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Conquering Thoracic Cancers Worldwide

InternatIonal assocIatIon for the study of lung cancer

Conquering Thoracic Cancers Worldwide

Chapter preprintScreening for Lung CancerJames r. Jett, Md nanda horeweg, Md harry J. de Koning, Md, Phd

Full textbook available for purchase May 2014

This Preprint Chapter is from the forthcoming text, The IASLC Multidisciplinary

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International Association for the Study of Lung

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James R. Jett, MD; Nanda Horeweg, MD; Harry J. de Koning, MD, PhD

SCREENING FOR LUNG CANCER

CHAPTER 7

Lung cancer is the most common cancer in the world. Accord-

ing to data from GLOBOCAN, an estimated 1.6 million cases of

lung cancer were diagnosed in 2008 and 1.38 million lung can-

cer-related deaths.1 In the European Union, 250,000 lung cancer-

related deaths were recorded in 2007 and 257,000 deaths from

lung cancer were projected in 2011.2 The American Cancer Soci-

ety estimates that in the United States, 228,000 new cases of lung

cancer and 160,000 lung cancer-related deaths occurred in 2013.3

The association between smoking and lung cancer was

described more than 50 years ago.4 Worldwide, smoking accounts

for 80% of lung cancers in men and for 50% in women.

The fatality rate (ratio of mortality to incidence) for lung

cancer is high, estimated to be 0.86 in the GLOBOCAN report.1

The 5-year survival rate varies by country but is generally 5-15%.

A substantial problem is that most patients have advanced and

incurable disease at the time of diagnosis. In the United States,

56% of patients have distant metastasis and 22% have regional

spread of disease; 15% of lung cancers are localized at the time of

initial diagnosis.3 The reason for this low percentage of early-stage

disease is that it is asymptomatic; most early-stage lung cancers

are currently detected by chance imaging procedures performed

for other reasons.5

Until recently, there has been no role for lung cancer screen-

ing. Screening trials in which chest radiography and sputum

cytology were evaluated did not demonstrate a decrease in lung

cancer-related mortality.6-8 In the 1990s, single-arm screening

trials with low-dose (radiation) computed tomography (LDCT)

of the chest demonstrated an increase in sensitivity for detect-

ing lung cancer compared with chest radiography.9-11 Authors of

the initial trials reported that 60-80% of detected lung cancers

were stage I and resulted in increased 5-year survival compared

with current clinical practice.12-15 These studies led to a number

of randomized screening trials to compare LDCT to either chest

radiography or observation alone.

Three European randomized control trials included an LDCT

screening arm and a control arm.16-18 However, these trials were

underpowered to detect a clinically plausible benefit in terms of

lung cancer-related mortality.19 The largest of the current ran-

domized LDCT screening trials are the National Lung Screening

Trial (NLST) and the Dutch-Belgian Randomised Lung Cancer

Screening (NELSON) Trial .20,21 The final results of the NLST have

been reported, and the NELSON trial is still in progress. In the

NLST, LDCT screening was associated with a 20% reduction in

mortality compared with chest radiography.20 The cost-efficacy

analysis of NLST is still pending.

In this chapter, we review the risks and benefits of screening

for lung cancer with LDCT, with an emphasis on the data from

the two largest prospective randomized controlled trials.

DESIGN, HYPOTHESIS, AND ENDPOINTS OF THE NLST AND THE NELSON TRIAL

NLSTObservational studies showed that LDCT screening detects

more lung cancer and more early-stage cancers than chest radi-

ography,10-15 which led the US National Cancer Institute to fund

the NLST.22,23 The NLST was a randomized multicenter study in

which LDCT was compared with chest radiography to deter-

mine whether screening with LDCT would reduce lung cancer-

related mortality among high-risk persons. Chest radiography

was chosen as the screening method for the control arm because

radiographic screening was already being compared with usual

care in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer

screening trial.24 Eligible participants were 55-74 years old and

were current or former smokers with a cigarette smoking history

of at least 30 pack-years. Participants were randomly assigned

to annual screening with LDCT or chest radiography for 3 years.

4 Chapter 7: Screening for Lung Cancer

With 25,000 participants in each arm, it was estimated that the

study would have a 90% power to detect a 21% decrease in mortal-

ity in the LDCT arm compared with the chest radiography arm.

The primary endpoint was a comparison of lung cancer-related

mortality between the two arms. A secondary analysis was done

to compare the rate of death from any cause and the incidence

of lung cancer in the two arms. Additional details on the study

design have been published.22 Thirty-three US centers enrolled

53,456 persons between September 2002 and April 2004. The

NLST screening centers maintained close contact with partici-

pants and collected medical records. Serial specimens of blood,

urine, and sputum were collected at 15 screening centers from a

total of 10,208 participants.23

NELSON TrialThe NELSON trial was initiated in 2003, 1 year after the start of the

NLST.21,22 The trial was designed as a randomized controlled trial

to compare LDCT screening with no screening.21 A population-

based recruitment strategy was chosen to minimize self-selection

bias; instead of recruitment through the media, potential partici-

pants were identified through population registries and received

a questionnaire by mail. The information obtained by the ques-

tionnaire was used to decide whom to invite for the trial.21,25-28

Eligible participants were 50-75 years old, were current or former

smokers who had quit less than 10 years ago, and had a smok-

ing history of at least 15 cigarettes per day for 25 years or at least

10 cigarettes per day for 30 years. Exclusion criteria have been

published previously.21

The primary endpoint of the NELSON trial is lung cancer-

specific mortality, a secondary endpoint is all-cause mortality.21,29

It was estimated that with a total sample size of 17,300 partici-

pants, a reduction in lung cancer-specific mortality of at least 25%

could be demonstrated with a power of 80%, assuming 95% com-

pliance in the screening group, 5% contamination in the control

group, and 10 years of follow-up after randomization.21 Details

on the equipment, execution of screening examinations, and the

protocol for management of nodules have been published.30-32

A total of 15,822 eligible individuals were included in the

NELSON trial and randomly assigned to screening with low-dose

CT scanning at baseline (first round), 1 year later (second round),

3 years later (third round), and 5½ years later (7,915 individuals),

or to no screening (7,907 individuals). All data on the diagnosis,

treatment, and follow-up of lung cancer until the death of the

individual were prospectively collected, and with use of a link-

age with the national cancer registries of the Netherlands and

Belgium, all participants with lung cancer not diagnosed through

screening will be identified.29,33 The collected data will be blinded

for study group and offered for cause of death evaluation to an

independent endpoint committee.29 These data will be used to

determine whether LDCT screening has reduced lung cancer

mortality by at least 25% at 10 years after randomization.21,29

SCREENING RESULTS AND TEST CHARACTERISTICS

NLSTFor LDCT, all noncalcified nodules with long-axis diameters of 4

mm or greater in the axial plane were considered to be positive for

potential lung cancer. For chest radiography, all noncalcified nod-

ules and masses were considered positive. Nodule size, margin

characteristics, attenuation, and location were recorded. Par-

ticipants who had a positive screening result received follow-up

recommendations; however, there were no NLST-wide diagnostic

algorithms.22 The rate of positive screening tests over three rounds

was 24.2% with LDCT and 6.9% with chest radiography. Of the

positive findings on LDCT, 96.4% were false-positive results, and

94.5% of the abnormal findings on chest radiography were false-

positive results.20 For the initial round of screening, there were

more positive screening tests in the LDCT arm than in the chest

radiography arm (27.3% vs 9.2%). With the baseline evaluation,

lung cancer was diagnosed in 292 participants in the LDCT arm

(1.1%) and in 190 participants (0.7%) in the chest radiography

arm.34 Among the participants who had lung cancer detected by

LDCT, 92.5% had a positive screening test (true-positive result)

and 6.2% had a negative screening test (false-negative results).

In the chest radiography arm, the screening test was positive in

71.6% of the participants with lung cancer and was negative in

25.8%.. The sensitivity and specificity of LDCT, based on the ini-

tial screen, was 93.8% and 73.4%, respectively, compared with

73.5% and 91.3% for chest radiography. The positive predictive

value (PPV) for an abnormal screen with LDCT was 3.8% versus

5.7% for chest radiography. The PPV increased in both arms of

the study with increasing size of the nodule. With LDCT, the PPV

increased from 3.8% for all nodules to 12% for nodules 11-20 mm

and 30% for nodules 21-30 mm.34

Of the participants with positive screening tests, 90.4% in the

LDCT arm and 92.7% in the radiography group had at least one

diagnostic test performed. The diagnostic tests were primarily

imaging studies (81% in the LDCT arm and 86% in the radiogra-

phy arm). Positron-emission tomography (PET) was performed

in 10% and 8% of participants with abnormal results on LDCT or

chest radiography, respectively. Percutaneous cytologic exami-

nation or a biopsy was performed in 2.2% of participants with

positive findings on LDCT and 3.5% of participants with posi-

tive findings on chest radiography. Ninety (30%) of 297 surgical

procedures performed yielded a nonlung cancer diagnosis in the

LDCT arm.

Screening tests identified clinically significant, nonlung

cancer abnormalities in 7.5% of the participants in the LDCT

arm and in 2.1% of the participants in the chest radiography arm

over the 3-year screening period. Further information on these

abnormalities has not been reported.20

5The IASLC Multidisciplinary Approach to Thoracic Oncology

NELSON TrialScreening in the NELSON trial could lead to three different out-

comes: a negative result (no action other than an invitation for

the next screening round), an indeterminate result (invitation for

a follow-up scan), or a positive result (referral to a pulmonologist

for a diagnostic workup). The size of detected pulmonary nodules

was assessed using software for semiautomated volume measure-

ments (Figure 1). For newly detected solid nodules and the solid

component of partially solid nodules, the volume determined

the screen result; a volume of less than 50 mm³ was negative, a

volume of 50-500 mm³ was indeterminate, and a volume greater

than 500 mm³ was positive.31 For previously detected and non-

solid nodules, the percentage volume change was calculated; a

change of less than 25% was a negative result and a change of

25% or more led to the assessment of the volume-doubling time

(VDT).31 For VDTs of 400-600 days, the result was indeterminate,

for VDTs of less than 400 days, the result was positive.31

The screening result was also positive if a new solid compo-

nent had emerged in a previously nonsolid nodule. The result was

negative for all nodules with fat, benign calcification patterns,

or other benign abnormalities.31,32 Participants with a positive

result were referred for diagnostic work-up to a pulmonologist

through their general practitioner. The trial provided guidelines

for follow-up of participants who had a positive result, but the

implementation of the work-up was not coordinated. The work-

up usually consisted of standard-dose contrast-enhanced CT,

18F-fluorodeoxyglucose PET, and bronchoscopy with endobron-

chial washing and brushing.35,36

Overall, 493 (2%) of the 24,353 scans performed in the first

three screening rounds were considered to have a positive result.37

Across the three rounds, lung cancer was diagnosed in 200 partici-

pants and the cumulative rate of lung cancer detectionwas 2.6%

(200 of 7,582).37 Among the participants with a positive screening

result, lung cancer was not diagnosed in 293. Consequently, the

overall false-positive rate was 59.4% (293 of 493).37

The results of the baseline scans were negative in 79.2%, indeter-

minate in 19.2%, and positive in 1.6% of the 7,582 participants.37

The participants with an indeterminate result had a follow-up

scan, which was positive in 77 participants (5.3%).37 In conclusion,

in round one, scan results were negative in 97.4% of participants

and positive in 2.6%.37 Lung cancer was diagnosed in 70 partici-

pants, which corresponds to a PPV of 35.5%.37

The results of the second-round scans were

negative in 92.2%, indeterminate in 6.6%, and

positive in 1.2% of participants.37 The follow-

up scan in participants with an indeterminate

result was positive in 41 participants.37 In sum-

mary, in the second round, 98.2% of partici-

pants had a negative screening result and 1.8%

had a positive screening result.37 Diagnostic

workup led to the diagnosis of lung cancer in

55 participants; the PPV in the second round

was 42%.37

Among the third-round scans, the results

were negative in 91.9%, indeterminate in 6.8%,

and positive in 0.9% of participants.37 The fol-

low-up scans in round 3 resulted in 76 addi-

tional positive screens.37 In summary, 2.4% of

the participants in the third round had a posi-

tive result and the remaining 97.6% had a nega-

tive result .37 Diagnostic evaluation led to the

diagnosis of lung cancer in 75 participants. The

PPV was 45.5% in the third round.37

Overall, 6.0% of the participants had at least

one positive screening result; 3.6% were false-

positive results.37 Invasive diagnostic proce-

dures were performed in 24.5% of participants

with a false-positive screening result.37 Of

these invasive procedures, 91% were surgical procedures and

the remaining were transthoracic biopsies.37 Hence, 0.9% of all

screened participants had an invasive diagnostic procedure that,

in retrospect, was unnecessary.37

At least one incidental finding was detected in 79.7% of a

subset of 1929 baseline scans; 91.6% of these findings were associ-

ated with no additional testing, treatment, or follow-up. The most

Figure 1. Example of assessment of nodule size using volumetric software in the NELSON trial. Baseline low-dose computed tomography shows a nodule with a volume of 302 mm3 in the right upper lobe of a 66-year-old man. Three months later, the volume increased to 575 mm3; the volume-doubling time (VDT) was 98 days. On diagnostic work-up, a pT1 N0 Mx squamous cell carcinoma was diagnosed.

Baseline 3-month follow-up

Volume 302 mm3 Volume 575 mm3

VDT 98 days


common findings were coronary artery calcifications (93%) and

emphysema (23%); less common were pulmonary fibrosis (8%),

pleural plaques (5%), pleural calcifications (4%), adrenal lesions

(0.9%), small lymph nodes (0.4%), and bronchiectasis (0.2%).38

Additional evaluation was performed for the remaining 8.4% of

the incidental findings; this yielded the detection of three abdom-

inal aortic aneurysms, two renal cysts, one gallbladder polyp, one

adrenal lesion, and one carcinoma of the pancreas that could

not be treated curatively because of metastases.38 In summary,

1.0% of the incidental findings had clinical implications, and the

NELSON researchers concluded that systematically searching for

incidental findings was not worthwhile because it did not save

any lives but exposed participants to potentially harmful addi-

tional procedures.38

LUNG CANCER CHARACTERISTICS

NLSTA total of 1,060 lung cancers were diagnosed in the LDCT arm

and 941 in the chest radiography arm. During the first 3 years of

active screening, 649 and 279 lung cancers were diagnosed in the

two arms, respectively. Forty-four lung cancers were diagnosed

after a negative result on LDCT, and 137 lung cancers were diag-

nosed after a negative result on chest radiography. These findings

demonstrate the greater sensitivity of LDCT for detecting lung

cancer.20 With a median follow-up time of more than 6.5 years

in the two arms, an additional 367 cancers were diagnosed in

the LDCT arm and 525 in the chest radiography arm (Figure 2).20

In the first 3 years of screening, stage IA or IB lung cancer

was present in 63% of participants with positive results on LDCT

and in 47.6% with positive results on chest radiography. Stage

IIIB or IV disease was present in 21% and 31% of participants

in the two arms, respectively, with positive screening results. By

comparison, at the end of the study, which included the follow-

up period without further screening, 50% of the lung cancers in

the LDCT arm were stage IA or IB and 31% were stage IIIB or IV.

This drop in the percentage of early-stage disease raises the ques-

tion of whether continued yearly LDCT screening throughout the

follow-up period would have resulted in more stage IA or IB and

fewer stage IIIB or IV lung cancers.20

In situ or minimally invasive adenocarcinoma or invasive

adenocarcinoma, lepidic predominant (formerly known as bron-

chioloalveolar carcinoma) and adenocarcinoma accounted for

55% of the cancers detected by LDCT and 45% of the cancers

detected by chest radiography. The greatest difference was in the

number of in situ, minimally invasive, and invasive adenocarci-

noma, lepidic predominant in the two arms: 14.7% in the LDCT

arm and 4.7% in the chest radiography arm. The percentage of

adenocarcinomas, squamous cell carcinomas, large cell carci-

nomas, non-small cell carcinomas not otherwise specified, and

small cell carcinomas did not differ substantially in the two arms.

NELSON TrialIn the first three screening rounds of NELSON, 209 lung cancers

were diagnosed in 200 participants.33 Of these lung cancers, 71%

were stage I at the time of diagnosis, 6.7% were stage II, 17.7%

were stage III, and 4.8% were stage IV.33 No significant differ-

ence in stage distribution was found across the three screening

rounds.33 The most frequently detected histologic subtype of lung

cancer was adenocarcinoma (51.2%), and these cancers were

usually detected at a favorable stage: 78.5% at stage I and 5.6%

at stage IIIB or IV.33 Squamous cell carcinomas were the second

most commonly diagnosed subtype, with a slightly less favorable

stage distribution than adenocarcinomas (61.8% at stage I and

5.9% stage IIIB or IV).33 A total of 5.3% of all screen-detected lung

cancers were in situ or minimally invasive adenocarcinoma or

adenocarcinoma, lepidic predominant, and all were stage IA at

the time of diagnosis.33 Small cell carcinomas were few (3.8%),

and all were diagnosed at an advanced stage: 62.5% at stage IIIA

and 37.5% at stage IV.33

1,000

800

600

400

200

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Years since Randomization1 2 3 4 5 6 7 8

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400

300

200

100

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Years since Randomization1 2 3 4 5 6 7 8

B

Low-dose CT

Chest radiography

Chest radiography

Low-dose CT

Figure 2. Cumulative numbers of lung cancers and deaths from lung cancer in the National Lung Cancer Screening Trial. The number of lung cancers (panel A) includes lung cancers that were diagnosed from the date of randomization through December 31, 2009. The number of deaths from lung cancer (Panel B) includes deaths that occurred from the date of randomization through January 15, 2009. Reprinted with permission from National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med.


There were no significant differences between men and

women with regard to the prevalence of the histologic subtypes.33

However, cancer was diagnosed at a significantly higher stage in

men than in women, even after correction for differences in age,

number of pack-years smoked, and body mass index .33

The screen-detected lung cancers were most often localized

in the right lung (65.6%), specifically, the right upper lobe (45%

of all lung cancers) (Figure 3).33 This finding could be explained

by the fact that the airflow at the beginning of a breath is the

largest toward the right upper lobe bronchus.39,40 As a result, the

deposition of particles in tobacco smoke and their carcinogenic

effects are the largest in the right upper lobe.41,42 Lung cancers

detected by LDCT were predominantly localized in the periphery

of lungs (Figure 4).33 Approximately two-thirds of the lung cancers

were found in the outer one-third of the hilar-costal diameter.33

This finding is probably a result of the large number of adeno-

carcinomas, which were significantly more often detected in the

periphery and attached to the pleura than in the middle or central

one-third of the lungs (82.2% vs 17.8%).33

SCREENING OUTCOMES

NLSTBoth arms of the NLST accrued more than 143,000 person-years

of observation, with 356 lung cancer-related deaths in the LDCT

arm and 443 lung cancer-related deaths in the chest radiography

arm. The corresponding rates of death from lung cancer were 247

and 309 per 100,000 person-years, respectively. The rate of death

from lung cancer represents a relative reduction of 20% (95% CI,

6.8-26.7) with LDCT screening. The number needed to screen

with LDCT to prevent one death from lung cancer was 320.20

Screening with LDCT could potentially avert 12,000 lung

cancer-related deaths per year in the United States if screening

were to be implemented in all eligible individuals.43 However, it

has been estimated that the NLST eligibility criteria apply to only

26.7% of all individuals in whom lung cancer is diagnosed in the

94(45.0%)

11(5.3%)

40(19.1)

3(1.4%)

32(15.3%)

28(13.4%)

1(0.5%)

Figure 3. Localization of lung cancers detected by low-dose computed tomography screening in the NELSON trial. In this schematic depiction of the lungs and large airways, the right lung is displayed on the left side and vice versa, as on a chest radiograph. The left upper lobe is divided into the pars superior and the lingula by the dotted line. The lung cancers are depicted as gray dots; their localization corresponds with the lobe where the nodule was detected, not with the exact localization. Reprinted with permission of the American Thoracic Society. Copyright ©2013 American Thoracic Society. Horeweg N, van der Aalst CM, Thunnissen E, et al. Characteristics of Lung Cancers Detected by Computer Tomography Screening in the Randomized NELSON Trial. Am J Respir Crit Care Med. Apr 15 2013;187(8):848-854. Official journal of the American Thoracic Society.

13(6.2%)

19(9.1%)13

(6.3%)92(44.0%) 11

(5.3%)39

(18.7%)

1(0.5%)

7(3.3%)

14(6.7%)

Figure 4. Localization of lung cancers in the transverse plane detected by low-dose computed tomography screening in the NELSON trial. In this schematic depiction of the lungs and main carina in the transverse plane, the right lung is displayed on the left side and vice versa, as on CT images. The lungs are categorized in four sections: central (inner one-third of the hilar-costal diameter), middle (middle one-third of the hilar-costal diameter), peripheral (outer one-third of the hilar-costal diameter) and pleural-attached nodules (nodules depicted on the bold outline of the lungs). The lung cancers are depicted as gray dots; their localization corresponds with the section where the nodule was detected, not with the exact localization. (One lung cancer is not represented in the figure because the participant was referred for a fast-growing nodule peripheral in the right upper lobe, but the nodule disappeared during the workup. However, soon thereafter, lung cancer developed in the left lower lobe (transversal localization unknown) and the patient was treated with radiation therapy.) Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Horeweg N, van der Aalst CM, Thunnissen E, et al. Characteristics of Lung Cancers Detected by Computer Tomography Screening in the Randomized NELSON Trial. Am J Respir Crit Care Med. Apr 15 2013;187(8):848-854. Official journal of the American Thoracic Society.


United States.44 Better models for assessing lung cancer risk and

for selecting whom to screen are needed.45 A lung cancer risk-

prediction model developed from data on the PLCO participants

has demonstrated improved sensitivity (83% vs 71% without loss

of specificity [62.9% vs 62.7%]) compared with the NLST eligibility

criteria43; 41% fewer lung cancers were missed. A retrospective

analysis of the NLST has shown that 88% of the LDCT screen-

ing-prevented deaths occurred in the three highest-risk quintiles

and 1% of prevented deaths occurred in the lowest-risk quintile.

Screening the highest-risk quintiles markedly decreased both

the number of false-positive screening results and the number

needed to screen to prevent one lung cancer death (161 for the

highest-risk quintile, 208 for the three highest-risk quintiles).46

NELSON TrialThe main outcome measure of the NELSON trial is lung cancer-

specific mortality, which will be compared between participants

who had four rounds of LDCT screening and participants who had

no screening. When NELSON was designed, it was hypothesized

that screening with LDCT could reduce lung cancer mortality by

at least 25%.

Because the random assignment of eligible participants took

place from 2004 to 2006, 10 years of follow-up will be reached for

all participants in 2016. In order to perform the mortality analy-

ses, data on all participants who died from lung cancer must be

obtained through linkages with the national cancer registry and

the national death certificate registry of both the Netherlands

and Belgium. The lag time for data from cancer registries is 2

years; thus complete data through 2016 will become available

in early 2019. Subsequently, the medical records of all identified

participants can be collected from the hospitals. These medical

records will be blinded and reviewed by an independent clinical

outcome committee to determine whether the participant died

from lung cancer. Once the cause of death is verified, the final

mortality analyses of NELSON can be performed.

OVERDIAGNOSIS

Overdiagnosis is the detection of a cancer that would not lead to

symptoms or death and never would have been detected with-

out screening. It is not currently possible to determine, based on

pathologic evaluation, which cancers will never lead to death.

In the Mayo Clinic screening trial with chest radiography and

sputum cytology, it was estimated that overdiagnosis may have

occurred in as many as 50% or participants in the screening

group.47,48 Yankelevitz et al. evaluated the median VDT of lung

cancer reported in the literature and postulated that a VDT of 400

days or longer would be a reasonable cut-off for distinguishing

overdiagnosed cancers.49 In reviews of lung cancers detected in

the Memorial Sloan-Kettering and Mayo Clinic chest radiography

screening trials, it was reported that four (5%) of 87 cancers had

a VDT of more than 400 days and another five cancers (6%) had

a VDT of 300-400 days.49

In an early Japanese CT screening trial, lung cancers that

were detected as ground glass opacities (GGO) on CT had a VDT

of 813 ± 375 days.50 The cancers that were partially solid and par-

tially ground glass had a VDT of 457 ± 260 days, and the cancers

that were solid nodules had a VDT of 149 ± 125 days. In a study

of CT lung cancer screening at Mayo Clinic, the VDT could be

quantified in 48 cancers detected with serial CT scans; 13 (27%) of

the 48 cancers had a VDT longer than 400 days. These 13 cancers

occurred mainly in women and were in situ or minimally invasive

adenocarcinoma; adenocarcinoma, lepidic predominant; or low-

grade adenocarcinoma.51 In the Pittsburgh CT screening trial,

volumetric analysis was used to divide cancers into three groups

based on VDT. Thirty (47%) of 63 cancers had a VDT longer than

365 days (slow-growing group); 24 (75%) of 32prevalent cancers

were in the slow-growing group.52 Prevalent cancers (baseline

screen) had a significantly longer VDT than nonprevalent cancers

and included a higher percentage of adenocarcinoma; in situ or

minimally invasive adenocarcinoma; and adenocarcinoma, lep-

idic predominant. Investigators from Italy volumetrically evalu-

ated 175 LDCT-detected lung cancers; slow-growing cancers had

a VDT of 400-599 days and indolent cancers had a VDT of 600 days

or longer.53 Slow-growing or indolent cancers accounted for 25%

of incident lung cancers.53 In the NLST trial, there was an excess

of 119 lung cancers (13%) in the LDCT arm (1,060 vs 941) and

some of these cancers may represent overdiagnosis. Accordingly,

the evidence supports the presence of overdiagnosed cancers in

LDCT screening trials, but the precise magnitude is uncertain.

Modeling studies by the Cancer Intervention and Surveillance

Modeling Network (CISNET) estimate that 9.5-11.9% of screen-

detected cancers are overdiagnosed.54

SMOKING CESSATION

Individuals who are eligible for lung cancer screening are typi-

cally current smokers or former smokers who quit smoking fewer

than 10 to 15 years previously.20,21,55-60 The proportion of current

smokers in screening trials ranges from 48.2% to 76.1% at base-

line.17,20,55-60 Cessation rates range from 6.6% to 29.0%,17,61-70 which

are higher than spontaneous quit rates in the general population

(1%-7%).61,62 It is not known whether this higher rate is a result of

selection bias, of increased health awareness due to participation

in a cancer screening trial, and/or of the accompanying smoking

cessation interventions.

The effect of CT screening on smoking cessation was evalu-

ated in the NELSON trial and in the Danish Lung Cancer Screen-

ing Trial.63,64 In both trials, the smoking status of participants in

the screening and control arms at baseline did not differ. During

follow-up, no differences were found in the cessation rate and

the number of quit attempts between the two study arms.63,64


Nonetheless, in the NELSON trial, the smoking cessation rate

was significantly higher for participants randomly assigned to

the control arm compared with that for participants randomly

assigned to the screening arm.64 Therefore, the concern was raised

that LDCT screening may lead to continued smoking—the so-

called health-certificate effect.

In a considerable number of studies, the number of quit

attempts by participants with an abnormal result on LDCT

screening has been higher than that by participants with a

normal result.63,65-70 This difference may indicate that the finding

of an abnormality on screening and the subsequent additional

examinations was a teachable moment for some participants. The

increased number of quit attempts actually led to higher cessation

rates in four studies,63,67-69 but in the remaining studies, only the

desire, but not the ability of the participants to quit smoking, was

increased.65,66,70

These results support the recommendation in several guide-

lines that smoking cessation interventions be part of any lung

cancer screening program.19,71-73 Smoking cessation aid has been

offered in a number of studies,63,68,70,74,75 but the effectiveness was

investigated only in the NELSON trial.74 No significant differences

in the number of quit attempts and smoking cessation were found

between participants who received a standard smoking cessation

information leaflet and those who received tailored smoking ces-

sation advice. The lack of an additional effect of tailored advice

on prolonged smoking cessation may be explained by insufficient

effectiveness but also by the poor uptake, with 23% of partici-

pants completing the additional questionnaire and receiving the

tailored advice.74 In an Irish lung cancer screening trial, 1.3% of

participants accepted smoking cessation group therapy.75 There-

fore, effective smoking cessation interventions, which could be

implemented along with lung cancer screening, should be devel-

oped to enhance reduction in lung cancer-specific and all-cause

mortality.

BIOMARKERS

There is intense interest in biomarkers to aid in both risk assess-

ment and early diagnosis.76 The development of biomarkers is

categorized in five phases: (1) preclinical exploration, (2) clinical

assay and validation, (3) retrospective longitudinal, (4) prospec-

tive screening, and (5) cancer control.77 To date, no biomarker has

demonstrated efficacy beyond the third phase.

The cost of genotyping the entire human genome is estimated

to be $1000 within the next few years. Genome wide association

studies (GWAS) have identified a number of genes believed to

be associated with lung cancer risk, including 15q25,78,79 13q31,80

and 6p21.81 In a GWAS study of more than 5000 never-smoking

Asian women with lung cancer, researchers identified three new

susceptibility loci at 10q25.2, 6q22.2, and 6p21.32 and confirmed

associations with loci 5p15.33, 3q28, and 17q24.3.82 The locus with

the strongest association with lung cancer was 10q25.2 (candidate

gene Vti1a), with a modest odds ratio of 1.28 (95% CI, 1.21-1.35).

The researchers found no association of 15q25 in this population

of never-smokers, which suggests that this locus is not associ-

ated with lung cancer risk in never-smokers. Identification of lung

cancer susceptibility genes associated with high risk would likely

influence an individual’s decision about screening.

Currently, studies are underway to evaluate the diagnostic

biomarker potential of gene expression in bronchial brushings83

and chromosomal aneusomy in sputum.84 Numerous blood

biomarkers are being evaluated and include serum proteins,85,86

autoantibodies to tumor antigens,87 and microRNA.88 There is

continued interest in the use of volatile organic compounds in

exhaled breath as biomarkers of lung cancer.89,90 Because of the

high number of noncalcified nodules detected by LDCT screen-

ing, there is particular interest in the use of biomarkers to help

differentiate benign from malignant nodules.91 Hassanein et al.

have published a state-of-the art indepth review of molecular

biomarkers.76

FUTURE DIRECTIONS

Since the NLST demonstrated that LDCT screening for lung

cancer significantly reduces lung cancer-specific mortality,20 sev-

eral organizations have recommended screening for high-risk

individuals.72,73,92-94 Research on methods to increase the yield and

reduce the harms and costs of LDCT screening for lung cancer

will be essential in the near future.

We anticipate continued efforts to help improve the selection

of individuals who benefit most from lung cancer screening by

using risk calculators45,95 and the management of screen-detected

pulmonary nodules by improved criteria for the traditional risk-

factors,72,73,92 prediction models,45,46,95 and biomarkers.76,96 Inves-

tigators involved in the Pan-Canadian Early Detection of Lung

Cancer Study developed a calculator to estimate the probability

that a screen-detected nodule is malignant, with areas under the

receiver operating characteristic curve of more than 0.90, even for

nodules that were 10 mm or smaller.97 The potential benefits of

LDCT screening may be increased by using the information the

images provide about the individual’s risk of cardiovascular dis-

ease,98-100 chronic obstructive pulmonary disease,101-103 and osteo-

porosis.104 Furthermore, personalization of the LDCT screening

program and screening intervals may be of interest for future

research because an individual’s risk factors45,46,95 and the screen-

ing result are highly predictive of future lung cancer risk.37,97 Lastly,

research on methods to use lung cancer screening as a catalyst

for interventions that promote a healthy lifestyle are warranted.105


CONCLUSION

Until recently, screening for lung cancer had not decreased lung

cancer-specific mortality and was not recommended by any

major medical organization. Screening trials in the 1970s and

1980s showed that screening with chest radiography or sputum

cytology did not decrease lung cancer-related deaths. This lack

of benefit of screening with chest radiography was confirmed in

the large PLCO trial in North America. LDCT screening has the

limitation of detecting a large number of noncalcified nodules

that require additional follow-up and occasional invasive test-

ing. These indeterminate nodules and diagnostic testing may

be associated with psychologic stress. Approximately 20-25%

of thoracic operations performed in LDCT screening trials have

been for benign lesions.

In terms of benefits, approximately 60-70% of non-small cell

lung cancers detected by LDCT have been stage I in the popula-

tions studied. In the NLST, the increase in stage I lung cancers was

accompanied by a decrease in advanced-stage disease. Screening

resulted in a 20% reduction in lung cancer-specific mortality for

the participants who had screening with LDCT. The NELSON trial

also showed a high percentage of stage I lung cancers detected

by LDCT, but the trial is ongoing and the comparison results with

the control arm are currently pending.

Various medical organizations in the United States have

endorsed screening for lung cancer with LDCT for high-risk indi-

viduals. The two most important endorsements have come from

the American Cancer Society72 and the United States Preventive

Services Task Force (USPSTF).19,92 Both organizations have cau-

tioned that screening should be conducted in centers with mul-

tidisciplinary expertise, similar to those centers that participated

in the NLST. The recommendation by the USPSTF is a grade B

recommendation. Based on this level of recommendation, it is

anticipated that LDCT screening will be paid for by Medicare and

insurance companies in the United States.

Screening with LDCT has not been endorsed in Europe. It is

likely that the decision on lung cancer screening in many Euro-

pean countries will be heavily influenced by the final results of

NELSON.

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