Virginia A. Moyer, MD, MPH; on behalf of the U.S. Preventive Services Task Force (*)
* For a list of the members of the USPSTF, see the Appendix.
This article was published online first at www.annals.org on 31 December 2013.
Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government.
They should not be construed as an official position of the Agency for Healthcare Research and Quality
or the U.S. Department of Health and Human Services.
Financial Support: The USPSTF is an independent, voluntary body. The U.S. Congress
mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.
Potential Conflicts of Interest: Disclosure forms from USPSTF members can be viewed at
Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).
Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation
Statement. Ann Intern Med. 2014;160:330-338. doi: 10.7326/M13-2771
Download citation file:
Published: Ann Intern Med. 2014;160(5):330-338.
Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for lung
The USPSTF reviewed the evidence on the efficacy of low-dose computed tomography, chest radiography,
and sputum cytologic evaluation for lung cancer screening in asymptomatic persons who are at average
or high risk for lung cancer (current or former smokers) and the benefits and harms of these screening
tests and of surgical resection of early-stage non–small cell lung cancer. The USPSTF also
commissioned modeling studies to provide information about the optimum age at which to begin and end
screening, the optimum screening interval, and the relative benefits and harms of different screening
This recommendation applies to asymptomatic adults aged 55 to 80 years who have a 30 pack-year smoking
history and currently smoke or have quit within the past 15 years.
The USPSTF recommends annual screening for lung cancer with low-dose computed tomography in adults
aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within
the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or
develops a health problem that substantially limits life expectancy or the ability or willingness to
have curative lung surgery. (B recommendation)
The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of
specific preventive care services for patients without related signs or symptoms.
It bases its recommendations on the evidence of both the benefits and harms of the service and an
assessment of the balance. The USPSTF does not consider the costs of providing a service in this
The USPSTF recognizes that clinical decisions involve more considerations than evidence alone.
Clinicians should understand the evidence but individualize decision making to the specific patient or
situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in
addition to the evidence of clinical benefits and harms.
The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults
aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past
15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health
problem that substantially limits life expectancy or the ability or willingness to have curative lung
surgery. (B recommendation)
See the Clinical Considerations section for suggestions for implementation in practice.
See the Figure for a summary of the recommendation and suggestions
for clinical practice.
Screening for lung cancer: clinical summary of U.S. Preventive Services Task Force
Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classification of levels of
certainty about net benefit.
Appendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice
Appendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit
Lung cancer is the third most common cancer and the leading cause of cancer-related death in the United
States (1). The most important risk factor for lung cancer is
smoking, which results in approximately 85% of all U.S. lung cancer cases (2). Although the prevalence of smoking has decreased, approximately 37% of U.S. adults
are current or former smokers (2). The incidence of lung cancer
increases with age and occurs most commonly in persons aged 55 years or older. Increasing age and
cumulative exposure to tobacco smoke are the 2 most common risk factors for lung cancer.
Lung cancer has a poor prognosis, and nearly 90% of persons with lung cancer die of the disease. However,
early-stage non–small cell lung cancer (NSCLC) has a better prognosis and can be treated with
Most lung cancer cases are NSCLC, and most screening programs focus on the detection and treatment of
early-stage NSCLC. Although chest radiography and sputum cytologic evaluation have been used to screen
for lung cancer, LDCT has greater sensitivity for detecting early-stage cancer (3).
Although lung cancer screening is not an alternative to smoking cessation, the USPSTF found adequate
evidence that annual screening for lung cancer with LDCT in a defined population of high-risk persons can
prevent a substantial number of lung cancer–related deaths. Direct evidence from a large,
well-conducted, randomized, controlled trial (RCT) provides moderate certainty of the benefit of lung
cancer screening with LDCT in this population (4). The magnitude
of benefit to the person depends on that person's risk for lung cancer because those who are at highest
risk are most likely to benefit. Screening cannot prevent most lung cancer–related deaths, and
smoking cessation remains essential.
The harms associated with LDCT screening include false-negative and false-positive results, incidental
findings, overdiagnosis, and radiation exposure. False-positive LDCT results occur in a substantial
proportion of screened persons; 95% of all positive results do not lead to a diagnosis of cancer. In a
high-quality screening program, further imaging can resolve most false-positive results; however, some
patients may require invasive procedures.
The USPSTF found insufficient evidence on the harms associated with incidental findings. Overdiagnosis of
lung cancer occurs, but its precise magnitude is uncertain. A modeling study performed for the USPSTF
estimated that 10% to 12% of screen-detected cancer cases are overdiagnosed—that is, they would not
have been detected in the patient's lifetime without screening. Radiation harms, including cancer
resulting from cumulative exposure to radiation, vary depending on the age at the start of screening; the
number of scans received; and the person's exposure to other sources of radiation, particularly other
The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT is of
moderate net benefit in asymptomatic persons who are at high risk for lung cancer based on age, total
cumulative exposure to tobacco smoke, and years since quitting smoking. The moderate net benefit of
screening depends on limiting screening to persons who are at high risk, the accuracy of image
interpretation being similar to that found in the NLST (National Lung Screening Trial), and the
resolution of most false-positive results without invasive procedures (4).
The risk for lung cancer increases with age and cumulative exposure to tobacco smoke and decreases with
time since quitting smoking. The best evidence for the benefit of screening comes from the NLST, which
enrolled adults aged 55 to 74 years who had at least a 30 pack-year smoking history and were current
smokers or had quit within the past 15 years. As with all screening trials, the NLST tested a specific
intervention over a finite period. Because initial eligibility extended through age 74 years and
participants received 3 annual screening computed tomographic scans, the oldest participants in the trial
were aged 77 years.
The USPSTF used modeling studies to predict the benefits and harms of screening programs that use
different screening intervals, age ranges, smoking histories, and times since quitting. A program that
annually screens adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke
or have quit within the past 15 years is projected to have a reasonable balance of benefits and harms.
The model assumes that persons who achieve 15 years of smoking cessation during the screening program
discontinue screening. This model predicts the outcomes of continuing the screening program used in the
NLST through age 80 years.
Screening may not be appropriate for patients with substantial comorbid conditions, particularly those at
the upper end of the screening age range. The NLST excluded persons who were unlikely to complete
curative lung cancer surgery and those with medical conditions that posed a substantial risk for death
during the 8-year trial. The baseline characteristics of the NLST showed a relatively healthy sample, and
fewer than 10% of enrolled participants were older than 70 years (5). Persons with serious comorbid conditions may experience net harm, no net benefit, or at
least substantially less net benefit. Similarly, persons who are unwilling to have curative lung surgery
are unlikely to benefit from a screening program.
Age, total exposure to tobacco smoke, and years since quitting smoking are important risk factors for
lung cancer and were used to determine eligibility in the NLST. Other risk factors include specific
occupational exposures, radon exposure, family history, and history of pulmonary fibrosis or chronic
obstructive lung disease. The incidence of lung cancer is relatively low in persons younger than 50 years
but increases with age, especially after age 60 years. In current and former smokers, age-specific
incidence rates increase with age and cumulative exposure to tobacco smoke.
Smoking cessation substantially reduces a person's risk for developing and dying of lung cancer. Among
persons enrolled in the NLST, those who were at highest risk because of additional risk factors or a
greater cumulative exposure to tobacco smoke experienced most of the benefit (6). A validated multivariate model showed that persons in the highest 60% of risk
accounted for 88% of all deaths preventable by screening.
Low-dose computed tomography has shown high sensitivity and acceptable specificity for the detection of
lung cancer in high-risk persons. Chest radiography and sputum cytologic evaluation have not shown
adequate sensitivity or specificity as screening tests. Therefore, LDCT is currently the only recommended
screening test for lung cancer.
Surgical resection is the current standard of care for localized NSCLC. This type of cancer is treated
with surgical resection when possible and also with radiation and chemotherapy. Annual LDCT screening may
not be useful for patients with life-limiting comorbid conditions or poor functional status who may not
be candidates for surgery.
Smoking cessation is the most important intervention to prevent NSCLC. Advising smokers to stop smoking
and preventing nonsmokers from being exposed to tobacco smoke are the most effective ways to decrease the
morbidity and mortality associated with lung cancer. Current smokers should be informed of their
continuing risk for lung cancer and offered cessation treatments. Screening with LDCT should be viewed as
an adjunct to tobacco cessation interventions.
Clinicians have many resources to help patients stop smoking. The Centers for Disease Control and
Prevention has developed a Web site with many such resources, including information on tobacco quit
lines, available in several languages (www.cdc.gov/tobacco/campaign/tips). Quit
lines provide telephone-based behavioral counseling and support to tobacco users who want to quit
smoking. Counseling is provided by trained cessation specialists who follow standardized protocols that
may include several sessions and are generally provided at no cost to users. The content has been adapted
for specific populations and can be tailored for individual clients. Strong evidence shows that quit
lines can expand the use of evidence-based tobacco cessation treatments in populations that may have
limited access to treatment options.
Combination therapy with counseling and medications is more effective at increasing cessation rates than
either component alone. The U.S. Food and Drug Administration has approved several forms of nicotine
replacement therapy (gum, lozenge, transdermal patch, inhaler, and nasal spray), as well as bupropion and
varenicline. More information on the treatment of tobacco dependence can be found in the U.S. Public
Health Service Reference Guide “Treating Tobacco Use and Dependence: 2008 Update” (available
The National Cancer Institute has developed a patient and physician guide for shared decision making for
lung cancer screening based on the NLST (available at www.cancer.gov/newscenter/qa/2002/NLSTstudyGuidePatientsPhysicians). This 1-page resource may be a
useful communication tool for providers and patients.
In addition, the National Comprehensive Cancer Network has developed guidelines for the follow-up of lung
nodules (7). The appropriate follow-up and management of
abnormalities found on LDCT scans are important given the high rates of false-positive results and the
potential for harms. Lung cancer screening with LDCT should be implemented as part of a program of care,
as outlined in the next section.
The NLST, the largest RCT to date with more than 50 000 patients, enrolled participants aged 55 to 74
years at the time of randomization who had a tobacco use history of at least 30 pack-years and were
current smokers or had quit within the past 15 years (4). The
USPSTF recommends extending the program used in the NLST through age 80 years. Screening should be
discontinued once the person has not smoked for 15 years.
The NLST enrolled generally healthy persons, and the findings may not accurately reflect the balance
of benefits and harms in those with comorbid conditions. The USPSTF recommends discontinuing screening
if a person develops a health problem that substantially limits life expectancy or the ability or
willingness to have curative lung surgery.
Clinicians will encounter patients who are interested in screening but do not meet the criteria of
high risk for lung cancer as described previously. The balance of benefits and harms of screening may
be unfavorable in these lower-risk patients. Current evidence is lacking on the net benefit of
expanding LDCT screening to include lower-risk patients. It is important that persons who are at lower
risk for lung cancer be aware of the potential harms of screening. Future improvements in risk
assessment tools will help clinicians better individualize patients’ risks (6).
All persons enrolled in a screening program should receive smoking cessation interventions. To be
consistent with the USPSTF recommendation on counseling and interventions to prevent tobacco use and
tobacco-related disease, persons who are referred to a lung cancer screening program through primary
care should receive these interventions before referral. Because many persons may enter screening
through pathways other than referral from primary care, the USPSTF encourages incorporating such
interventions into the screening program.
Shared decision making is important for the population for whom screening is recommended. The benefit
of screening varies with risk because persons who are at higher risk because of smoking history or
other risk factors are more likely to benefit. Screening cannot prevent most lung cancer deaths, and
smoking cessation remains essential. Lung cancer screening has substantial harms, most notably the
risk for false-positive results and incidental findings that lead to a cascade of testing and
treatment that may result in more harms, including the anxiety of living with a lesion that may be
cancer. Overdiagnosis of lung cancer and the risks of radiation are real harms, although their
magnitude is uncertain. The decision to begin screening should be the result of a thorough discussion
of the possible benefits, limitations, and known and uncertain harms.
The evidence for the effectiveness of screening for lung cancer with LDCT comes from RCTs done in
large academic medical centers with expertise in using LDCT and diagnosing and managing abnormal lung
lesions. Clinical settings that have high rates of diagnostic accuracy using LDCT, appropriate
follow-up protocols for positive results, and clear criteria for doing invasive procedures are more
likely to duplicate the results found in trials. The USPSTF supports adherence to quality standards
for LDCT (8) and establishing protocols to follow up abnormal
results, such as those proposed by the National Comprehensive Cancer Network (7). A mechanism should be implemented to ensure adherence to these standards.
In the context of substantial uncertainty about how best to manage individual lesions, as well as the
magnitude of some of the harms of screening, the USPSTF encourages the development of a registry to
ensure that appropriate data are collected from screening programs to foster continuous improvement
over time. The registry should also compile data on incidental findings and the testing and
interventions that occur as a result of these findings.
Smoking prevalence and lung cancer incidence are higher among socioeconomically disadvantaged
populations, and more research is needed in these groups. In addition, if lung cancer screening with LDCT
is implemented more widely in diverse community settings, it is important to evaluate whether variability
in follow-up protocols of positive results on LDCT scans results in a different balance of benefits and
harms than that observed in RCTs.
More research is also needed on the use of biomarkers to focus LDCT efforts in persons who are at highest
risk for lung cancer. The role of biomarkers in accurately discriminating between benign and malignant
nodules and in identifying more aggressive disease needs to be determined.
Lung cancer is the third most common cancer in the United States. Age-adjusted incidence rates per 100
000 persons are higher in men and vary according to the duration of and exposure to tobacco smoke. The
most important risk factor for lung cancer is smoking, which results in approximately 85% of all lung
cancer cases in the United States. Although the prevalence of smoking has decreased, approximately 37% of
U.S. adults are current or former smokers. In 2008, an estimated 7 million U.S. adults aged 55 to 75
years had a 30 pack-year or more smoking history (2).
The incidence of lung cancer increases with age and is most common in adults aged 55 years or older. Lung
cancer is the leading cause of cancer-related death in the United States, accounting for approximately
28% of all deaths from cancer. Death from lung cancer is often related to the initial stage of diagnosis.
The average 5-year survival rate for lung cancer is among the lowest (17%) of all types of cancer but is
higher when the disease is diagnosed at an early stage (52%). However, only 15% of lung cancer cases are
diagnosed at such a stage (2).
To update the 2004 recommendation, the USPSTF commissioned a systematic evidence review to assess the
efficacy of LDCT, chest radiography, and sputum cytologic evaluation for lung cancer screening in
asymptomatic persons who are at average or high risk for lung cancer (current or former smokers) (3). The review focused on new evidence from RCTs to determine the
effectiveness of these screening tests in improving health outcomes. Information about the harms
associated with these screening tests was obtained from RCTs and cohort studies. The benefits and harms
associated with surgical resection of early-stage NSCLC were also examined.
In addition to the evidence review, the USPSTF commissioned modeling studies from the Cancer Intervention
and Surveillance Modeling Network (CISNET) to provide information about the optimum age at which to begin
and end screening, the optimum screening interval, and the relative benefits and harms of different
screening strategies (9, 10). The modeling studies
complement the evidence from the systematic review.
The sensitivity of chest radiography for detecting lung cancer varies depending on the size and location
of the lesion, image quality of the scan, and skill of the radiologist who interprets the scan. Low-dose
computed tomography has emerged as a test with higher sensitivity and specificity for lung cancer than
chest radiography. In 2004, the USPSTF found inadequate evidence to recommend for or against screening
for lung cancer with LDCT, chest radiography, sputum cytologic evaluation, or a combination of these
tests (I statement). Since then, many RCTs have been done and published, resulting in more data on the
benefits and harms of screening. Recent data from the NLST showed a sensitivity of 93.8% and specificity
of 73.4% for LDCT and a sensitivity of 73.5% and specificity of 91.3% for chest radiography (11). Sputum cytologic evaluation is now rarely used for lung cancer
screening, and no studies reported on the test characteristics of this screening method.
Four RCTs reported the effectiveness of LDCT for lung cancer screening. The largest trial, the NLST,
showed a reduction in lung cancer mortality of 16% (95% CI, 5.0% to 25.0%) (12) and a reduction in all-cause mortality of 6.7% (CI, 1.2% to 13.6%) (4). This trial included more than 50 000 asymptomatic adults aged 55
to 74 years who had at least a 30 pack-year smoking history.
Participants were current or former smokers and were randomly assigned to LDCT or chest radiography. They
received annual testing at baseline and years 1 and 2 and were followed for a median of 6.5 years. After
6 to 7 years of follow-up, 2.06% of patients in the chest radiography group and 1.75% of those in the
LDCT group had died of lung cancer, for an absolute difference of 0.31% and a number needed to screen of
about 320 (4). The number needed to screen is based on 3 annual
screenings; screening the same sample over a longer period will result in a much lower estimate.
In contrast to the NLST, 3 small European trials showed potential harm or no benefit of screening. Two
small fair-quality trials, the DANTE (Detection and Screening of Early Lung Cancer by Novel Imaging
Technology and Molecular Essays) trial and the DLCST (Danish Lung Cancer Screening Trial), showed no
benefit associated with LDCT compared with no LDCT (13–15). However, these were smaller trials (n = 2472 and 4104,
respectively) that may have had limited power to detect a true benefit.
Of note, the inclusion criteria in the DLCST resulted in younger and healthier participants than in other
trials. The relative risk for all-cause mortality in the DLCST was 1.46 (CI, 0.99 to 2.15). This finding
raises the possibility of potential harm of screening a young, healthy population. Follow-up in the DLCST
was 4.7 years (15). Combined data from the DLCST and the NELSON
(Dutch–Belgian Randomised Lung Cancer Screening) trial will be reported soon (2).
When these 3 fair- or good-quality trials were combined in a meta-analysis, the relative risk for lung
cancer mortality was 0.81 (CI, 0.72 to 0.91) (2). Another
European trial, the MILD (Multicentric Italian Lung Detection) study, was rated as poor quality because
of concerns about the adequacy of randomization; its results were not included in the final meta-analysis
Two fair- to good-quality trials found no benefits associated with chest radiography screening (2). The larger of these trials, the PLCO (Prostate, Lung, Colorectal,
and Ovarian) Cancer Screening Trial, evaluated more than 150 000 participants from the general
population and found no benefits of this type of screening in this group or in a subgroup that had
tobacco smoke exposure (17).
Smaller RCTs from Europe had different eligibility criteria and have not yet duplicated the findings of
the NLST; therefore, only moderate certainty exists about the magnitude of benefit from screening (3). As with all screening trials, these studies were done over a
limited time frame, with the NLST evaluating the effect of 3 annual screenings. Modeling is required to
estimate the effect of screening beyond that evaluated in a clinical trial. Estimates of the results of
different screening intervals, ages at which to start and stop screening, and thresholds for smoking
history come from modeling studies that CISNET conducted for the USPSTF.
Annual screening with LDCT provides the greatest benefit in decreasing lung cancer mortality compared
with biennial or triennial screening (9, 10). The Table shows the results of annual screening strategies between the
ages of 55 and 80 years that had a better balance of benefits and harms than other strategies in this age
range. Focusing screening efforts on the highest-risk persons, those with at least a 40 pack-year smoking
history, results in the lowest number of screening scans per death averted and, therefore, the least harm
to patients in terms of risk for overdiagnosis and consequences of false-positive results.
Table. Screening Scenarios From CISNET Models
Screening progressively larger proportions of the population by lowering the screening threshold
increases the number of deaths averted but with a progressively higher number of screening scans per
death averted, therefore increasing harm. The Table shows that
increasing the proportion of the population screened from 13% to 36% increases the number of deaths
averted by 75% but increases the number of screening scans by 327%, greatly increasing the probability of
an untoward event after the evaluation of a false-positive result and the number of radiation-induced
cancer deaths. The “bolded” program—screening current or former smokers aged 55 to 80
years who have at least a 30 pack-year smoking history and discontinuing (or not starting) screening
after 15 years of smoking abstinence—most closely resembles the strategy applied to participants in
the NLST and offers a reasonable balance of benefits and harms.
The CISNET modeling studies show similar life-years gained per death averted and proportion of cancer
cases detected at an early stage across the screening strategies. The modeling studies estimate that 9.5%
to 11.9% of screen-detected cancer cases are overdiagnosed—that is, they would not have been
detected in the patient's lifetime without screening (9,
Harms associated with LDCT screening include false-negative and false-positive results, incidental
findings, overdiagnosis, radiation exposure, and psychological distress. The sensitivity of LDCT ranged
from 80% to 100%, suggesting a false-negative rate of 0% to 20%. The specificity of LDCT ranged from 28%
The positive predictive value for lung cancer of an abnormal test result ranged from 2% to 42% (2). As mentioned previously, the NLST is the largest trial of lung
cancer screening to date, and recent results showed a sensitivity of 93.8% and specificity of 73.4% for
LDCT. In the NLST, the positive predictive value for a positive finding of a pulmonary nodule measuring 4
mm or larger was 3.8% (11).
Over the 3 rounds of screening in the NLST, 24.2% of screening test results were positive; 96.4% of these
were false-positives. Most positive test results were followed by additional imaging. Approximately 2.5%
of positive test results required additional invasive diagnostic procedures, such as bronchoscopy, needle
biopsy, or thoracoscopy. Of the 17 053 positive test results evaluated, there were approximately 61
complications and 6 deaths after a diagnostic procedure. Recently published data from the first round of
screening in the NLST showed an average of 1 follow-up scan per positive screening test result.
Approximately 1.9% of NLST participants had a biopsy (11).
The most common incidental findings on LDCT were emphysema and coronary artery calcifications. Other
pulmonary findings included bronchiectasis, pulmonary fibrosis, carcinoid tumors, and hamartomas. The
NLST reported that 7.5% of non–lung cancer abnormalities were clinically significant. None of the
studies reported data on the evaluations that may have occurred in response to the incidental findings.
Therefore, the harms and benefits associated with incidental findings cannot currently be determined
Overdiagnosis was not formally reported in any study. The NLST found 119 more lung cancer cases in
approximately 26 000 participants in the LDCT group than in the chest radiography group after 6.5 years
of follow-up, which suggests some overdiagnosis. Recent data from the Italian Continuing Observation of
Smoking Subjects cohort study of approximately 5000 participants showed that of the 120 incident cancer
cases, 25% were slow-growing or indolent (based on volume-doubling time), thus possibly indicating some
overdiagnosis with LDCT (18).
Radiation exposure associated with LDCT ranged from 0.61 to 1.5 mSv per scan. To provide context, annual
background radiation exposure in the United States averages 2.4 mSv, radiation exposure from mammography
is 0.7 mSv, and radiation exposure from head computed tomography is 1.7 mSv. The risk for
radiation-induced lung cancer depends on the age at which a person begins screening and the amount of
cumulative radiation received. On the basis of modeling studies, starting annual LDCT screening before
age 50 years may result in more radiation-related lung cancer deaths than starting annual screening after
age 50 years (9, 10).
Overall, LDCT screening did not seem to result in substantial long-term psychological distress, although
assessment has been limited. No studies reported long-term differences in anxiety or distress levels
associated with LDCT in participants.
No RCTs compared treatment of stage IA or IB lung cancer with surgical resection versus no treatment.
Surgical resection is the standard of care in the United States for early-stage NSCLC. Studies of
symptomatic and unselected patients reported 5-year survival rates associated with surgical resection of
71% to 90% for stage IA cancer and 42% to 75% for stage IB cancer. No RCTs of LDCT screening evaluated
the harms associated with screen-detected cancer. Studies that reported the harms of surgical resection
were done in patients who were identified in clinical practice and had comorbid conditions (3).
On the basis of data from the systematic evidence review and modeling studies, the USPSTF determined with
moderate certainty that annual LDCT screening provides substantial net benefit in persons aged 55 to 80
years at high risk for lung cancer. Evidence from the NLST supports this recommendation because
participants in that trial were in this age range and had a similar degree of lung cancer risk from
cumulative tobacco exposure. Persons who do not meet the minimum eligibility criteria for the NLST may
have less net benefit and more harms from screening (persons aged 55 to 74 years at enrollment who have a
≥30 pack-year smoking history and are current smokers or have quit in the past 15 years). For these
persons, the absolute benefit of screening is strongly associated with their age and smoking history.
Modeling studies conducted by CISNET investigators for the USPSTF showed that annual LDCT screening
yielded the greatest net benefit (compared with biennial or triennial screening) (9, 10). Benefits were measured as percentage of early-stage detection of lung
cancer, percentage and absolute number of lung cancer deaths averted, and number of life-years gained.
Harms were measured as the number of total LDCT screenings per 100 000 persons and per person, number of
cases of overdiagnosed lung cancer, and number of radiation-induced lung cancer deaths. The
microsimulation models used standardized data on smoking history and non–lung cancer mortality to
simulate the effects of various screening programs on the mortality rate of a U.S. cohort born in 1950.
This cohort was chosen because these persons reach age 63 years (approximate midrange of
participants’ ages in the NLST) in 2013.
Modeling evidence suggests that an annual screening program starting at age 55 years and ending after age
80 years (in persons who have a 30 pack-year smoking history and currently smoke or have quit in the past
15 years) resulted in approximately 50% of lung cancer cases detected at an early stage (9, 10). This screening protocol would result in a 14% reduction
in lung cancer mortality, or an estimated 521 lung cancer deaths prevented per 100 000 persons in the
population. The harms associated with this screening protocol are an estimated overdiagnosis of 10% of
screen-detected cases and radiation-induced lung cancer deaths of less than 1%. As mentioned previously,
a person's absolute net benefit from screening may depend not just on age but functional status and the
presence of other comorbid conditions.
Lung cancer is a proliferation of malignant cells arising in the tissues or airways of the lungs. In
addition to age and exposure to tobacco smoke, other risk factors for lung cancer include family history;
chronic obstructive pulmonary disease; pulmonary fibrosis; and exposure to indoor cooking fumes, radon,
asbestos, arsenic, chromium, and coal tar. Non–small cell lung cancer is a heterogeneous category
that includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and undifferentiated
carcinoma. Adenocarcinoma is the most common subtype, encompassing 36% of all lung cancer cases.
Currently, 75% of patients with lung cancer present with symptoms of advanced local or metastatic disease
that result in a poor prognosis (2). At the earliest stage,
median 5-year survival for NSCLC is 77%. Patients with localized disease (defined as cancer limited to
the lung without metastasis to other organs or lymph nodes) have a median 5-year survival of 52% compared
with 25% for those with regional spread and 4% for those with distant metastasis. Thus, earlier detection
and treatment of lung cancer give patients a greater chance for cure.
A draft version of this recommendation statement was posted for public comment on the USPSTF Web site
from 30 July to 26 August 2013. Most of the comments generally agreed with the recommendation statement,
although some suggested restricting screening to a higher-risk group and others suggested expanding
eligibility criteria beyond those used in the NLST. Many comments expressed concerns about implementation
of a screening program, predicting substantially greater harm in the community setting than was found in
the NLST. Some comments expressed concern about the cost of implementing a screening program and the
potential paradoxical effect of enabling persons to continue smoking with the perception that medical
care can mitigate the risks of smoking.
In response to these comments, the USPSTF further emphasized the importance of tobacco cessation as the
primary way to prevent lung cancer and provided links to resources that clinicians can use to help their
patients quit smoking. A section on implementation of a screening program was added, emphasizing the need
for monitoring this implementation, quality assurance in diagnostic imaging, and appropriate follow-up to
replicate the benefits observed in the NLST in the general population. The USPSTF also clarified that, in
addition to age and smoking history, such risk factors as occupational exposure, family history, and
history of other lung diseases are important when assessing patients’ risks for lung cancer.
The USPSTF acknowledges the importance of accurately identifying persons who are at highest risk to
maximize the benefits and minimize the harms of screening and calls for more research to improve risk
assessment tools. The USPSTF did not incorporate the costs of a screening program or the potential
savings from a reduction in treatment of advanced lung cancer into the recommendation.
This recommendation updates the 2004 recommendation, in which the USPSTF concluded that the evidence was
insufficient to recommend for or against screening for lung cancer in asymptomatic persons with LDCT, chest
radiography, sputum cytologic evaluation, or a combination of these tests. In the current recommendation,
the USPSTF recommends annual screening for lung cancer with LDCT in persons who are at high risk based on
age and cumulative tobacco smoke exposure.
In 2012, the American College of Chest Physicians, the American Society of Clinical Oncology, and the
American Thoracic Society (19) recommended screening for lung
cancer with LDCT primarily on the basis of results from the NLST, using eligibility criteria that closely
modeled those of the NLST (persons aged 55 to 74 years who have a ≥30 pack-year smoking history and
currently smoke or have quit in the past 15 years). The recommendations also stipulated that screening
should be offered only in clinical settings similar to those in the trial.
The American Association for Thoracic Surgery (20) recommends
annual screening with LDCT in current and former smokers aged 55 to 79 years who have a 30 pack-year smoking
history. It also recommends annual screening starting at age 50 to 79 years in patients who have a 20
pack-year smoking history and additional comorbid conditions that produce a cumulative risk for cancer of at
least 5% over the next 5 years. Furthermore, it recommends annual screening in long-term cancer survivors
aged 55 to 79 years.
In 2013, the American Cancer Society (21) also began recommending
screening for lung cancer with LDCT in high-risk patients who are in relatively good health and meet the
NLST criteria (persons aged 55 to 74 years who have a ≥30 pack-year smoking history and currently
smoke or have quit in the past 15 years). It recommends against the use of chest radiography and strongly
suggests that all adults who receive screening enter an organized screening program that has experience in
In addition, the National Comprehensive Cancer Network (7)
recommends LDCT screening in selected patients who are at high risk for lung cancer. High risk is defined as
persons aged 55 to 74 years who have at least a 30 pack-year smoking history and, if a former smoker, 15
years or less since quitting or persons aged 50 years or older who have at least a 20 pack-year smoking
history and 1 additional risk factor. It does not recommend lung cancer screening in persons who are at
moderate risk (aged ≥50 years and ≥20 pack-year smoking history or secondhand smoke exposure but
no additional lung cancer risk factors) or low risk (younger than 50 years or smoking history of <20
Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized†
are Virginia A. Moyer, MD, MPH, Chair (American Board of Pediatrics, Chapel Hill, North
Carolina); Michael L. LeFevre, MD, MSPH, Co-Vice Chair (University of Missouri School of
Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Sinai
School of Medicine, New York, and James J. Peters Veterans Affairs Medical Center, Bronx, New York);
Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD,
MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University
of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens,
Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Francisco A.R. García,
MD, MPH (Pima County Department of Health, Tucson, Arizona); Adelita Gonzales Cantu, RN, PhD (University
of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health
Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania);
Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North
Carolina); Douglas K. Owens, MD, MS (Veterans Affairs Palo Alto Health Care System, Palo Alto, and
Stanford University, Stanford, California); William R. Phillips, MD, MPH (University of Washington,
Seattle, Washington); and Michael P. Pignone, MD, MPH (University of North Carolina, Chapel Hill, North
† For a list of current Task Force members, go to www.uspreventiveservicestaskforce.org/members.htm.
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Tanu Pramanik, Lecturer (1); Hj Abdul Halim Hj Mansar, Professor (1) ; Narazah Mohd. Yusoff, Professor (2); Jogenananda Pramanik, Professor (1)
(1) Allianze University College of Medical Sciences, Kepala Batas-13200, Pulau Pinang, Malaysia and, (2) Advanced Dental and Medical Institute, University Sains Malaysia, Kepala Batas-13200, Pulau P
January 14, 2014
Simple, cost effective, minimally invasive or non-invasive molecular screening test for lung cancer A need of the hour!
Lung cancer-related mortality is one of the most common causes of cancer death worldwide. Detecting lung cancer at an earlier stage and, ideally, predicting who will develop the disease and particularly the most aggressive forms of cancer are presenting a daunting challenge. We studied with interest and sincerely applauded the insightful reviews on the efficacy of low-dose computed tomography, chest radiography, and sputum cytologic evaluation for lung cancer screening in asymptomatic persons who are at average or high risk for lung cancer (current or former smokers) and the benefits and harms of these screening tests and of surgical resection of early-stage non–small cell lung cancer (1, 2, 3).
Despite batteries of advanced screening techniques available in this 21st century, lung cancer alone continues to be the third most common cancerous condition causing cancer-related deaths in the United States (1), and 75% of lung cancer patients report with symptoms of advanced local or metastatic disease that result in poor prognosis (2). While appreciating the recent initiative for an update of the U.S. Preventive Services Task Force (USPSTF) recommendation on screening for lung cancer, we accepted the crude reality that 95% of all low-dose-computerised tomography (LDCD) positive results do not necessarily lead to a diagnosis of cancer (1), and the harms associated with LDCD screening include false-negative and false-positive results, incidental findings, over-diagnosis, and risk of radiation exposure while false-positive LDCT results occur in a substantial proportion (4,5,6).
Since past two decades a considerable effort has been devoted to develop a cost effective non-invasive molecular screening test with higher predictive value to use for screening larger population at risk of lung cancer.
In recent years, a great potential has been documented in miRNA molecular profiling as a powerful diagnostic and prognostic biomarker in defining the signature of lung cancinogenesis. miRNA microarray analysis identified statistical unique profiles, which could discriminate lung cancers from noncancerous lung tissues as well as molecular signatures that differ in tumor histology (7).
MicroRNAs (miRNAs) are short, noncoding RNA molecules with regulatory function on protein-coding genes, and because of their fundamental role in development and differentiation, their involvement in the biological mechanisms underlying tumorigenesis, as well as their low complexity, stability, and easy detection, they represent a promising class of tissue- and blood-based biomarkers of cancer(8).
Two approaches are used to characterize miRNAs: studying expression of known miRNAs by hybridization-based techniques (e.g., northern blots, RNase protection, primer extension, real-time, quantitative PCR and microarrays) or discovery of novel miRNAs molecules by cloning and sequencing (9). various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell-free miRNAs could serve as non-invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets (10). Moreover, in a recent study, molecular researchers demonstrated that the profiling of 10-serum miRNAs provides a novel non-invasive biomarker for non-small cell lung Cancer (NSCLC) diagnosis (11).
“The 5-fold reduction in false positives obtained by combining the MicroRNA signature classifier (MSC) Lung Cancer assay to the results of the LDCT scan is of great clinical relevance in the context of reducing the false positive rate and the potential side effects associated with repeated LDCT scans or other unnecessary invasive diagnostic follow-ups,” stated Dr. Ugo Pastorino, Head of Thoracic Surgery Unit, Chairman of Department of Surgery, Istituto Nazionale dei Tumori, Milan, Italy (12).
1. Virginia A. Moyer, MD, MPH. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. Published online 31 December 2013 doi:10.7326/M13-2771
2. Humphrey L, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for Lung Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation Statement. Evidence synthesis no. 105. AHRQ publication no. 13-05196-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
3. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med. 2013;159:411-20. [PMID: 23897166]
4. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating over-diagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2012;157:776-84. [PMID: 23208167]
5. de Koning HJ, Plevritis S, Hazelton WD, ten Haaf K, Munshi V, Jeon J, et al. Benefits and Harms of Computed Tomography Lung Cancer Screening Programs for High-Risk Populations. AHRQ publication no. 13-05196-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
6. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 2012;307:2418-29. [PMID: 22610500]
7. Yanaihara N, Caplen N, Bowman E, et al., Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006 Mar;9(3):189-98.
8. Ahmed FE. Role of miRNA in carcinogenesis and biomarker selection: a methodological view. Expert Rev Mol Diagn. 2007 Sep;7(5):569-603.
9. Boeri M, Pastorino U, Sozzi G., Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J. 2012 May-Jun;18(3):268-74. doi: 10.1097/PPO.0b013e318258b743.
10. Chen X, Hu Z, Wang W, Ba Y, Ma L, et al., Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel non-invasive biomarkers for non-small cell lung cancer diagnosis. Int J Cancer. 2012 Apr 1;130(7):1620-8. doi: 10.1002/ijc.26177. Epub 2011 Aug 3.
11. Zandberga E, Kozirovskis V, Ābols A, et al., Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes Chromosomes Cancer. 2013 Apr;52(4):356-69. doi: 10.1002/gcc.22032. Epub 2012 Dec 10.
12. Ugo Pastorino ( Gensignia Ltd., London,UK), Simple blood test can detect lung cancer with high sensitivity and specificity. Journal of Clinical Oncology, January 13, 2014. (http://www.redorbit.com/news/health/1113045405/simple-blood-test-can-detect-lung-cancer-with-high-sensitivity/).
Steven B. Zeliadt, PhD MPH, David H Au, MD MS
VA Seattle, Washington
January 23, 2014
Discussing Gender Differences in the Efficacy of Lung Cancer Screening
The US Preventive Services Task Force provided a “B” level recommendation for annual low-dose computed tomography screening among at-risk individuals between ages 55-80. While the USPSTF recommended that clinicians should individualize decision making based on a patient’s lung cancer risk – primarily driven by cumulative exposure to tobacco smoke – USPSTF’s evidence review omitted critical recent data about gender differences in the efficacy of LDCT screening.1,2 The recent publication of updated outcomes of the National Lung Screening Trial (NLST) at 8 years by Pinksy et al.3 highlights significant differences between women and men. This report found 158 (1.44%) lung cancer deaths among women randomized to LDCT screening compared to 215 (1.96%) deaths in the comparison group, and 311 (1.97%) lung cancer deaths among men randomized to LDCT compared to 337 (2.14%) in the comparison group.While these differences do not necessarily mean that men are at higher risk of developing or dying from lung, they do suggest that men may not benefit as much as women from lung cancer screening. Based on these data, for women, the number needed to screen (NNS) to avoid one lung cancer death is 194, while for men this number jumps to 603. Put another way, for every 1000 eligible patients who undergo screening, 5.2 (95% CI 1.9 to 7.8) women are likely to benefit compared to 1.7 (95% CI -1.7 to 4.3) men. When these benefits are compared alongside the potential harms of screening, it is possible women and men may make different choices. For example, of the 1000 hypothetical individuals considering screening, nearly 250 will have some type of suspicious finding requiring repeat testing or invasive procedure, and around 11 will have a complication such as a pneumothorax. Given that NLST was conducted by large academic centers with expertise in radiology and cancer care, it is possible that these harms may be higher in the community.These differences by gender should not be surprising. Solitary pulmonary nodules are most often adenocarcinomas that also present more commonly in women.4,5 Although the reason is unknown, the implications are critical to the implementation and effectiveness of lung cancer screening in men. As we begin to individualize the discussions of screening with patients, these results suggest that we need to have different conversations about the risks and benefits of screening for women and men.Steven B. Zeliadt, PhD MPHInvestigator, Center of Innovation for Veteran-Centered and Value Driven Care, Seattle, WA.Steven.Zeliadt@VA.govDavid H Au, MD MSActing Director, Center of Innovation for Veteran-Centered and Value Driven Care, Seattle, WA.David.Au@VA.gov1. Moyer VA on behalf of USPSTF. Screening for lung cancer: U.S. Preventive Services Ann Intern Med. Dec 31; 2013 2. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, Zakher B, Fu R, Slatore CG. Screening for lung cancer with low-dose computed tomography: A systematic review to update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med. Sep 17;159(6):411-20; 20133. Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: Results Stratified by Demographics, Smoking History, and Lung Cancer Histology. Cancer. Aug 23; 20134. Fu JB, Kau TY, Severson RK, Kalemkerian GP. Lung cancer in women: Analysis of the National Surveillance Epidemiology, and End Results Database. Chest. 127(3): 768-777; 2005. 5. Gould MK, Fletcher J, Iannettoni MD, Lynch WR, Midthun DE, Naidich DP, Ost DE; American College of Chest Physicians. Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest Sep 132(3 Suppl): 108S-130S.
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