Download Computed Tomography Screening for Lung Cancer

CLINICAL CROSSROADS
CLINICIAN’S CORNER
CONFERENCES WITH PATIENTS AND DOCTORS
Computed Tomography Screening
for Lung Cancer
Phillip M. Boiselle, MD, Discussant
DR TESS: Ms L is a 64-year-old woman considering screening for lung cancer. She began smoking 1 to 2 cigarettes a
day at age 12 years. She eventually accumulated 30 packyears of smoking before successfully quitting when her father was diagnosed as having lung cancer in 1990. In 2003,
she enrolled in the National Lung Screening Trial (NLST)
and was randomized into the computed tomography (CT)
screening group of the study. Her baseline CT scan in 2003
showed numerous bilateral micronodules (⬍4 mm) that did
not meet study criteria for a positive screening result
(FIGURE 1). As part of the trial, she underwent 2 annual
screening CT scans, which showed no change in the micronodules and no new findings to suggest the presence of
lung cancer. Now that the trial has concluded, she is deciding whether to electively undergo continued CT screening.
Her medical history includes hypertension, restless legs
syndrome, bilateral knee replacements, and anxiety. She is
employed as a real estate agent and has health insurance.
She has no history of drug or alcohol abuse and reports no
history of occupational exposures. Her family history is remarkable for a mother who died of emphysema, a father who
died of lung cancer, and a brother who died of a gastrointestinal stromal tumor. Her medications include hydrochlorothiazide, oxycodone, and escitalopram. On a recent physical examination, her blood pressure was 120/78 mm Hg and
her pulse was 68/min. Her height is 5 ft 4 in and her weight
is 165 lb. The remainder of her physical examination results were normal.
MS L: HER VIEW
My father was diagnosed with lung cancer on June 26, 1990,
and he passed away 6 weeks later on August 15, 1990. It
happened so fast, and I made up my mind that he was not
going to die for nothing. So I quit smoking and I made my
husband quit. I felt that if his cancer had been diagnosed
earlier, then he may not have died. So, I volunteered for the
screening study because I thought it could help in understanding the disease.
The screening test the first year indicated that I had nodules, but they were very small, and consistently for the 2
CME available online at www.jamanetworkcme.com
and questions on p 1175.
Importance Low-dose computed tomography (CT) screening was shown to reduce lung cancer–specific mortality in a large
randomized trial of a high-risk population. The decision to pursue CT screening for lung cancer is a timely question raised by
individuals at risk of lung cancer and by their health care practitioners.
Objectives To discuss the evidence for use of chest x-rays and
low-dose CT in screening for lung cancer; to describe potential
benefits, harms, and uncertainties of CT screening; and to review current guidelines for CT screening.
Evidence Review MEDLINE and the Cochrane Library were
searched from 1984 to 2012. Additional citations were obtained from lists of references from select research and review
articles on this topic. Evidence was graded using the American
Hospital Association level of evidence guidelines.
Findings Low-dose CT screening has been associated with a
20% reduction in lung cancer mortality in a large randomized
controlled trial (National Lung Screening Trial [NLST]) of a
high-risk population. Mortality data have not yet been
reported for 5 other randomized controlled trials, and the
sample sizes were too small to detect a meaningful difference
in 2 other completed trials. A major risk of CT screening is a
high false-positive rate, with associated risks and costs associated with follow-up CT scans and the potential for more invasive diagnostic procedures. Published guidelines for screening
indicate a consensus that screening may be indicated for individuals who meet entry criteria for the NLST, but some guidelines expand their recommendations for screening beyond
these criteria.
Conclusions and Relevance Individuals at high risk of lung
cancer who meet the criteria for CT screening in published guidelines should participate in an informed and shared decisionmaking process by discussing the potential benefits, harms, and
uncertainties of screening with their physicians.
JAMA. 2013;309(11):1163-1170
www.jama.com
The conference on which this article is based took place at the Medicine Grand
Rounds at Beth Israel Deaconess Medical Center, Boston, Massachusetts, on January 19, 2012.
Author Affiliations: Dr Boiselle is Professor of Radiology and Associate Dean for
Academic and Clinical Affairs, Harvard Medical School, and Director, Center for
Airway Imaging, Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Corresponding Author: Phillip Boiselle, MD, Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, TCC-4, Boston, MA 02215
([email protected]).
Clinical Crossroads at Beth Israel Deaconess Medical Center is produced and edited by Risa B. Burns, MD, series editor; Tom Delbanco, MD, Howard Libman, MD,
Eileen E. Reynolds, MD, Marc Schermerhorn, MD, Amy N. Ship, MD, and Anjala
V. Tess, MD.
Clinical Crossroads Section Editor: Edward H. Livingston, MD, Deputy Editor, JAMA.
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
JAMA, March 20, 2013—Vol 309, No. 11 1163
CLINICAL CROSSROADS
Figure 1. Ms L’s Low-Dose CT Screening Scans for Lung Cancer
Baseline (2003)
Second screening (2006)
Baseline lung screening computed tomography (CT) scan from 2003 (left) demonstrates a 2-mm noncalcified nodule in the right lower lobe (arrowhead) that remained stable through the time of the second annual screening CT performed in
2006 (right). Computed tomography images are displayed in lung window settings and are coned down to highlight the right lower lung.
years after that there was no change in them. Since the study
has been over, I have been thinking about going back and
having another screening scan done. As a diagnostic tool, I
thought it was very good. It offers peace of mind. I am not
anxious at all about it. No matter what the diagnosis is, early
is much better than late.
I think there are probably some downsides. There are hoops
to go through because of society and the insurance companies. I have 2 daughters who work in the health care field, so
I know the cost is exorbitant. My insurance won’t pay for it. I
am in a position where I can pay. It is not okay for other people
who can’t afford it. It is a double-edged sword. You want to
know if you have cancer at an early stage because there is more
hope, and yet there is a cost to it. My question for my primary care doctor and for Dr Boiselle is, do they think it prudent for me to go forward and have another screening done?
AT THE CROSSROADS:
QUESTIONS FOR DR BOISELLE
What are the risk factors for lung cancer? What is the evidence for use of chest x-ray in the screening for lung cancer? What is the evidence for use of CT in the screening for
lung cancer? What are the associated risks and costs? What
do current guidelines recommend? What do you recommend for Ms L?
DR BOISELLE: Ms L is a healthy woman with 2 major risk
factors for lung cancer—a history of cigarette smoking and
a positive family history of lung cancer. She has undergone
low-dose CT screening in the past as part of a randomized
control trial, and her CT scans did not show evidence of lung
1164
JAMA, March 20, 2013—Vol 309, No. 11
cancer. Her decision as to whether to pursue further lung
cancer screening with CT is a timely question that is being
raised by an increasing number of individuals at risk of lung
cancer and by their health care practitioners.
LUNG CANCER PREVALENCE
AND RISK FACTORS
Lung cancer remains the leading cause of cancer deaths in
the United States and the world.1 In 2012, it was estimated
that there were more than 225 000 new cases of lung cancer and more than 160 000 deaths due to lung cancer in the
United States.1 The number of estimated lung cancer deaths
for 2012 surpassed the combined total of estimated deaths
from cancers of the breast, prostate, and colon.1
Although these numbers are relatively bleak, longitudinal
US cancer statistics show some progress. Between 2004 and
2008, the overall US cancer death rate declined by 2%.1 Among
men, 40% of this reduction can be attributed to the decline in
lung cancer mortality related to smoking reduction over the
last 50 years.1 A decline in lung cancer mortality among women
has also been observed, but this trend began more than a decade later among women than in men.1 This lag reflects historical differences in tobacco use, with cigarette smoking peaking among women 2 decades later than in men.1
The positive relationship between smoking trends and lung
cancer deaths relates to the fact that tobacco use is by far the
most important risk factor for lung cancer. It is estimated that
at least 85% of all lung cancers can be attributed to cigarette
smoking.2 Tobacco use remains the major modifiable risk factor for lung cancer, with an associated 20-fold relative increase
in risk of lung cancer.2,3 It is estimated that there are 94 million current and former smokers in the United States alone.
In fact, 45 million people (approximately 20% of the US population) are thought to be active smokers.4 Prolonged smoking
cessation markedly reduces the future rate of increase in risk
of developing lung cancer over time; however, the level of risk
never declines to that of a lifetime nonsmoker.5 For example,
a study from the United Kingdom showed that the cumulative risk of lung cancer by age 75 years among continuing
women smokers was 9.5% compared with 5.3% for women
who stopped smoking at age 60 years and 2.2% among those
who stopped at age 50 years.5 Thus, the most important advice
for current smokers is to stop smoking.6,7
Other risk factors for lung cancer include occupational
exposures, residential radon exposure, personal cancer history (particularly smoking-related cancers such as head and
neck cancer), family history of lung cancer, and chronic lung
diseases, including chronic obstructive pulmonary disease
and chronic interstitial lung disease (such as idiopathic pulmonary fibrosis).3,8
SCREENING FOR LUNG CANCER
WITH CHEST RADIOGRAPHS
Although chest radiographs have been studied as a potential lung cancer screening test for decades, they have not
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
CLINICAL CROSSROADS
shown a benefit in reducing lung cancer mortality.9-16 For
example, the Mayo Lung Project included 10 933 men
who were aged 45 years or older and smoked more than
1 pack of cigarettes daily who were randomized to 1 of 2
study groups. 10,11 The control group was assigned to
yearly chest radiograph and sputum cytology, which was
the standard of care at that time. The study group was
assigned to receive the same tests more frequently (every
4 months). Compared with the controls, the study group
had more cancers detected (206 vs 160), a higher resectability rate (46% vs 32%), and a 5-year survival benefit.
However, the death rates for the 2 groups were statistically similar (3.2 per 1000 person-years vs 3.0 per 1000
person-years), and there was no mortality benefit either
at the end of the trial or 15 years after completion of the
study.10,11
Reexamination of the data from the Mayo Lung Project
and other similar trials has raised issues regarding their
methods and low power.17 Because of the concern that a
positive effect of chest radiographic screening may have
been missed because of the small size of the study populations in prior trials, this topic was reexamined in the 1990s
in the Prostate, Lung, Colorectal, and Ovarian (PLCO)
Cancer Screening Trial.18 In this population-based study of
men and women aged 55 to 74 years, 154 901 participants
were randomly assigned to receive either annual chest
radiographs for 4 years or standard of care (no chest radiograph) and were followed up for approximately 12 years.
Participants in the 2 study groups were similar in terms of
smoking status, sex distribution, and age. At the end of the
study, the 2 groups demonstrated similar cumulative lung
cancer incidences (20.1 vs 19.2 per 10 000 person-years),
similar cumulative lung cancer mortality (n=1213 vs
n=1230), and similar stage and histologic findings of
detected lung cancers.
Relevant to Ms L, the PLCO study also included an
ancillary analysis that compared annual chest radiographs with standard of care in a subset of 15 183 participants who met entry criteria for the NLST (BOX 1). Cumulative lung cancer incidence and mortality rates were
similar between the 2 groups in this ancillary analysis, showing no benefit of chest radiographic screening in this highrisk cohort.18
The results of the PLCO trial, which was sufficiently powered to detect a 10% reduction in lung cancer mortality in
the intervention group, provide high-quality evidence that
screening with an annual chest radiograph for 4 years does
not reduce lung cancer mortality. Thus, there is no role for
chest radiography in screening for lung cancer.
SCREENING FOR LUNG CANCER
WITH LOW-DOSE CT
In the 1990s, researchers in the United States and Japan independently began looking at low-dose CT as a screening
tool for lung cancer. These studies were designed as single-
Box 1. Entry Criteria for National Lung Screening
Trial
Age 55-74 years
Smoking history
ⱖ30 Pack-years a
Former smokers must have quit within past 15 years
Exclusions
Previous lung cancer
Other prior cancer (except nonmelanoma skin cancer)
in past 5 years
Chest computed tomography within past 18 months
Hemoptysis
Unexplained weight loss ⬎15 lb in past year
Metallic implants or devices in chest or back
Requirement for home oxygen supplementation
Pneumonia or other acute respiratory tract infection
treated with antibiotics in past 12 weeks
a Pack-years refers to number of cigarette packs smoked per day
(20 cigarettes per pack) multiplied by the number of years of
smoking.
group studies in which low-dose CT was compared with chest
radiography in the same cohort.19-21 Despite differences in
study entry criteria, all 3 single-group cohort studies found
a strikingly high percentage (84%-93%) of CT screening–
detected stage 1 lung cancers (TABLE 1) among all screeningdetected cancers and a consistent superiority of CT over chest
radiography in the detection of cancers.19-21
Because these studies were not designed as randomized
clinical trials, they were unable to assess the influence of
CT screening on lung cancer mortality, the gold-standard
measure of a screening test. However, these and other early
studies22-24 effectively placed CT screening on the map and
laid the groundwork for the NLST, the largest randomized
controlled lung cancer screening trial ever performed.25 This
study was designed to answer the question of whether lung
cancer screening using low-dose helical CT can reduce lung
cancer–specific mortality relative to screening with chest radiographs in a high-risk cohort.
As a participant in the NLST, Ms L was randomized to
the CT group of the trial and underwent low-dose CT at baseline and annually thereafter for 2 years. Particularly relevant to Ms L’s experience in the study, the NLST defined a
positive screening study result as a nodule measuring at least
4 mm in diameter.25,26 This criterion was based on a growing body of evidence that suggested that nodules less than
4 mm in diameter are very likely benign, even when detected in a patient at high risk for lung cancer.27,28 Based on
this criterion, Ms L’s scans were interpreted as negative for
lung cancer.
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
JAMA, March 20, 2013—Vol 309, No. 11 1165
CLINICAL CROSSROADS
The NLST results were officially announced in 2010 and
published in 2011.26 A total of 1060 lung cancers were diagnosed in the CT group compared with 941 in the radiography group. There were nearly twice as many very earlystage (1A) cancers detected in the CT group (40%) compared
with the chest radiography group (21%).28 It should be noted
that the percentage of stage 1A and 1B lung cancers detected by CT in the NLST was substantially lower than that
reported in the early lung screening trials highlighted in
Table 1 (50% compared with 85%-93%).
With regard to lung cancer–specific mortality, among participants who underwent at least 1 screening test, there were
346 lung cancer deaths among 26 455 participants (1.3%)
in the CT group compared with 425 deaths among 26 232
participants (1.6%) in the radiography group.26 The overall rates of lung cancer death were 247 and 309 deaths per
100 000 participants in the CT and radiography groups, respectively. This represents a 20% reduction in lung cancer
mortality in the CT screening group (95% CI, 6.8%-26.7%;
P=.004) and a number needed to screen of 320 patients to
prevent 1 lung cancer death.26
What are the implications of the NLST? First, this study
has shown that in selected individuals at high risk of lung
cancer, CT screening reduces lung cancer mortality by 20%.
Second, it has demonstrated that CT screening is relatively
safe. However, before public policy decisions about widespread screening can be addressed, several important questions remain to be answered. First, how does CT screening
influence utilization of medical resources? Second, what is
the added monetary cost due to CT screening and what are
the quality-adjusted life-years gained by screening? Third, how
does the process of CT screening influence participants’ quality of life and smoking habits? These questions will be addressed by forthcoming publications from the NLST.
There are also several outstanding questions that the NLST
was not designed to directly answer. These questions include (1) Will other populations at risk of lung cancer benefit from CT screening? (2) Will less frequent screening regimens be equally effective as annual screening? (3) How long
should screening continue? and (4) Will the NLST results
be reproducible in community hospital settings?26 Some of
these questions will be addressed by computer modeling of
the NLST data27 and others will be addressed by pooling of
results of several ongoing screening trials in Europe.29-34
TABLE 2 provides an overview of enrollment, entry criteria,
and available published mortality data for completed and
ongoing randomized control trials of low-dose CT screening for lung cancer.
Table 1. Early Low-Dose Computed Tomography Screening Studies
No./Total (%)
Source
Kaneko et al,19 1996
Patients
1369
Sone et al,20 1998
5483
Henschke et al,21 1999
1000
Enrollment Criteria
⬎20 Pack-years of smoking
Aged ⬎50 y
Smokers and nonsmokers enrolled
Aged 40-74 y
⬎10 Pack-years of smoking
Aged ⬎60 y
No. of Detected
Lung Cancers
15
Lung Cancer
Prevalence
15/1369 (1)
Stage I Cancers
14/15 (93)
19
19/5483 (0.5)
16/19 (84)
27
27/1000 (2.7)
23/27 (85)
Table 2. Randomized Controlled Trials of Computed Tomography Screening for Lung Cancer a
Reported No. Randomized
Entry Criteria
DANTE
Dépiscan
DLCST
DVAFS
ITALUNG
Computed
Tomography
1276
385
2052
92
1613
Control
1196
380
2052
98
1593
Age Range, y
60-74
47-76
50-70
50-80
55-69
Smoking
Pack-Years b
ⱖ20
ⱖ15
ⱖ20
ⱖ30
ⱖ20
Years Since
Quitting Smoking
⬍10
⬍15
⬍10
NR
⬍10
Mortality
Reduction, % c
NSD d
NR
NSD d
NR
NR
LSS
NELSON
NLST
1660
7907
26 722
1658
7915
26 732
55-74
50-75
55-74
ⱖ30
⬎15
ⱖ30
⬍10
ⱕ10
⬍15
NR
NR
20
Trial
Abbreviations: DANTE, Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays; DLCST, Danish Lung Cancer Screening Trial; DVAFS,
Denver Veterans Administration Feasibility Study; LSS, Lung Screening Study; NELSON, Dutch Belgian Randomized Lung Cancer Screening Trial; NLST, National Lung Screening Trial; NR, not reported; NSD, no significant difference.
a Data are from Bach et al.35
b Pack-years refers to number of cigarette packs smoked per day (20 cigarettes per pack) multiplied by the number of years of smoking.
c Mortality reduction refers to reduction in lung cancer–specific mortality in the computed tomography group compared with the control group.
d Although no significant difference in lung cancer mortality was observed between the 2 study groups, the study size and length of follow-up were not sufficient to detect a clinically
meaningful reduction in lung cancer mortality.
1166
JAMA, March 20, 2013—Vol 309, No. 11
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
CLINICAL CROSSROADS
RISKS AND COSTS OF LOW-DOSE
CT SCREENING FOR LUNG CANCER
The risks of low-dose CT screening for lung cancer are summarized in BOX 2. First and foremost, a false-positive result (defined as a positive screening study result that was
later found to not represent lung cancer) is the most common risk associated with CT screening for lung cancer. As
described in detail later in this section, false-positive results are significant because of associated risks and costs associated with follow-up CT scans and the potential for more
invasive diagnostic procedures.
In the NLST CT group, almost 40% of participants had
at least 1 positive CT result during the study. Notably, more
than 96% of the positive test results in the CT group of the
NLST were false-positive for lung cancer. Most participants with positive study results were followed up noninvasively by CT, but a small percentage underwent more invasive diagnostic testing, including percutaneous needle
biopsy, and bronchoscopic and surgical procedures
(FIGURE 2).26 It is reassuring that complications related to
diagnostic evaluation of positive screening results were uncommon (1.4% in the CT group and 1.6% in the radiography group) and that deaths were rare. Although surgery for
benign disease was rare in the NLST,26 a higher frequency
has been reported in other screening studies.22,36
Although Ms L underwent a baseline and 2 annual screening CT scans without a positive screening result, she is still
at risk of false-positive results should she undergo additional CT screening. Additionally, there is the possibility that
a lung cancer may be missed by CT (false-negative result).37
Second, anxiety is an important consideration for individuals such as Ms L who are contemplating CT screening.
For example, the period of waiting for results of screening
studies has been shown to be a source of short-term anxiety for almost half of all low-dose CT screening participants in an ongoing European lung cancer CT screening
trial (NELSON).38 Although the news of a “negative” scan
result has the potential to bring relief or peace of mind to
participants such as Ms L, indeterminate low-dose CT
screening results have been associated with a short-term
increase in lung cancer–specific distress in NELSON.37 In
addition to anxiety, false-positive results from a variety of
different cancer screening tests have been shown to be
associated with depression and changes in the overall perception of one’s health status.39 Quantification of such psychological costs of CT screening is an important aspect of
the NLST design, and this data will be shared in a future
publication.25
A third potential risk is radiation exposure. When considering this factor, it is important to keep in mind that the
exposures associated with CT screening are very low and
generally considered safe. For example, the mean effective
dose per scan in the NLST was 1.4 mSv, which is less than
half of annual background exposure from living in the United
States and represents about one-fifth the dose of a diagnos-
Box 2. Risks Associated With Low-Dose
Computed Tomography Screening
False-positive and false-negative results
Anxiety
Potential unnecessary testing
Radiation exposure
Financial costs
Overdiagnosis
tic chest CT scan.26 Ms L’s cumulative exposure from participation in the NLST is estimated at 4.2 mSv, which is about
half the estimated total exposure for all NLST participants
(many of whom underwent ⱖ1 follow-up diagnostic CT or
positron emission tomography–CT scans).35 For patients such
as Ms L and others with similar lung cancer risk profiles,
the potential benefits of CT screening outweigh the small
risk of cancer deaths related to cumulative radiation exposure.35 However, the risk-benefit ratio is less favorable for
persons at very low risk of lung cancer and those of relatively young age.35
A fourth concern is the possibility of overdiagnosis, a term
that refers to detection of indolent cancers that may never
have become symptomatic and would not have been detected outside of a screening program.26,35,39 Because current technology does not allow for accurately distinguishing between cancers that a patient will die of and those that
a patient is likely to die with, potentially curable lung cancers detected by screening are treated surgically, with the
associated risks and morbidity.
For example, prior chest radiography screening studies
for lung cancer have an estimated overdiagnosis rate of approximately 25%.35 Because the period of follow-up in the
NLST was not sufficient to quantify overdiagnosis, further
follow-up is needed to determine the magnitude of this issue.26
With regard to financial costs of CT screening, the Medicare reimbursement rate of $300 for a CT scan has been used
as a benchmark rate for low-dose CT screening studies performed on a self-pay basis.40 The Medicare contract rates vary
geographically but are much lower than the out-of-pocket
charges for a self-pay diagnostic CT scan performed outside of the screening setting.
The cost of self-pay CT screening is reportedly not a significant barrier to Ms L, but as she notes, it could pose a
significant challenge to other patients. Until broad coverage for CT screening is available by insurers and other payers, one of the greatest barriers to implementation of CT
screening is the ability to provide it to individuals at risk
across all socioeconomic strata.41
The cost of the screening CT scan is only a small part of
the overall costs related to screening, which has substantial
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
JAMA, March 20, 2013—Vol 309, No. 11 1167
CLINICAL CROSSROADS
eagerly awaited NLST cost-effectiveness analysis will provide a more realistic estimate of costs associated with CT
screening.
downstream costs related to workup of positive screening
results and treatment-related costs for detected cancers,
among other economic factors. To date, estimates of the
cost-effectiveness of low-dose CT screening have relied on
decision analysis modeling, with varying estimates of costs
ranging from less than $50 000 to more than $2 000 000
per quality-adjusted life-year gained.42-44 Such variability
relates to different assumptions regarding the risk level of
the population being screened, adherence to screening,
smoking cessation efforts, and other measures.42-44 The
CURRENT GUIDELINES FOR CT SCREENING
FOR LUNG CANCER
In 2011, following the publication of the NLST results, the
American Cancer Society (ACS) issued interim guidelines
for lung cancer screening, which have recently been published as formal guidelines.45 In these guidelines, the ACS
recommends that physicians should initiate a discussion
about lung cancer screening with patients who meet NLST
criteria (Box 1). This discussion should include a review of
the potential benefits and harms and current uncertainties
about screening. These guidelines also state that CT screening is not recommended at this time for individuals who do
not meet the NLST entry criteria. Similar recommendations have recently been put forth in a set of clinical practice guidelines developed by the American College of Chest
Physicians (ACCP) and American Society of Clinical
Oncology (ASCO) with input from the American Thoracic
Society.35
Two sets of practice guidelines expand the recommendations for screening beyond the NLST entry criteria. The
first is a wide-ranging set of CT screening guidelines offered by the National Comprehensive Cancer Network
(NCCN), a consortium of 21 cancer centers in the United
States.3 The NCCN recommends CT screening for 2 groups
of patients at high risk of lung cancer. The first group is individuals who meet the entry criteria for the NLST. For this
Figure 2. Example of a False-Positive CT Lung Screening Result
Low-dose CT screening scans
2003
2004
Annual screening low-dose computed tomography (CT) scans from 2003 (left) and
2004 (right) from a patient at risk for lung cancer. The scan from 2004 shows a
spiculated right lung nodule (arrowhead) that was not present in 2003. Because
of high suspicion of primary lung cancer, this nodule was further evaluated by a
series of tests, including positron emission tomography–CT, CT-guided needle biopsy, and follow-up CT imaging. The nodule eventually resolved on follow-up CT
imaging.
Table 3. Computed Tomography Screening Recommendations
Other Populations for Screening
Primary Population for Screening
AHA Level of Evidence a
Recommendations
Aged 55-79 y
ⱖ30 Pack-years of smoking
B
American College of
Chest Physicians
(ACCP) and American
Society of Clinical
Oncology (ASCO)
American Cancer Society
Aged 55-74 y
ⱖ30 Pack-years of smoking
Former smokers must have
quit within past 15 y
Bc
Aged ⱖ50 y
ⱖ20 Pack-years of smoking
Additional risk factor(s) b
or
Lung cancer survivor ⱖ5 y
NR
Aged 55-74 y
ⱖ30 Pack-years of smoking
Former smokers must have
quit within past 15 y
B
NR
NA
Aged 55-74 y
ⱖ30 Pack-years
Former smokers must have
quit within past 15 y
B
Aged ⱖ50 y
ⱖ20 Pack-years of smoking
Additional risk factor(s) d
B
National Comprehensive
Cancer Network
(NCCN)
Recommendations
AHA Level of Evidence a
B
Organizations
American Association for
Thoracic Surgery
(AATS)
C
NA
Abbreviations: NA, not applicable; NR, not recommended for other populations.
a American Hospital Association (AHA) level of evidence: A, multiple populations evaluated; data derived from multiple randomized trials or meta-analysis; B, limited populations
evaluated; data derived from single randomized trial or nonrandomized studies; C, very limited populations evaluated; only consensus opinion of experts, case studies, or standard of care.
b Additional risk factors for lung cancer defined by AATS include chronic obstructive pulmonary disease, environmental and occupational exposures, any prior cancer or thoracic
radiation, and genetic or family history.
c Although ACCP and ASCO evaluated more than 1 randomized trial, their recommendations are graded B because they were based on a single randomized trial (other studies
were deemed “too small, too preliminary, or too poorly designed to support meaningful conclusions”).47
d Additional risk factors for lung cancer defined by NCCN include cancer history, lung disease history, family history of lung cancer, radon exposure, and occupational exposure.
1168
JAMA, March 20, 2013—Vol 309, No. 11
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
CLINICAL CROSSROADS
group, there is uniform NCCN consensus that intervention (CT screening) is appropriate. The second group is individuals aged 50 years or older with at least a 20-packyear smoking history plus 1 other defined risk factor (cancer
history, lung disease history, family history of lung cancer,
radon exposure, or occupational exposure).3 For this group,
there is nonuniform NCCN consensus that intervention (CT
screening) is appropriate.
The second is a set of guidelines by the American Association of Thoracic Surgeons (AATS).46 This group has modified the NLST entry criteria by removing the stipulation about
duration of smoking cessation from the NLST entry criteria to focus solely on age and overall tobacco exposure, which
the group considers to be the primary risk generators.46 Computed tomography screening guidelines from the AATS and
other organizations are summarized in TABLE 3.
RECOMMENDATIONS FOR MS L
Because of Ms L’s long-standing success at smoking cessation, she no longer meets strict entry criteria for the NLST.
Thus, if consideration is given only to clinical practice guidelines that rely solely on NLST entry criteria, such as those
issued by the ACS, ACCP, and ASCO,35,45 Ms L is no longer
considered a candidate for screening.
Notably, because the NLST criteria were not originally
designed for the purpose of clinical guidelines, they do not
allow for a consideration of the contribution of increased
risk based on her advancing age since the time she entered
that study.46 In the future, it is likely that individualized lung
cancer risk prediction will allow for a more personalized decision-making approach when weighing the potential benefits and risks of screening.48
Currently, however, based on Ms L’s age, cumulative
smoking history, and family history of lung cancer, CT
screening is still considered an appropriate, albeit less strong,
recommendation under the NCCN guidelines.3 Moreover,
her age and cumulative smoking history also qualify her for
screening based on guidelines from the AATS.46
Given that Ms L meets CT screening criteria for some but
not all available guidelines for screening, and in the absence of current recommendations from the US Preventive
Services Task Force (USPSTF), I believe that it is appropriate for her to carefully consider CT screening after cautiously weighing the risks and benefits with her primary care
physician. In this conversation, it should also be emphasized that the most effective frequency and duration of screening are currently unknown.
If she chooses to undergo screening, she should select a
site with experience in CT screening using a low-dose protocol and with access to a multidisciplinary team of lung
cancer specialists.3,49,50 Because it is uncertain whether the
results of the NLST can be replicated in the community,
screening should ideally be performed in academic centers
similar to those where the NLST was conducted.35
QUESTIONS AND DISCUSSION
QUESTION: What is the degree of agreement among CT radiologists when reading screening CT scans?
DR BOISELLE: Although there is substantial interreader variability in the detection of small nodules, there is less variability for larger nodules. Two studies addressing various
aspects of interobserver agreement in the interpretation of
screening CT scans from the Lung Screening Study and the
NLST have shown moderate to substantial agreement at baseline and annual screening.51,52 Several new technologies offer the opportunity to improve reader agreement in the future, including computer-aided detection programs and
volumetric nodule measurement software programs, among
others.53,54
QUESTION: Many primary care clinicians look to the
USPSTF to answer screening questions. Have they weighed
in yet?
DR BOISELLE: The most recent USPSTF guidelines from
2004 state that there is insufficient evidence to recommend for or against screening for lung cancer with lowdose CT, radiography, sputum cytology, or a combination
of these tests. An updated recommendation is anticipated,
but the evidence review process for this recommendation
is currently ongoing. Public policy decisions about widespread screening such as the USPSTF guidelines will await
the publication of NLST data regarding cost-effectiveness
of CT screening and its effect on quality of life. These publications are anticipated later in 2013.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest and none were reported.
Additional Contribution: We thank the patient for sharing her story and for providing permission to publish it and James Ravenel, MD, Medical University of South
Carolina, for his review of a draft of the manuscript. No compensation was received.
REFERENCES
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin.
2012;62(1):10-29.
2. Paoletti L, Jardin B, Carpenter MJ, Cummings KM, Silvestri GA. Current status
of tobacco policy and control. J Thorac Imaging. 2012;27(4):213-219.
3. Wood DE, Eapen GA, Ettinger DS, et al. Lung cancer screening. J Natl Compr
Canc Netw. 2012;10(2):240-265.
4. Centers for Disease Control and Prevention. Vital signs: current cigarette smoking among adults aged ⱖ18 years—United States, 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212.
5. 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 2 case-control studies. BMJ. 2000;321(7257):323-329.
6. Schroeder SA. How clinicians can help smokers to quit. JAMA. 2012;308
(15):1586-1587.
7. Livingston EH, Lynm C. Smoking cessation. JAMA. 2012;308(15):1599.
8. Matakidou A, Eisen T, Houlston RS. Systematic review of the relationship
between family history and lung cancer risk. Br J Cancer. 2005;93(7):825833.
9. Boucot KR, Weiss W. Is curable lung cancer detected by semiannual screening?
JAMA. 1973;224(10):1361-1365.
10. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR.
Lung cancer screening: the Mayo program. J Occup Med. 1986;28(8):746750.
11. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic
study. Am Rev Respir Dis. 1984;130(4):561-565.
12. Melamed MR, Flehinger BJ, Zaman MB, Heelan RT, Perchick WA, Martini N.
Screening for early lung cancer: results of the Memorial Sloan-Kettering study in
New York. Chest. 1984;86(1):44-53.
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013
JAMA, March 20, 2013—Vol 309, No. 11 1169
CLINICAL CROSSROADS
13. Tockman MS. Survival and mortality from lung cancer in a screened population: the Johns Hopkins Study. Chest. 1986;89(4)(suppl):324S-325S.
14. Kubı́k A, Polák J. Lung cancer detection: results of a randomized prospective
study in Czechoslovakia. Cancer. 1986;57(12):2427-2437.
15. Kubı́k A, Haerting J. Survival and mortality in a randomized study of lung cancer detection. Neoplasma. 1990;37(4):467-475.
16. Ebeling K, Nischan P. Screening for lung cancer—results from a case-control
study. Int J Cancer. 1987;40(2):141-144.
17. Strauss GM, Gleason RE, Sugarbaker DJ. Chest x-ray screening improves outcome in lung cancer: a reappraisal of randomized trials on lung cancer screening.
Chest. 1995;107(6)(suppl):270S-279S.
18. Oken MM, Hocking WG, Kvale PA, et al; PLCO Project Team. Screening by
chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and
Ovarian (PLCO) randomized trial. JAMA. 2011;306(17):1865-1873.
19. Kaneko M, Eguchi K, Ohmatsu H, et al. Peripheral lung cancer: screening and
detection with low-dose spiral CT vs radiography. Radiology. 1996;201(3):
798-802.
20. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile
spiral computed tomography scanner. Lancet. 1998;351(9111):1242-1245.
21. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action
Project: overall design and findings from baseline screening. Lancet. 1999;
354(9173):99-105.
22. Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: 5-year
prospective experience. Radiology. 2005;235(1):259-265.
23. Nawa T, Nakagawa T, Kusano S, Kawasaki Y, Sugawara Y, Nakata H. Lung
cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest. 2002;122(1):15-20.
24. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer
with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology. 2002;
222(3):773-781.
25. Aberle DR, Berg CD, Black WC, et al; National Lung Screening Trial Research
Team. The National Lung Screening Trial: overview and study design. Radiology.
2011;258(1):243-253.
26. Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
27. Henschke CI, Yankelevitz DF, Naidich DP, et al. CT screening for lung cancer:
suspiciousness of nodules according to size on baseline scans. Radiology. 2004;
231(1):164-168.
28. MacMahon H, Austin JH, Gamsu G, et al; Fleischner Society. Guidelines for
management of small pulmonary nodules detected on CT scans: a statement from
the Fleischner Society. Radiology. 2005;237(2):395-400.
29. van Iersel CA, de Koning HJ, Draisma G, et al. Risk-based selection from the
general population in a screening trial: selection criteria, recruitment and power
for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial
(NELSON). Int J Cancer. 2007;120(4):868-874.
30. Pedersen JH, Ashraf H, Dirksen A, et al. The Danish randomized lung cancer
CT screening trial—overall design and results of the prevalence round. J Thorac
Oncol. 2009;4(5):608-614.
31. Lopes Pegna A, Picozzi G, Mascalchi M, et al; ITALUNG Study Research Group.
Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer. 2009;64(1):34-40.
32. Infante M, Cavuto S, Lutman FR, et al; DANTE Study Group. A randomized
study of lung cancer screening with spiral computed tomography: 3-year results
from the DANTE trial. Am J Respir Crit Care Med. 2009;180(5):445-453.
33. Becker N, Delorme S, Kauczor H-U. LUSI: the German component of the European trial on the efficacy of multi-slice CT for the early detection of lung cancer
[abstract]. Onkologie. 2008;31(suppl 1):PO320.
34. Baldwin DR, Duffy SW, Wald NJ, Page R, Hansell DM, Field JK. UK Lung Screen
(UKLS) nodule management protocol: modelling of a single screen randomised
controlled trial of low-dose CT screening for lung cancer. Thorax. 2011;66
(4):308-313.
35. Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for
lung cancer: a systematic review. JAMA. 2012;307(22):2418-2429.
36. Infante M, Chiesa G, Solomon D, et al; DANTE Study Group. Surgical procedures in the DANTE trial, a randomized study of lung cancer early detection with
spiral computed tomography: comparative analysis in the screening and control
arm. J Thorac Oncol. 2011;6(2):327-335.
37. Li F, Sone S, Abe H, MacMahon H, Armato SG III, Doi K. Lung cancers
missed at low-dose helical CT screening in a general population: comparison of
clinical, histopathologic, and imaging findings. Radiology. 2002;225(3):673683.
38. van den Bergh KA, Essink-Bot ML, Bunge EM, et al. Impact of computed tomography screening for lung cancer on participants in a randomized controlled
trial (NELSON trial). Cancer. 2008;113(2):396-404.
39. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol. 2010;37(3):202-215.
40. White CS. National Lung Screening Trial: a breakthrough in lung cancer
screening? J Thorac Imaging. 2011;26(2):86-87.
41. Aberle DR, Henschke CI, McLoud TC, Boiselle PM. Expert opinion: barriers to
CT screening for lung cancer. J Thorac Imaging. 2012;27(4):208.
42. Wisnivesky JP, Mushlin AI, Sicherman N, Henschke C. The cost-effectiveness
of low-dose CT screening for lung cancer: preliminary results of baseline screening.
Chest. 2003;124(2):614-621.
43. Mahadevia PJ, Fleisher LA, Frick KD, Eng J, Goodman SN, Powe NR. Lung
cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA. 2003;289(3):313-322.
44. Chirikos TN, Hazelton T, Tockman M, Clark R. Screening for lung cancer with
CT: a preliminary cost-effectiveness analysis. Chest. 2002;121(5):1507-1514.
45. Wender R, Fontham ET, Barrera E, et al. American Cancer Society lung cancer screening guidelines [published online January 11, 2013]. CA Cancer J Clin.
doi:10.3322/caac.21172.
46. Jaklitsch MT, Jacobson FL, Austin JHM, 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. J Thorac
Cardiovasc Surg. 2012;144(1):33-38.
47. van den Bergh KA, Essink-Bot ML, Borsboom GJJM, et al. Short-term healthrelated quality of life consequences in a lung cancer CT screening trial (NELSON).
Br J Cancer. 2010;102(1):27-34.
48. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Intern Med.
2012;157(8):571-573.
49. Donnelly EF. Technical parameters and interpretive issues in screening computed tomography scans for lung cancer. J Thorac Imaging. 2012;27(4):224229.
50. Wood DE. Maximizing the benefit and minimizing the risks of lung cancer
screening. J Thorac Imaging. 2012;27(4):211-212.
51. Gierada DS, Pilgram TK, Ford M, et al. Lung cancer: interobserver agreement
on interpretation of pulmonary findings at low-dose CT screening. Radiology. 2008;
246(1):265-272.
52. Singh S, Pinsky P, Fineberg NS, et al. Evaluation of reader variability in the
interpretation of follow-up CT scans at lung cancer screening. Radiology. 2011;
259(1):263-270.
53. van Klaveren RJ. Is CT screening for lung cancer ready for prime time? J Thorac Imaging. 2011;26(1):4-5.
54. Armato SG III, Li F, Giger ML, MacMahon H, Sone S, Doi K. Lung cancer:
performance of automated lung nodule detection applied to cancers missed in a
CT screening program. Radiology. 2002;225(3):685-692.
Author in the Room
Join Dr Boiselle, author of this article, on Wednesday, April 17, from 2 to 3
PM eastern time for “Author in the Room,” an interactive teleconference. Author in the Room is brought to you by JAMA and the Institute for Healthcare
Improvement. To register for Author in the Room, please visit http://www
.ihi.org/authorintheroom. You can listen to past conferences or subscribe to
the podcast at http://jama.jamanetwork.com/multimedia.aspx#Teleconferences.
1170
JAMA, March 20, 2013—Vol 309, No. 11
©2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Anne Arundel Medical Center User on 04/04/2013