Screening for Lung Cancer
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Transcript of Screening for Lung Cancer
03-05-12 Screening for lung cancer
1/25www.uptodate.com/contents/screening-for-lung-cancer?view=print
Official reprint from UpToDate® www.uptodate.com
©2012 UpToDate®
AuthorsMark E Deffebach, MDLinda Humphrey, MD
Section EditorsRobert H Fletcher, MD, MScJames R Jett, MD
Deputy EditorH Nancy Sokol, MD
Screening for lung cancer
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2012. | This topic last updated: mar 29, 2012.
INTRODUCTION — Lung cancer is the leading cause of cancer-related death among men and women and second
leading cause of cancer in the United States. Worldwide, lung cancer and lung cancer-related deaths have been
increasing in epidemic proportions, largely reflecting increased rates of smoking [1,2]. In the year 2012, the
American Cancer Society predicts that there will be approximately 226,160 new cases of lung cancer diagnosed
and approximately 160,340 lung cancer-associated deaths in the US [3]. Worldwide, it is estimated that there were
1.4 million deaths in the year 2008 [4].
Unfortunately, 75 percent of patients with lung cancer present with symptoms due to advanced local or metastatic
disease that is not amenable to cure [5]. Despite advances in therapy, five-year survival rates average approximately
16 percent for all individuals with lung cancer [6].
Prevention, rather than screening, is the most effective strategy for reducing the burden of lung cancer. The
promotion of smoking cessation is essential, as cigarette smoking is felt to be causal in almost 90 percent of all
lung cancer [1]. Progress in smoking cessation is now reflected in declining lung cancer rates and mortality in men
in the US. However, the smoking rate in the US remains high at 24 percent and is increasing in many parts of the
world [1]. A high percentage of lung cancer occurs in former smokers, since the risk for lung cancer does not
decline for many years following smoking cessation [7-10]. Secondhand smoke exposure is common and is also
associated with lung cancer [11]. (See "Secondhand smoke exposure: Effects in adults".)
Lung cancer is the leading cause of cancer-related death among women in the United States. Most lung cancer in
women is attributed to smoking. However, a significant proportion of lung cancer in non-smoking women is
attributed to other causes, including passive smoking [11]. Some [12,13], but not all [14] studies suggest that for
any level of smoking, women are at higher risk of developing cancer than men. (See "Women and lung cancer".)
Screening for lung cancer will be reviewed here. General principles of screening, risk factors associated with the
development of lung cancer, and techniques for smoking cessation are discussed separately. (See "Evidence-
based approach to prevention" and "Overview of smoking cessation management in adults" and "Cigarette smoking
and other risk factors for lung cancer".)
POTENTIAL FOR EARLY DETECTION — Clinical outcome for non-small cell lung cancer is directly related to
stage at the time of diagnosis, ranging from over 60 percent five year survival for stage I disease, to less than 5
percent for stage IV disease (table 1 and figure 1) [15]. In addition, within early lung cancers (stage I) there is a
relationship between tumor size and survival [16]. Available data are more limited for patients with small cell lung
cancer, but also support an improved outcome when disease is diagnosed at an early stage.
Many characteristics of lung cancer suggest that screening would be effective: high morbidity and mortality;
significant prevalence (0.5 to 2.2 percent), identified risk factors allowing targeted screening for high risk, a lengthy
preclinical phase, and evidence that therapy is more effective in early stage disease [17,18].
These observations have stimulated great interest in lung cancer screening for asymptomatic high-risk individuals,
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with a focus on imaging techniques and cytological analysis of sputum. The potential of screening to detect early
cancers may both increase the overall cure rate and allow more limited surgical resection to achieve cure. However,
screening will not accomplish these goals unless it takes place in the context of a multidisciplinary program to
assure that screening results are properly performed, interpreted, and followed-up, and that disease, when detected,
is managed appropriately.
Screening test attributes — The goal of screening is to identify asymptomatic patients with unrecognized disease
(pulmonary nodule) and to identify patients at increased risk (smoking, family, and occupational history).
The concept of cancer screening is based on the assumption that identifying and treating precancer or cancer in
asymptomatic individuals will prevent cancer or improve survival. This assumes that there is a treatable phase of
precancer or cancer that, if untreated, would progress, and that early treatment improves outcomes compared with
late treatment. While it is believed that most lung cancers progress to late stage cancer, it has not been proven that
all lung malignancies progress [19]. The ideal screening test would have high sensitivity for detecting disease prior
to development of advanced disease; high specificity; relative safety; acceptability to patients and physicians;
relative low cost; and, most importantly, would either reduce mortality, improve quality of life, or both [17].
The effectiveness of a screening test ideally is evaluated in randomized controlled trials to minimize methodological
biases. Several biases may impact screening studies: lead-time bias, length bias, and overdiagnosis (figure 2 and
figure 3 and figure 4). A fourth type of bias, volunteer bias, results because study volunteers may not be
representative of the general population; subjects may volunteer because they are concerned that they have
increased risk for the condition, or may volunteer because they are more than usually health-conscious and
therefore are at lower risk. The types of lung cancer most prevalent in screening trials (adenocarcinoma and
bronchioalveolar cell carcinoma) [20], may have a very long preclinical phase; lead-time bias could therefore result
in overdiagnosis [21]. These issues are discussed in detail separately. (See "Evidence-based approach to
prevention".)
Outcomes to be assessed — The success of lung cancer screening can be assessed using various outcome
measures, including cancer detection rates, stage at detection, survival, disease-specific mortality, and overall
mortality. For a lethal disease such as lung cancer, that requires invasive procedures for detection and treatment,
the most important outcomes to assess are disease-specific and overall mortality.
Potential harms of screening — While screening for lung cancer has the potential benefits of decreased
morbidity and mortality from lung cancer, it also has potential harms which may include:
Detection of abnormalities that require further evaluation, most of which are benign nodules. Evaluation may
involve needle biopsy and/or surgery, with associated morbidity and mortality [22,23]. In the National Lung
Screening Trial, as an example, over 53,000 high risk individuals were randomly assigned to low dose CT
scan or chest radiograph screening [24]. Among abnormal results (24.2 percent of CT scans and 6.9 percent
of radiographs), 96 percent were false positive (that is, did not lead to a diagnosis of lung cancer) and 11
percent of the positive results led to an invasive study.
Radiation from serial imaging in a screening program may add independently to the risk of developing
cancers, including lung cancer [25]. The increased radiation exposure associated with spiral CT scanning,
compared with plain radiographs, may further add to cancer risk [26]. Although the average effective dose of
radiation for the screening low-dose spiral CT was 1.5 mSv, compared to approximately 8 mSv for a
diagnostic chest CT scan, screening would require annual CT scans. Additional radiation exposure is
generated by further imaging studies ordered in the work-up of false-positive findings [23]. (See "Radiation-
related risks of imaging studies".)
Prolonged follow-up of nodules, often lasting several years, may cause anxiety related to fear of having lung
cancer. In one study of the impact of screening on quality of life measures, patients who had indeterminate
findings on an initial screen did report increased anxiety, although anxiety was only short-term and did not
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persist for the second round of screening [27].
Some cancers identified at screening may represent overdiagnosis. That is, cancers may be detected and
treated that, if never found, would not have affected morbidity or mortality during the patient’s lifetime. (See
'Overdiagnosis' below.)
SCREENING WITH CHEST X-RAY/SPUTUM CYTOLOGY — There have been at least seven large scale controlled
clinical trials of chest x-ray screening for lung cancer: six randomized controlled trials [28-42], and one non-
randomized controlled trial [43]. These studies began as early as 1960, and a 20-year follow-up analysis has been
published for one randomized trial [39,44,45]. No randomized trial has demonstrated a mortality benefit for chest x-
ray screening although there have been no studies comparing screening to no screening, only trials comparing
intense screening to less intense screening.
Biannual chest x-ray — The earliest trial, the Northwest London Mass Radiography Service, randomly assigned
55,000 male workers to receive chest x-rays every six months for three years, or a baseline and end-of-study chest
x-ray only. After three years, the annual mortality from lung cancer was 0.7 to 0.8 per 1000, and not different in the
two groups [29,30].
Annual sputum cytology plus chest x-ray — Two large randomized screening trials in the United States, the
Memorial-Sloan Kettering (MSK) Study and The Johns Hopkins Study, evaluated the incremental benefit of annual
sputum analysis to annual chest x-rays [28,35,40-42]. In both studies, all subjects (combined n >20,000) were
offered annual chest x-rays, with half randomly assigned to dual screening with sputum cytology; follow-up was five
to eight years. In both studies, no difference in lung cancer incidence or mortality was detected comparing the dual
screening and chest x-ray only groups. Neither of these studies specifically addressed the role of chest x-ray in
lung cancer screening.
More frequent screening
Czechoslovakian study — A study in Czechoslovakia of 6364 male smokers, aged 40 to 64 years, included
twice yearly sputum and chest x-ray examination for three years in the intervention group and annual x-ray in both
control and intervention groups in years three through six [37]. More cancers were found in the intervention group
(108 versus 82 in the control group), and more early stage cancer occurred in the intervention group, but there was
no difference in late stage cancer or cancer mortality [38].
Mayo Lung Project — The first North American trial to evaluate the value of intense screening with chest x-ray
and sputum cytology was the Mayo Lung Project, involving male smokers (n = 10,993) [32,33,39]. All participants
underwent prevalence screening (baseline) evaluation with chest x-ray and sputum cytology. Subjects were then
randomly assigned to the study group with a six year program of chest x-ray and sputum cytology every four
months (incidence screening), or to the control group receiving "usual care" and advised to have an annual chest x-
ray.
Prevalence screening identified 91 cancers (0.8 percent). After six years, 206 new cancers were identified in the
screening group, and 160 in the control group. After 20 years of follow-up, lung cancer death rates were significantly
higher in the screened group (4.4 versus 3.9 deaths per 1000 patient years). Significantly more early cancers were
detected in the screened cohort, but there was no reduction in late stage cancers.
This large randomized study has been the most influential in guiding prevention and public health recommendations
and is the most analyzed study of chest x-ray screening for lung cancer [46-49]. The study, however, has several
flaws, including "screening" chest x-rays in nearly half of the control group during the course of the study, with one-
third of the malignancies in the control group discovered by a screening chest x-ray. In addition, screening
compliance in the intervention group was only 75 percent. Finally, because the baseline (prevalence) screening
chest x-ray detected 91 cases of lung cancer, there was no completely unscreened group.
Overdiagnosis — There is no single explanation for the findings from the chest x-ray screening trials that have
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shown increased numbers of small early-stage lung cancers with screening but no associated reduction in mortality
over time. One possibility is overdiagnosis: that lung cancer screening detects cancers that would not otherwise
become clinically apparent. Whether overdiagnosis occurs with lung cancer is controversial. Autopsy studies show
low rates of unsuspected lung cancers among individuals who have died of other causes [50]. Clinical experience
suggests that clinically detected lung cancers are generally progressive.
However, twenty year follow-up data from the Mayo Lung Project do support the concept of overdiagnosis in lung
cancer screening [45]. In the absence of overdiagnosis and with successful randomization, the number of cases of
lung cancer (identified either by screening or clinical presentation) in both control and intervention groups should
equalize over time, as cancers in the control group become clinically apparent. Follow-up data in 1999 from 6101 of
the 7118 Mayo Lung participants who had been alive and without lung cancer at the end of the trial in 1983, found a
persistence of excess lung cancer in the screened group compared to controls (585 versus 500). Unless one
hypothesizes that the intervention itself increased the rate of lung cancer in the screened group, these data suggest
either overdiagnosis or inequalities between the randomized groups.
Overdiagnosis is difficult to quantify, but would be expected to have greater impact in screening programs where
subjects are at increased risk for other potentially life-threatening comorbidities, such as smokers [51]. The risk for
unnecessary invasive studies and therapy for "overdiagnosed" lung cancer might be greatest in this population. Only
randomized controlled trials of screening that evaluate lung cancer mortality as well as all cause mortality can
quantify the amount and impact of overdiagnosis.
Meta-analysis — All cause mortality was calculated in a meta-analysis, using data available from five of the
controlled trials on chest x-ray screening [52]. Pooled analysis comparing frequent with less frequent screening
found no significant impact of intensified x-ray screening on all-cause mortality; the identified summary relative risk
of death was 0.97 (95% CI 0.94-1.01).
PLCO Cancer Screening Trial — The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a
large randomized trial (n = 154,942) evaluating the impact of screening individuals aged 55 through 74 for several
cancers, including lung cancer [53]. Screening for lung cancer consisted of a single posterior-anterior chest-x-ray at
baseline and annually for three years, while the control group received usual care. This study differs from prior chest
x-ray screening trials in several important aspects: the cohort includes men and women in equal numbers;
participants are not specifically high-risk (51.6 percent current or former smokers); and prevalence screening results
are included in the trial and analysis, allowing a true comparison of screening with no screening.
At the initial screening, 5991 (8.9 percent) of all chest-x-rays were abnormal, ranging from 11.0 percent in current
smokers to 8.0 percent in never smokers [54] After up to three rounds of annual screening (non-smokers did not
participate in the third screening round), participants were followed through 13 years, with a screening adherence of
86.6 percent at baseline and 79.0 to 84.0 percent years one through three [55]. There was no significant difference
in lung cancer incidence rates comparing screening and usual care groups (20.1 and 19.2 per 10,000 person-years,
RR 1.05, 95% CI 0.98-1.12). There was no difference in lung cancer mortality rates (RR 0.99, 95% CI 0.87-1.22) or
in stage of disease. Lung cancer incidence was higher among smokers than nonsmokers, but there was also no
difference in incidence or mortality comparing smokers who were in the screening or control groups. Only about 20
percent of the cancers occurring in the screening group were detected by screening. Thus annual screening with
chest x-ray, compared with usual care, did not reduce lung cancer mortality.
The lung cancer arm of the PLCO trial was designed to be completed in 2015. However, the monitoring board felt
that results would be unlikely to change with longer follow-up and that the current findings had public health
significance because of the recent report of the National Lung Screening Trial (NLST) that compared CT screening
with chest x-ray screening in a high-risk population. Data from the PLCO trial were also analyzed for a subset of
patients who would meet the criteria for the NLST. (See 'National Lung Screening Trial' below.)
Case-control studies — Six case-control studies, five conducted in Japan, have evaluated the role of chest x-ray
screening for lung cancer [56-62]. A 1950s case-control study, based on a tuberculosis screening program in which
chest x-ray was offered every one to two years to all adults in the former German Democratic Republic, showed no
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association between periodic chest x-ray and reduced lung cancer mortality [56]. In contrast, the five fair-quality
Japanese case-control studies suggest benefit with chest x-ray screening among men with smoking exposure and
women without direct smoking exposure or of mixed risk. Interpretation of these studies is limited by the potential
screening biases associated with non-randomized studies.
SCREENING WITH CHEST CT — The lack of a mortality benefit from chest x-ray screening and the refinement of
CT scanning techniques have led to the evaluation of low-dose helical CT for lung cancer screening [63]. New
multidetector CT scanners generate high-resolution imaging in a single breath hold with radiation exposure
significantly less than for diagnostic chest CT scanning. A study found that the overall average effective dose of low-
dose CT used in the National Lung Screening Trial was 2 mSv, compared with 7 mSv for a standard-dose diagnostic
chest CT examination [64]. (See 'National Lung Screening Trial' below.)
Results are available from one large randomized trial [24] and several observational cohort studies [65,66];
additional randomized trials are ongoing.
Randomized trials
National Lung Screening Trial — The National Lung Screening Trial (NLST), a randomized trial conducted
under the auspices of the National Cancer Institute, compared annual screening by low-dose chest CT scanning
with chest x-ray for three years in 53,454 high risk persons at 33 US medical centers [24,67,68]. Participants were
men and women 55 to 74 years of age with a history of at least 30 pack-years of smoking, and included current
smokers and those who had discontinued smoking within 15 years of enrollment.
The trial was stopped in November 2010 after an interim analysis found a statistically significant benefit for CT
scanning. At a median follow-up of 6.5 years, there were 645 cases of lung cancer per 100,000 person years (1060
cancers) in the CT group and 572 cases per 100,000 person years (941 cancers) in the chest x-ray group, resulting
in an incidence rate ratio of 1.13 (95% CI 1.03-1.23). Per 100,000 person years, there were 247 lung cancer deaths
in the CT group and 309 in the x-ray group, yielding a relative mortality reduction of 20.0 percent (95% CI 3.8-26.7).
Importantly, there was also a 6.7 percent (CI 1.2-13.6 percent) reduction in all-cause mortality in the CT group.
Positive findings were defined as a noncalcified nodule ≥4 mm on CT scan or any noncalcified nodule on x-ray. Over
all three screening rounds, 24.2 and 6.9 percent of participants in the CT and x-ray groups respectively had a
positive screen. The cumulative rate of false positive findings was high: 96.4 and 94.5 percent for CT and x-ray
screening respectively. Follow-up for false positive findings was at the discretion of the institution, but largely
entailed follow-up imaging. The rate of adverse events related to complications from the diagnostic work-up was low:
among participants with a positive finding, at least once complication occurred in 1.4 percent of the CT group and
1.6 percent of the x-ray group.
The rate of detection of lung cancer did not diminish between screening years, suggesting that ongoing screening
would be necessary. However, fewer stage IV cancers were observed in the CT group than the chest x-ray group
with the second and third screening rounds. Lung cancers detected by screening were mostly stage I or II (70
percent of CT-detected and 56.7 percent of x-ray detected), except for small cell cancers that accounted for less
than 10 percent of detected cancers. Chest CT identified a preponderance of adenocarcinomas.
Generalizability of these findings may be affected by the following factors: trial participants had a higher education
level and were younger than tobacco users identified in US census data; a low complication rate of follow-up
procedures may reflect the expertise at the participating academic centers; radiologic performance and
interpretation may not be representative of community-based radiology.
Since the control group in the NLST had screening with chest x-ray rather than usual care, findings of the Prostate,
Lung, Colorectal, and Ovarian (PLCO) trial, in which participants were randomly assigned to usual care or annual
chest radiography, are pertinent [55]. Results of the PLCO were analyzed for the subset of patients who would meet
criteria for participation in the NLST. There was no significant difference in mortality at six-year follow-up for the
PLCO high-risk subset who were assigned to chest x-ray screening or usual care (RR 0.94, 95% CI 0.81-1.10).
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In summary, the NLST demonstrated that CT screening reduced mortality in a high-risk population, compared to
screening by x-ray and, by inference from the PLCO data, compared to usual care. The number needed to screen
with low-dose CT to prevent one lung cancer death was 320 in the NLST. However, the cost of screening per life
saved is unknown but likely to be high, given the high (≈95 percent) false-positive rate leading to the need for
additional studies, the need for ongoing screening, and the relatively low absolute number of deaths prevented (73
per 100,000 person years). Modeling studies will be needed to determine actual cost-effectiveness.
Ongoing trials — As of 2010, eight randomized trials in addition to the NLST were in progress [69]. Among
them are the NELSON trial, the DANTE trial and the Danish Randomized Lung Cancer CR Screening Trial. Of
these, the only trial of large enough size to possibly show a mortality reduction is the NELSON trial.
The NELSON trial is a randomized CT-based lung cancer trial being conducted in the Netherlands and
Belgium; CT screening is being compared to no screening in 7557 current or former smokers [70]. The study
is powered to detect a 25 percent decrease in lung cancer mortality after ten years, as well as the effects of
screening on quality of life, smoking cessation, and an estimate of cost-effectiveness. Unlike other screening
studies, five-year lung cancer survivors, a group at very high risk of developing a new lung cancer, are also
eligible for enrollment. This is the only large-scale randomized trial to compare CT-screening to no screening.
Information is available at www.trialregister.nl/trialreg/admin/rctview.asp?TC=636.
A total of 90 subjects (1.2 percent) were found to have lung cancer after two rounds of screening [71]. The
proportion of stage I cancers in round one was 64 percent, lower than the 86 percent reported in the I-ELCAP
study, an observational study of low dose CT screening. (See 'Early Lung Cancer Action Project (ELCAP
and I-ELCAP)' below.) Follow-up for identified nodules was based on initial nodule volume and subsequent
change in size to limit invasive testing for false positive studies; using this protocol, 20 lung cancers were
found after two years of follow-up in the 7361 subjects who had initial negative screening.
CT screening results (indeterminate versus negative) did not significantly impact the smoking abstinence rate
among male smokers in this trial [72]. However, smokers with an indeterminate result on CT scanning
reported more quit attempts than those with a negative scan.
The DANTE trial, a randomized trial in Italy which enrolled 2472 male smokers age 60 to 74 years, is
designed to assess lung cancer-specific mortality over ten years, comparing five years of annual screening
by single slice spiral CT scan or annual clinical followup; the control group received baseline screening with
chest x-ray and sputum cytology [73]. At initial evaluation, lung cancer was found in 2.2 percent of the CT
group (71 percent stage I) and 0.67 percent of the controls (50 percent stage I) [74]. Fifteen percent of
subjects had an abnormal CT, and 4 percent underwent an invasive procedure. Benign pulmonary lesions
were found in 19 percent (6 of 32) of the patients who underwent thoracotomy.
Follow-up at an average of 33.7 months from enrollment, and after completion of the baseline and annual
screens, has been reported [75]. Lung cancer was found in 4.7 percent of patients who received CT
screening and 2.8 percent of controls. Although there were more stage I cancers in the screened group (54
compared to 34 percent), the number of advanced lung cancer cases and lung cancer mortality were the
same for both screened and control patients. The authors caution that these interim findings should not be
considered as definitive evidence that screening is ineffective but suggest that any effect may be smaller
than hoped for. It is possible that longer follow-up may be required to detect differences in disease-specific
mortality. Additionally, the trial size is small, compared to the NLST, and may not be of sufficient power to
detect a mortality difference.
The Danish Randomized Lung Cancer CT Screening Trial is another randomized trial of 4104 smokers (at
least 20 pack years) aged 50 to 70 years [76]. The trial is coordinated with the NELSON trial, so that final
results of both studies can be pooled to achieve an 80 percent power to detect a reduction in lung cancer
mortality of at least 25 percent. Baseline data from the Danish trial found a prevalence of lung cancer of 0.83
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percent (17 cases in 2052 participants), employing the algorithm from the I-ELCAP study for follow-up of
abnormal initial findings on CT scan, nine of the 17 cases were stage I. Of the 11 cases considered to be
surgically resectable, 8 were amenable to minimally invasive (VATS) technique. Initial results are anticipated
in 2012.
Observational studies
Early Lung Cancer Action Project (ELCAP and I-ELCAP) — The ongoing Early Lung Cancer Project
(ELCAP) reported results of baseline screening with low-dose spiral chest CT in 1000 asymptomatic patients who
had a ≥10 pack-year smoking history [77,78]. Each participant underwent both plain film and CT imaging; CT
detected malignant nodules in significantly more patients than plain films (2.7 versus 0.7 percent), but also detected
more nodules that ultimately proved benign (20.6 versus 6.1 percent). Twenty-seven lung cancers were identified,
with only one considered unresectable; 23 of the 27 cancers were stage I disease. Many benign lesions were
followed radiographically and did not require biopsy.
ELCAP has collaborated with lung cancer screening programs in 38 community and academic centers in five
countries to form the International ELCAP (I-ELCAP) [79]. Standard protocols for screening, follow-up imaging, and
evaluation of detected abnormalities, including follow-up CT scans, PET scans, and biopsies, were designated for
the I-ELCAP study. These evaluation algorithms depended heavily on follow-up imaging for detection of growth and
biopsy. Subsequent treatment of cancer, if detected, was at the discretion of patient and center.
I-ELCAP screened 31,567 asymptomatic participants with baseline CT scans; 27,456 received an annual screening
scan, and follow-up was performed according to the designated protocols. Positive CT results requiring further
workup were found in 13 percent (n = 4186) of initial scans and 5 percent (n = 1460) of annual scans. Lung cancer
was identified in 484 patients; 412 were stage I. The majority (405) of the cancers were detected at baseline
screening. This study confirms earlier observations that lung cancers detected through CT screening are early
stage. Because ELCAP and I-ELCAP are observational cohort studies without a control group, lead-time and
length-time bias cannot be controlled for, overdiagnosis cannot be estimated, and the results do not directly
address the effect of screening on lung cancer-specific and overall mortality [80].
Mayo Clinic CT study — Another large prospective observational study of low-dose CT screening for lung
cancer, conducted by the Mayo Clinic in conjunction with the National Cancer Institute, is following a cohort (n =
1520) of asymptomatic current or former smokers over age 50 years [81-84]. Baseline (prevalence) CT scans
identified one or more non-calcified nodules in 51 percent, with 1.7 percent diagnosed with primary lung cancer.
After three years of annual CT scanning, a total of 3356 non-calcified nodules were found in 73.5 percent of the
cohort; approximately 95 percent of the nodules were benign with clinical follow-up or surgical biopsy. Fifteen
surgeries were performed for benign disease.
Overall, a total of 68 primary lung cancers were documented in 66 subjects, 34 on annual (incidence) studies and 3
interval lung cancers not detected through annual screening. Of the incidence cancers, 61 percent were stage I and
33 percent presented at an advanced stage (III or IV).
Observational data versus modelled prediction — The above Mayo data were included as one arm of a
three arm study, also including data from CT scan observational studies conducted at centers in Milan and Florida
[22]. A total pooled group of 3246 asymptomatic high risk subjects underwent baseline and follow-up CT screening
for a median follow-up period of 3.9 years. The frequency of observed events related to lung cancer (any diagnosis,
diagnosis of advanced stage disease, surgical resection, or death) was compared with predictions based on two
validated models estimating risk of diagnosis and risk of death due to lung cancer derived from a similar high risk
population (over 18,000 individuals enrolled in a primary prevention trial for lung cancer [85]). The following results
were reported [22]:
144 study participants were diagnosed with lung cancer, compared to 44.5 predicted cases (RR 3.2, 95% CI
2.7-3.8).
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109 lung resections were performed, compared to 10.9 predicted (RR 10, 95% CI 8.2-11.9).
42 cases of advanced lung cancer were diagnosed, compared to a prediction of 33.4 to 51.2 cases,
depending on how patients lost to follow-up would be considered in the model. The difference between
observed and predicted rates is not significant.
38 deaths due to lung cancer were observed and 38.8 were predicted (RR 1.0, 95% CI 0.7 to 1.3).
Thus, CT scan did not decrease predicted lung cancer death or observed advanced lung cancer rates, but increased
the number of patients diagnosed with cancer and undergoing surgical resection. Estimated lung-cancer specific
survival for patients in this study was approximately the same as survival estimates in the I-ELCAP study. The
contrasting findings for this study compared to I-ELCAP most likely relate to the difference in primary outcome
measures: cancer survival (I-ELCAP) versus cancer mortality [86]. The limitations of this study were that it was not
a randomized control trial, and the sample size was such that it could not absolutely rule out as much as a 30
percent reduction in mortality with screening.
Patient-specific data from the Mayo Lung Project were also used in another modeling study, based on the Lung
Cancer Policy Model that incorporates cancer stage at time of diagnosis and non-cancer related mortality risks
[84]. Findings from this simulation were that annual screening with CT for four years, compared with no screening,
would lead to a decrease in lung cancer-specific mortality (relative decrease of 28 percent at six years and 15
percent at 15 years). All-cause mortality would also decrease (2 percent at 15 years), but the relative decrease
would be significantly lower than for cancer specific mortality because deaths from other causes (cardiovascular or
pulmonary in smokers) would occur, even if lung cancer deaths were prevented.
Other observational studies — The Pittsburgh Lung Screening Study (PLuSS), the largest single-institution
CT lung cancer screening study, reported outcomes within three years for 3642 high risk individuals who were to
have initial and one year follow-up lung CT screening [87]. Forty percent had noncalcified nodules on initial
screening and 55 percent of these patients had a subsequent diagnostic test (usually imaging) before the next
screening CT. Eighty patients were identified with lung cancer within three years of initial screening, including 53
with tumors observed at the first screening. Of the 69 with non small cell lung cancer, stage 1 disease was
diagnosed in 58 percent and stage 3 disease or higher in 36 percent.
One percent of the initial cohort had a major procedure (thoracotomy, video-assisted thorascopic surgery [VATS],
sternotomy, or mediastinoscopy) for a noncancer diagnosis, and one-third of all patients who underwent
thoracotomy or VATS (28 of 82) had a benign diagnosis. Subjects frequently underwent procedures prior to the
recommended interval for follow-up, despite protocols recommending specified imaging follow-up for CT findings not
considered to be high risk, with protocol reinforcement by nurses and consultation access to study physicians.
Long-term follow-up of this cohort will be useful in clarifying the natural history of various stages of screen detected
lung cancer.
There have been many reports of additional observational studies from Japan [88,89] and Europe [90-93]. Studies of
low dose CT and sputum cytology screening in Japan (>5000 prevalence screens and 8000 incidence screens in
both high and low risk participants) found 60 cancers; 55 were stage 1.
LUNG CANCER SCREENING IN WOMEN — Lung cancer is the leading cause of cancer-related death among
women in the United States [6]. Most lung cancer in women is attributed to smoking. However, a significant
proportion of lung cancer in non-smoking women is attributed to other causes, including passive smoking [11].
Some [12,13], but not all [14] studies suggest that for any level of smoking, women are at higher risk of developing
cancer than men. (See "Women and lung cancer".)
Women tend to develop adenocarcinoma of the lung disproportionately to men and adenocarcinoma is also found
more commonly among non-smokers [10]. This cell type tends to occur peripherally and may be more readily
detectable with chest x-ray and/or CT than other cell types. As a consequence, radiologic imaging and screening
for lung cancer may perform differently among women than men.
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Although several early studies focused primarily on men, newer and ongoing randomized trials have included both
men and women. Whether screening recommendations should be different for men and women remains to be
determined.
SYNTHESIZING THE AVAILABLE EVIDENCE — In summary, randomized controlled trials of chest x-ray based
screening and non-randomized cohort studies of CT based screening demonstrate:
Chest x-ray and CT screening frequently detect early stage asymptomatic lung cancers in screened
individuals.
CT screening is significantly more sensitive than chest x-ray for identifying small, asymptomatic lung
cancers. Chest x-ray screening does not reduce mortality from lung cancer.
Chest x-ray and CT screening have high rates of "false positive" (non-cancer) findings leading to additional
testing which usually includes serial imaging, but may include invasive procedures.
One large randomized trial of screening CT in high-risk individuals has demonstrated a lung cancer mortality
benefit of 20 percent, with all cause mortality reduced by 6.7 percent. However, the question of cost-
effectiveness is a major issue because of the significant costs associated with screening and, especially,
follow-up of the many false positive tests identified with CT screening in this trial. Additionally, relatively low
procedural complication rates in this trial may not be reproducible in other settings, and thus harms may be
greater than reported. These findings have generated conflicting opinions in the literature regarding the
initiation of screening [94,95].
If further analysis, including cost effectiveness analysis, determines a role for screening, issues of screening
frequency, appropriate population targets, criteria for a “positive” finding, and diagnostic follow-up protocols
remain to be addressed.
Cost-effectiveness — Decisions regarding implementation of a lung cancer screening program, based upon the
results of the NLST, should in part be based upon a cost-effectiveness analysis of a screening program. One
analysis, based upon a model designed prior to completion of the NLST, modeled the potential cost-effectiveness of
screening by CT scan for six different patient cohorts (differing ages and smoking histories) [96]. The modelers also
varied whether patients who underwent screening were more likely to quit smoking because of the opportunity for
smoking cessation intervention (nicotine replacement plus bupropion) or less likely to quit smoking because of
reassurance from a negative test result. Projections from this analysis were that CT screening might decrease lung
cancer mortality at 10 years by 18 to 25 percent, at a cost ranging from $126,000 to $269,000 per quality adjusted
life year (QALY). In comparison, the cost-effective ratios for colorectal and breast cancer screening are $47,700 and
$13,000 to $32,000 per QALY, respectively. Additionally, the model found that a smoking cessation program was
more cost-effective than CT screening alone or CT screening combined with smoking cessation.
Recommendations for screening by expert groups — Most expert screening groups have not yet incorporated
results from the NLST in their recommendations. Updated guidelines from the American Society of Clinical
Oncology (ASCO), the American Cancer Society, and the American College of Chest Physicians are anticipated in
2011 to 2012 [97].
The National Comprehensive Cancer Network (NCCN) issued guidelines for lung cancer screening in October 2011
[98]. These guidelines recommend annual low-dose CT scan screening for those at high risk; they recommend no
routine screening for moderate- or low-risk individuals. High risk was defined by the NCCN as age 55 to 74 years
with a 30 pack-year history of smoking and, if no longer smoking, smoking cessation within 15 years, or a 20 pack
year history of smoking with one additional risk factor (other than secondhand smoke exposure). Although the
guidelines note that the duration of screening is uncertain, they advise a minimum of three scans, so that
individuals initiating screening at age 74 would stop screening at age 76. The guidelines emphasize that lung
cancer screening should be done within the context of a multidisciplinary program (that may include radiology,
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pulmonary medicine, internal medicine, thoracic oncology, and/or thoracic surgery) to manage downstream testing.
Systematic screening with either CT or chest x-ray is not currently recommended by professional organizations
other than the NCCN (table 2). The US Preventive Services Task Force (USPSTF) concluded in 2004 that evidence
was insufficient to recommend for or against screening for lung cancer [44,99]. The USPSTF guidelines are also
undergoing review.
The International Association for the Study of Lung Cancer (IASLC) chartered an advisory committee in 2011 to
work with professional societies who are developing guidelines for screening [100]. The IASLC identified several
issues that need to be addressed in guideline development and implementation: defining the optimal population for
screening; determining the cost-effectiveness of screening; developing consistent CT screening protocols; defining
the optimal work-up for abnormal findings; defining optimal management of screen-detected nodules; determining
the optimal screening interval and number of screening rounds; and encouraging data collection and further research
to improve screening outcomes and limit complications. There was consensus that smoking cessation programs
need to be integrated into screening programs and that a lung cancer screening program should involve a
multidisciplinary team experienced in evaluation and management of early lung cancer.
Counseling for screening — Any program of lung cancer screening, if screening is undertaken, requires more
than CT capability. Screening should only be performed when the clinician and patient are committed to pursuing
follow-up investigations, including serial imaging and possible surgical lung biopsy.
Providers need to be experienced in the principles of screening and the management of small lung nodules. If these
components are in place and at-risk individuals (mostly through smoking and occupational exposure) are highly
motivated to be screened for lung cancer, the following points should be discussed with the patient before beginning
screening. Some have advocated formal informed consent including these points:
Smoking cessation is a more proven and powerful intervention for preventing death and complications from
lung cancer than screening. (See "Cigarette smoking and other risk factors for lung cancer".)
Lung cancer screening requires an ongoing commitment; cancers are detected on initial and annual studies,
and a single baseline study is insufficient.
The most likely "positive" result of screening is detection of benign nodules requiring further evaluation, and
this evaluation may require invasive studies, possibly even surgery.
For patients who would opt to be screened after appropriate counseling, and pending results of cost-effectiveness
analyses and ongoing randomized trials, we suggest screening with low dose helical CT scanning only for those
who meet all of the following criteria:
Are in general good health
Are at increased risk for lung cancer (similar to the risk of the group participating in the NLST trial)
Have access to centers whose radiologic, pathologic, surgical and other treatment capabilities in the
management of indeterminate lung lesions are equivalent to those in the NLST trial
Are able to manage the cost of annual screening and the possible need for subsequent evaluation of
abnormal findings. The role of insurance coverage in screening has not been determined following the NLST
results.
OTHER TECHNOLOGIES
Positron emission tomography — At least two studies evaluated annual low-dose CT followed by positron
emission tomography (PET) with fluorodeoxyglucose (FDG) for evaluating patients with noncalcified lesions ≥7 mm
in diameter, each with similar results [92,101].
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The more recent study enrolled 911 volunteers ≥50 years of age who had smoked for ≥20 pack-years [101].
Baseline CT identified 11 non-small cell lung cancers (NSCLC) and one small cell lung cancer (SCLC) (1.3 percent
prevalence); two NSCLCs were found in 424 subjects at annual follow-up study (0.5 percent incidence). All NSCLCs
were stage I. FDG-PET correctly diagnosed 19 of 25 indeterminate nodules. The sensitivity, specificity, positive
predictive value, and negative predictive value of FDG-PET for the diagnosis of malignancy were 69, 91, 90, and 71
percent, respectively. When a negative FDG-PET was followed three months later with a repeat CT, the negative
predictive value was 100 percent. If these results are validated by future studies, the simple algorithm employed
could have substantial implications for incorporation of PET imaging into large-scale screening programs.
Other approaches — Non-radiographic technologies may also contribute to the early detection of lung cancer.
Detection and treatment of small lung tumors (prior to radiographic visualization) may produce superior outcomes,
though the possibility of lead-time and other types of bias influencing the assessment of these technologies is
great. Outcome benefits must be thoroughly investigated prior to their widespread use [102].
These and similar techniques may also help identify people with significantly higher lung-cancer risk, in whom the
likelihood would be increased that radiographic studies would detect early stage lung cancer.
Technologies under investigation include:
Immunostaining or molecular analysis of sputum for tumor markers. As examples, p16 ink4a promoter
hypermethylation and p53 mutations have been shown to occur in chronic smokers before there is clinical
evidence of neoplasia [103-107].
Automated image cytometry of sputum [108].
Fluorescence bronchoscopy [109,110]. (See "Fluorescence bronchoscopy".)
Exhaled breath analysis of volatile organic compounds, which appear to be more common in patients with
lung cancer [111-113].
Genomic and proteomic analysis of bronchoscopic samples [114,115].
Serum protein microarrays for detecting molecular markers [116].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and
“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)
Basics topic (see "Patient information: Lung cancer screening (The Basics)")
Beyond the Basics topics (see "Patient information: Lung cancer prevention and screening (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
Lung cancer is the leading cause of cancer-related death. Prevention (promoting smoking cessation) is likely
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to have far greater impact on lung cancer mortality than is screening. (See 'Introduction' above.)
Detection of early-stage cancers through screening may allow more limited treatment and improved cancer
cure rates. The important outcome for cancer screening, however, is its impact on overall mortality. (See
'Outcomes to be assessed' above.)
Early trials of chest x-ray screening in males at high risk for lung cancer found no mortality benefit for x-ray
alone or x-ray plus sputum cytology. The Mayo Lung Project found more early cancers in the screened
cohort but no reduction in late-stage cancers and no reduction in mortality. Follow-up data suggest
overdiagnosis.
A large randomized trial (the PLCO) of single view chest x-ray found no decrease in lung cancer incidence or
mortality with screening. We recommend NOT screening for lung cancer with chest x-ray (Grade 1A). (See
'Screening with chest x-ray/sputum cytology' above.)
Lung cancer screening is a rapidly evolving field, with potential to significantly reduce the burden of lung
cancer. A large randomized trial (NLST) of annual low-dose CT screening in patients with a 30 pack-year
history of smoking, including those who quit smoking in the preceding 15 years, demonstrated a decrease in
lung cancer and all-cause mortality. Other large randomized trials are ongoing and guidelines from
professional organizations are undergoing revisions. (See 'Randomized trials' above and 'Recommendations
for screening by expert groups' above.)
All patients who smoke should be strongly counselled to quit smoking as the most-effective intervention to
reduce the risk of lung cancer. Patients who currently smoke or have a history of smoking should be advised
of the risks and benefits of screening for lung cancer (see 'Counseling for screening' above):
For patients in good health who are felt to have a risk for lung cancer at least as great as those in the
NLST and who have access to centers with radiologic, diagnostic, and treatment capabilities similar to
those in the NLST trial, and for whom the cost of screening is not an issue, we suggest annual
screening with low-dose helical CT (Grade 2B). Patients who wish to avoid the high risk of false-positive
results with such a program can reasonably choose not to be screened.
While awaiting the results of cost-effectiveness analyses and additional randomized trials of screening,
for patients at increased risk for lung cancer who do not meet the above criteria, we suggest not
screening (Grade 2C).
Plain chest x-ray screening has been shown to be ineffective for lung cancer screening.
Use of UpToDate is subject to the Subscription and License Agreement.
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99. Humphrey LL, Teutsch S, Johnson M, U.S. Preventive Services Task Force. Lung cancer screening withsputum cytologic examination, chest radiography, and computed tomography: an update for the U.S.Preventive Services Task Force. Ann Intern Med 2004; 140:740.
100. Field JK, Smith RA, Aberle DR, et al. International Association for the Study of Lung Cancer ComputedTomography Screening Workshop 2011 report. J Thorac Oncol 2012; 7:10.
101. Bastarrika G, García-Velloso MJ, Lozano MD, et al. Early lung cancer detection using spiral computedtomography and positron emission tomography. Am J Respir Crit Care Med 2005; 171:1378.
102. Mulshine JL, Tockman MS, Smart CR. Considerations in the development of lung cancer screening tools. JNatl Cancer Inst 1989; 81:900.
103. Belinsky SA, Liechty KC, Gentry FD, et al. Promoter hypermethylation of multiple genes in sputum precedeslung cancer incidence in a high-risk cohort. Cancer Res 2006; 66:3338.
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104. Kersting M, Friedl C, Kraus A, et al. Differential frequencies of p16(INK4a) promoter hypermethylation, p53mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomaticchronic smokers. J Clin Oncol 2000; 18:3221.
105. Mulshine JL, Scott F. Molecular markers in early cancer detection. New screening tools. Chest 1995;107:280S.
106. Ahrendt SA, Chow JT, Xu LH, et al. Molecular detection of tumor cells in bronchoalveolar lavage fluid frompatients with early stage lung cancer. J Natl Cancer Inst 1999; 91:332.
107. Baryshnikova E, Destro A, Infante MV, et al. Molecular alterations in spontaneous sputum of cancer-freeheavy smokers: results from a large screening program. Clin Cancer Res 2008; 14:1913.
108. Henschke CI. Medicine on lung cancer screening: a different paradigm. Am J Respir Crit Care Med 2003;168:1143.
109. George PJ. Fluorescence bronchoscopy for the early detection of lung cancer. Thorax 1999; 54:180.
110. Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection ofpreneoplastic lesions: a randomized study. J Natl Cancer Inst 2001; 93:1385.
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116. Zhong L, Hidalgo GE, Stromberg AJ, et al. Using protein microarray as a diagnostic assay for non-small celllung cancer. Am J Respir Crit Care Med 2005; 172:1308.
Topic 7566 Version 24.0
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GRAPHICS
TNM staging system for lung cancer (7th edition)
Primary tumor (T)
T1 Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion moreproximal than lobar bronchus
T1a Tumor ≤2 cm in diameter
T1b Tumor >2 cm but ≤3 cm in diameter
T2 Tumor >3 cm but ≤7 cm, or tumor with any of the following features:
Involves main bronchus, ≥2 cm distal to carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region butdoes not involve the entire lung
T2a Tumor >3 cm but ≤5 cm
T2b Tumor >5 cm but ≤7 cm
T3 Tumor >7 cm or any of the following:
Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinalpleura, parietal pericardium, main bronchus <2 cm from carina (without involvement ofcarina)
Atelectasis or obstructive pneumonitis of the entire lung
Separate tumor nodules in the same lobe
T4 Tumor of any size that invades the mediastinum, heart, great vessels, trachea,recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separatetumor nodules in a different ipsilateral lobe
Regional lymph nodes (N)
N0 No regional lymph node metastases
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes andintrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateralscalene, or supraclavicular lymph node(s)
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignantpleural or pericardial effusion
M1b Distant metastasis (in extrathoracic organs)
Stage groupings
StageIA
T1a-T1b N0 M0
StageIB
T2a N0 M0
Stage T1a,T1b,T2a N1 M0
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IIA T2b N0 M0
StageIIB
T2b N1 M0
T3 N0 M0
StageIIIA
T1a,T1b,T2a,T2b N2 M0
T3 N1,N2 M0
T4 N0,N1 M0
StageIIIB
T4 N2 M0
Any T N3 M0
StageIV
Any T Any N M1a or M1b
Adapted from: Goldstraw, P, Crowley, J, Chansky, K, et al. The IASLC Lung Cancer Staging Project:
Proposals for the revision of the TNM stage groups in the forthcoming (seventh) edition of the TNM
classification of malignant tumours. J Thorac Oncol 2007; 2:706.
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Overall survival by TNM grouping, NSCLC
Overall survival, expressed as median survival time (MST) and five-year survival,using the sixth edition of TNM staging system by (A) clinical stage and (B) pathologicstage. Reproduced with permission from: Goldstraw P, Crowley J, Chansky K, et al. The IASLC
Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the
forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;
2:706. Copyright © 2007 Lippincott Williams & Wilkins.
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Lead-time bias
Image
Lead-time bias occurs when screening identifies disease at anearlier time but the time of death remains unchanged. In theabove diagram, lead-time bias for population B creates theimpression that patients diagnosed by screening have a longersurvival, although actual mortality is unchanged. Population Cdoes have improved survival, compared to the unscreenedpopulation A. O: onset of disease; Dx: diagnosis. Adapted from Fletcher
RF, Fletcher SW. Prevention. In: Clinical Epidemiology: The Essentials, 4th
ed. Lippincott Williams & Wilkins, Baltimore, 2005. Copyright © 2005
Lippincott Williams & Wilkins.
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Length-time bias
Length-time bias occurs when screening detects lessaggressive tumors. Cases that progress rapidly from onset(O) to symptoms and diagnosis (Dx) are less likely to bedetected during a screening examination. Thus, patientswhose tumors are identified by screening may appear to havebetter outcomes, but their tumors may differ biologically fromthe general cohort of patients with that cancer. Adapted with
permission from: Fletcher, RH, Fletcher, SW. Prevention. In: Clinical
Epidemiology - The Essentials, 4th ed. Lippincott Williams & Wilkins,
Baltimore 2005. p. 147 - 167.) Copyright © 2005 Lippincott Williams and
Wilkins.
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Overdiagnosis in cancer screening
Overdiagnosis occurs when cancers that are non-progressive,as well as some very slow growing cancers, are detected byscreening but will never cause clinical harm during a patient'slifetime. Overdiagnosis is an extreme form of length-time bias. Originally reprinted from Welsh, HG. Should I be tested for cancer? Maybe
not and here's why. Berkeley and Los Angeles, California: University of
California Press, 2004. Adapted with permission from: Fletcher, RH,
Fletcher, SW. Prevention. In: Clinical Epidemiology - The Essentials, 4th
ed. Lippincott Williams & Wilkins, Baltimore 2005. p. 147-167. Copyright
© 2005 Lippincott Williams & Wilkins.
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Guidelines for lung cancer screening
Organization Recommendation Year
US PreventiveServices TaskForce
Evidence is insufficient to recommend for or against screeningasymptomatic persons for lung cancer with either low-dosecomputerized tomography, chest x-ray, sputum cytology, or acombination of these tests.
2004
American Collegeof ChestPhysicians
Recommends against the use of low-dose CT, chest radiographs,or sputum cytology for lung cancer screening, including smokersor others at high risk, except in the context of a clinical trial.
2007
American CancerSociety
Informed individual decision-making; if testing is chosen, spiralCT should be performed only in centers with multidisciplinaryspecialties experienced in screening and treatment.
2006
AmericanAcademy ofFamily Physicians
Recommends against the use of chest x-ray and/or sputumcytology in asymptomatic persons.
1997
Canadian TaskForce on thePeriodic HealthExamination
Recommends against the use of chest x-ray in asymptomaticpersons. Evidence is insufficient to recommend for or againstscreening with spiral CT in asymptomatic persons.
2003
NationalComprehensiveCancer Network
Recommends annual low-dose CT scan screening for high-riskindividuals (age 55 to 74 years with 30 pack-year history ofsmoking or 20 pack-year history with an additional risk factor).
2011
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