K.
      • McKee A.B.
      • Regis S.M.
      • Wald C.
      • Flacke S.
      • McKee B.J.
      Smoking cessation results in a clinical lung cancer screening program.
      Opportunities for increased smoking cessation rates in CTLS programs have additional benefits of improving health outcomes from other tobacco-related diseases, such as heart disease, chronic obstructive pulmonary disease (COPD), and many other cancers. Including smoking cessation in CTLS also improves the cost-effectiveness of the program.
      • Villanti A.C.
      • Jiang Y.
      • Abrams D.B.
      • Pyenson B.S.
      A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions.

      Use of Risk Models

      In recent years, a number of risk-prediction models have been developed (Table 4A, Table 4BA
      • Tammemägi M.C.
      • Katki H.A.
      • Hocking W.G.
      • et al.
      Selection criteria for lung-cancer screening.
      • Hoggart C.
      • Brennan P.
      • Tjonneland A.
      • et al.
      A risk model for lung cancer incidence.
      • Wilson D.O.
      • Weissfeld J.
      A simple model for predicting lung cancer occurrence in a lung cancer screening program: the Pittsburgh Predictor.
      • Katki H.A.
      • Kovalchik S.A.
      • Berg C.D.
      • Cheung L.C.
      • Chaturvedi A.K.
      Development and validation of risk models to select ever-smokers for CT lung cancer screening.
      • Muller D.C.
      • Johansson M.
      • Brennan P.
      Lung cancer risk prediction model incorporating lung function: development and validation in the UK Biobank prospective cohort study.
      • Markaki M.
      • Tsamardinos I.
      • Langhammer A.
      • Lagani V.
      • Hveem K.
      • Roe O.D.
      A validated clinical risk prediction model for lung cancer in smokers of all ages and exposure types: a HUNT study.
      • Bach P.B.
      • Kattan M.W.
      • Thornquist M.D.
      • et al.
      Variations in lung cancer risk among smokers.
      • Cronin K.A.
      • Gail M.H.
      • Zou Z.
      • Bach P.B.
      • Virtamo J.
      • Albanes D.
      Validation of a model of lung cancer risk prediction among smokers.
      • D’Amelio Jr., A.M.
      • Cassidy A.
      • Asomaning K.
      • et al.
      Comparison of discriminatory power and accuracy of three lung cancer risk models.
      • Cassidy A.
      • Myles J.P.
      • van Tongeren M.
      • et al.
      The LLP risk model: an individual risk prediction model for lung cancer.
      • Raji O.Y.
      • Duffy S.W.
      • Agbaje O.F.
      • 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.
      • Spitz M.R.
      • Hong W.K.
      • Amos C.I.
      • et al.
      A risk model for prediction of lung cancer.
      • Etzel C.J.
      • Kachroo S.
      • Liu M.
      • et al.
      Development and validation of a lung cancer risk prediction model for African-Americans.
      and B
      • Bach P.B.
      • Kattan M.W.
      • Thornquist M.D.
      • et al.
      Variations in lung cancer risk among smokers.
      ,
      • Cassidy A.
      • Myles J.P.
      • van Tongeren M.
      • et al.
      The LLP risk model: an individual risk prediction model for lung cancer.
      ,
      • Spitz M.R.
      • Hong W.K.
      • Amos C.I.
      • et al.
      A risk model for prediction of lung cancer.
      • Markaki M.
      • Tsamardinos I.
      • Langhammer A.
      • Lagani V.
      • Hveem K.
      • Roe O.D.
      A validated clinical risk prediction model for lung cancer in smokers of all ages and exposure types: a HUNT study.
      ), with the aim of improving the selection of individuals for lung cancer screening. Compared with applying the eligibility criteria of the NLST trial, or related criteria such as those recommended by the USPSTF or CMS, risk prediction modeling more accurately selects individuals at higher risk of lung cancer. These models may optimize screening outcomes, such as the number needed to screen to avoid one death.
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      UK lung cancer RCT pilot screening trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.
      ,
      • Katki H.A.
      • Kovalchik S.A.
      • Berg C.D.
      • Cheung L.C.
      • Chaturvedi A.K.
      Development and validation of risk models to select ever-smokers for CT lung cancer screening.
      ,
      • Tammemagi M.C.
      • Schmidt H.
      • Martel S.
      • et al.
      Participant selection for lung cancer screening by risk modelling (the pan-Canadian Early Detection of Lung Cancer [PanCAN] study): a single-arm, prospective study.
      Recently, the International Lung Screening Trial (ILST) initiative used both the PLCOm2012 and USPSTF models as entry criteria in a screening program.
      • Lam S.
      • Myers R.
      • Ruparel M.
      • et al.
      PL02.02 Lung cancer screening selection by USPSTF versus PLCOm2012 Criteria—interim ILST findings.
      PLCOm2012 alone identified 25% of cancers, whereas only 1.6% of cancers were found using USPSTF criteria.
      • Lam S.
      • Myers R.
      • Ruparel M.
      • et al.
      PL02.02 Lung cancer screening selection by USPSTF versus PLCOm2012 Criteria—interim ILST findings.
      Risk modeling is more granular when assessing individual risks and can account for nonlinear relationships to improve predictive accuracy. In addition, the PLCOm2012 risk model has been found to reduce the disparity in eligibility for screening using age and tobacco history for blacks as compared with whites.
      • Borondy Kitts A.K.
      The patient perspective on lung cancer screening and health disparities.
      Risk models can be enhanced by including additional predictors, such as the patient’s latest CTLS or biomarker results.
      • Tammemagi M.C.
      • Ten Haaf K.
      • Toumazis I.
      • et al.
      Development and validation of a multivariable lung cancer risk prediction model that includes low-dose computed tomography screening results: a secondary analysis of data from the National Lung Screening Trial.
      ,
      • Larose T.L.
      • Meheus F.
      • Brennan P.
      • Johansson M.
      • Robbins H.A.
      Assessment of biomarker testing for lung cancer screening eligibility.
      As technologies improve, deep learning algorithms may further enhance lung cancer screening.
      • Ardila D.
      • Kiraly A.P.
      • Bharadwaj S.
      • et al.
      End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography.
      However, many models are not practical for population-based CTLS, because they require blood or genetic tests, or extensive medical record data, or are limited to specific populations. There is a need for greater incorporation of prediction modeling into the CTLS guidelines and programs.
      Table 4ASelected Risk Prediction Models for Lung Cancer
      ModelStudy DetailsValidation (AUC)Advantages/Limitations
      InternalExternal
      Bach
      • Bach P.B.
      • Kattan M.W.
      • Thornquist M.D.
      • et al.
      Variations in lung cancer risk among smokers.
      U.S.; CHS; n = 18,17245–69 y

      20 pack-years, or quit in last 15 y
      0.72
      • Bach P.B.
      • Kattan M.W.
      • Thornquist M.D.
      • et al.
      Variations in lung cancer risk among smokers.
      Finland: 0.69
      • Cronin K.A.
      • Gail M.H.
      • Zou Z.
      • Bach P.B.
      • Virtamo J.
      • Albanes D.
      Validation of a model of lung cancer risk prediction among smokers.
      Only tested in high-risk CS/FS.

      Complicated data collection for asbestos exposure; may not be suitable for lung cancer screening programs
      Massachusetts: 0.66
      • D’Amelio Jr., A.M.
      • Cassidy A.
      • Asomaning K.
      • et al.
      Comparison of discriminatory power and accuracy of three lung cancer risk models.
      Liverpool Lung Project
      • Cassidy A.
      • Myles J.P.
      • van Tongeren M.
      • et al.
      The LLP risk model: an individual risk prediction model for lung cancer.
      U.K.; C-CS; n = 173620–80 y0.71
      • Cassidy A.
      • Myles J.P.
      • van Tongeren M.
      • et al.
      The LLP risk model: an individual risk prediction model for lung cancer.
      Europe: 0.67; U.S.: 0.76; U.K.: 0.82
      • Raji O.Y.
      • Duffy S.W.
      • Agbaje O.F.
      • 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.
      Evidence for accurate prediction in people who do not smoke is lacking.

      Calibration appears poor in areas where decision thresholds may lie
      • Raji O.Y.
      • Duffy S.W.
      • Agbaje O.F.
      • 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.
      Massachusetts: 0.69
      • D’Amelio Jr., A.M.
      • Cassidy A.
      • Asomaning K.
      • et al.
      Comparison of discriminatory power and accuracy of three lung cancer risk models.
      Spitz
      • Spitz M.R.
      • Hong W.K.
      • Amos C.I.
      • et al.
      A risk model for prediction of lung cancer.
      Texas

      C-CS; n = 3852
      No restrictions
      Emphasis on enrolling subsets of special interest, including minority patients, younger patients (<50 y old), and people who had never smoked during their lifetime.
      Test: NS: 0.57;

      FS: 0.63; CS 0.58
      Massachusetts

      NS: 0.68; FS: 0.70; CS: 0.68
      • D’Amelio Jr., A.M.
      • Cassidy A.
      • Asomaning K.
      • et al.
      Comparison of discriminatory power and accuracy of three lung cancer risk models.
      Some variables used to match case-control data were strong predictors of lung cancer; this reduced the predictive ability of the model
      African American
      • Etzel C.J.
      • Kachroo S.
      • Liu M.
      • et al.
      Development and validation of a lung cancer risk prediction model for African-Americans.
      Houston C-CS; n = 988African AmericanDevelopment: 0.75

      Test: 0.63
      No external validations conducted outside of the original study
      PLCOm2012
      • Tammemägi M.C.
      • Katki H.A.
      • Hocking W.G.
      • et al.
      Selection criteria for lung-cancer screening.
      U.S., 10 centers; CHS; n = 80,375CS/FDevelopment: 0.803

      Test: 0.797
      Multiple true external validations, in countries where AUC is ∼0.80Included African Americans and indigenous Americans (at increased risk)
      Hoggart
      • Hoggart C.
      • Brennan P.
      • Tjonneland A.
      • et al.
      A risk model for lung cancer incidence.
      Western Europe; CHS40–65 y

      ≥30 pack-years
      Test: 1 y. CS: 0.824;

      FS: 0.830; ES: 0.843

      5 y. CS: 0.767;

      FS: 0.715; ES: 0.787
      Limited range of predictors

      Needs external validation in other populations
      Pittsburgh predictor
      • Wilson D.O.
      • Weissfeld J.
      A simple model for predicting lung cancer occurrence in a lung cancer screening program: the Pittsburgh Predictor.
      Pittsburgh; CHS; n = 57,09650–79 y

      CS/FS; strong smoking history
      0.678Pittsburgh: 0.701Relatively simple model; lower accuracy of prediction. Derived/validated in preselected high-risk populations (not representative of general population of people who smoke)
      LCRAT/ LDCRAT
      • Katki H.A.
      • Kovalchik S.A.
      • Berg C.D.
      • Cheung L.C.
      • Chaturvedi A.K.
      Development and validation of risk models to select ever-smokers for CT lung cancer screening.
      U.S.: CHS; n = 154,90155–74 y0.70–0.80Included Hispanic, Asian, and black (non-Hispanic) people
      Biobank
      • Muller D.C.
      • Johansson M.
      • Brennan P.
      Lung cancer risk prediction model incorporating lung function: development and validation in the UK Biobank prospective cohort study.
      U.K.: CHS; n = 502,32137–73 yDevelopment: 0.84

      Test: 0.83
      First model to use lung function (no increase in predictive ability). People who had never smoked inflated AUC
      HUNT
      • Markaki M.
      • Tsamardinos I.
      • Langhammer A.
      • Lagani V.
      • Hveem K.
      • Roe O.D.
      A validated clinical risk prediction model for lung cancer in smokers of all ages and exposure types: a HUNT study.
      Norway n = 65,237>20 y0.87Developed/tested in patients with wide range of smoking exposure and ages, including approximately 30 y old, who are at low risk (may have inflated AUC)
      Note: Frequently reported and assessed plus recently developed risk prediction models, with potential to identify high-risk individuals for lung cancer screening.
      AUC, area under the curve; CS, people who currently smoke; C-CS, case-control study; CHS, cohort study; ES, people who have smoked during their lifetime; FS, people who used to smoke; GP, general population; LCRAT, lung cancer risk assessment tool; LDCRAT, lung cancer death risk assessment tool; NA, not available; NS, people who have never smoked.
      a Emphasis on enrolling subsets of special interest, including minority patients, younger patients (<50 y old), and people who had never smoked during their lifetime.
      Table 4BPredictive Factors Included in Risk Prediction Models for Lung Cancer
      ModelBach
      • Bach P.B.
      • Kattan M.W.
      • Thornquist M.D.
      • et al.
      Variations in lung cancer risk among smokers.
      Liverpool Lung Project
      • Cassidy A.
      • Myles J.P.
      • van Tongeren M.
      • et al.
      The LLP risk model: an individual risk prediction model for lung cancer.
      Spitz
      • Spitz M.R.
      • Hong W.K.
      • Amos C.I.
      • et al.
      A risk model for prediction of lung cancer.
      African American
      • Etzel C.J.
      • Kachroo S.
      • Liu M.
      • et al.
      Development and validation of a lung cancer risk prediction model for African-Americans.
      PLCOm2012
      • Tammemägi M.C.
      • Katki H.A.
      • Hocking W.G.
      • et al.
      Selection criteria for lung-cancer screening.
      Hoggart
      • Hoggart C.
      • Brennan P.
      • Tjonneland A.
      • et al.
      A risk model for lung cancer incidence.
      Pittsburgh Predictor
      • Wilson D.O.
      • Weissfeld J.
      A simple model for predicting lung cancer occurrence in a lung cancer screening program: the Pittsburgh Predictor.
      LCRAT/LDCRAT
      • Katki H.A.
      • Kovalchik S.A.
      • Berg C.D.
      • Cheung L.C.
      • Chaturvedi A.K.
      Development and validation of risk models to select ever-smokers for CT lung cancer screening.
      Biobank
      • Muller D.C.
      • Johansson M.
      • Brennan P.
      Lung cancer risk prediction model incorporating lung function: development and validation in the UK Biobank prospective cohort study.
      HUNT
      • Markaki M.
      • Tsamardinos I.
      • Langhammer A.
      • Lagani V.
      • Hveem K.
      • Roe O.D.
      A validated clinical risk prediction model for lung cancer in smokers of all ages and exposure types: a HUNT study.
      Predictive Factors
      Age
      Sex
      Body mass index
      Race/ethnicity
      Socioeconomic status (education)
      Smoking history/abstinence
      Lung function test
      Recent chest radiography
      History of hay fever
      Family history of lung cancer
      Personal history of cancer
      Secondary smoke exposure
      Asbestos exposure
      Dust exposure
      Pneumonia (previous diagnosis)
      Malignant tumor
      COPD
      Previous respiratory disease.
      ,
      Previous diagnosis of emphysema.
      Previous diagnosis of emphysema.
      SNPs
      Environment
      Ten occupational/environmental exposures previously implicated with lung cancer.
      COPD, chronic obstructive pulmonary disease; LCRAT, lung cancer risk assessment tool; LDCRAT, lung cancer death risk assessment tool; SNPs, single-nucleotide polymorphisms associated with lung cancer.
      a Previous respiratory disease.
      b Previous diagnosis of emphysema.
      c Ten occupational/environmental exposures previously implicated with lung cancer.

      Summary

      Understanding of the risks and benefits of CTLS and important components of a successful CTLS program have evolved with increasing studies/trials and CTLS program experience. Some early assumptions and conclusions have persisted, and some have been misinterpreted and incorrectly reported. It is essential that comprehensive CTLS programs be implemented, rather than arising as a byproduct of sporadic ordering of scans by providers without a program infrastructure in place. Given the potential for such a large number of lives to be positively affected by a timely diagnosis of early stage treatable disease, the initiation of CTLS programs should be given the highest priority by health care institutions and providers.

      Acknowledgments

      Medical writing support, which was in accordance with the Good Publication Practice guidelines, was provided by Michael Simpson, of Cirrus Communications (Macclesfield, U.K.), an Ashfield company, and was funded by AstraZeneca . AstraZeneca played no role in the collection, analysis, and interpretation of data or the writing of the report; the decision to submit the article for publication was made solely by the authors. Dr. Sands contributed to Conceptualization, funding acquisition, writing—original draft, writing—review and editing of the manuscript. Drs. Tammemägi, Sebastien Couraud, Baldwin, Borondy-Kitts, Yankelevitz, Lewis, Grannis, Kauczor, Stackelberg, Sequist, Pastorino, and McKee writing—review and editing of the manuscript.

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