Screening for lung cancer: a review

Screening for lung cancer: a review
Renee Manser
Purpose of review
After the disappointing results of lung cancer screening trials
conducted in the 1960s to the 1980s, a renewed interest in
lung cancer screening emerged in the 1990s with the
development of new technologies such as low-dose spiral CT.
The literature regarding screening with biomarkers and CT
continues to expand rapidly.
Recent findings
Although the specificity of CT screening is relatively poor, the
sensitivity for the detection of early-stage cancers, particularly
adenocarcinoma, is considerably superior to that of chest
radiography used in older screening trials. The results of
uncontrolled cohort studies of CT screening are promising, but
such studies are susceptible to screening biases such as
overdiagnosis.
Summary
There is insufficient evidence to support widespread screening
in current practice. However, randomized controlled trials are
now being conducted to determine whether improved
detection by CT will translate into reduced lung cancer
mortality. Alternative approaches to secondary prevention such
as screening with biomarkers, autofluorescence
bronchoscopy, and chemoprevention hold great promise for
the future but await further development and evaluation in
prospective trials.
Keywords
mass screening, computed tomography, chest radiography,
sputum cytology, lung neoplasms
Curr Opin Pulm Med 10:266–271. © 2004 Lippincott Williams & Wilkins.
Clinical Epidemiology and Health Service Evaluation Unit, Royal Melbourne
Hospital, Victoria, Australia, and the Department of Respiratory Medicine, St.
Vincent’s Hospital, Victoria, Australia
Correspondence to Renee Manser, Clinical Epidemiology and Health Service
Evaluation Unit, Ground Floor, Charles Connibere Building, Royal Melbourne
Hospital, Grattan Street, Parkville 3050, Victoria, Australia
Tel: +61 3 9342 8772; fax: +61 3 9342 7060; e-mail: ManserRL@mh.org.au
Supported by a National Health and Medical Research Council postgraduate
scholarship (scholarship number 201713).
Current Opinion in Pulmonary Medicine 2004, 10:266–271
Abbreviation
RCT randomized controlled trial
© 2004 Lippincott Williams & Wilkins
1070-5287
266
Introduction
Lung cancer remains a major public health problem in
most industrialized countries [1,2]. Most lung cancers are
attributable to cigarette smoking, and primary prevention
is a continuing priority. Increasingly, lung cancer is
now occurring in ex-smokers [3]. Additional preventive
strategies are needed to reduce the mortality from this
epidemic. Whereas early lung cancer screening trials
have yielded disappointing results, more sensitive
screening techniques have been developed, including
biomarkers and low-dose CT. Research progress has
been most rapid with radiological approaches and randomized
controlled trials (RCTs) of CT screening are
currently being conducted. In the interim. debate
continues over the potential cost effectiveness of CT
screening and its appropriate use in contemporary clinical
practice.
Screening with plain chest radiography
The efficacy of chest radiography screening for lung cancer
continues to be debated [4•,5•,6••]. A systematic
review of controlled trials of lung cancer screening reviewed
the evidence from seven trials [6••,7]. In all
studies, the control group received some type of screening.
Five studies effectively compared more frequent
chest radiography screening with less frequent chest radiography
screening [8–12]. In the meta-analysis, more
frequent chest radiograph screening was associated with
an 11% relative increase in mortality from lung cancer
(relative risk 1.11, 95% confidence interval 1.00–1.23)
[6••,8,10–12]. Although the possibility of harm from
screening exists, the finding of increased mortality in the
frequently screened group could be due to inadequate
randomization resulting in population heterogeneity between
the control and intervention groups. However, the
trend to increased mortality was seen in all studies reviewed.
Another alternative explanation is that lung cancer
deaths could have been undetected or unreported in
the control group and that some deaths in the intervention
group due to comorbid disease were misclassified as
death due to lung cancer [13,14]. None of the trials reported
have adequately assessed the efficacy of annual
chest radiograph screening compared with no screening,
and this issue is currently being evaluated in the Prostate,
Lung, Colorectal, and Ovarian Cancer Screening
Trial [15]. However, this trial has already attracted criticism
for a failure to enroll high-risk groups [16].

Low-dose spiral computed
tomography screening
Bepler et al. [17••] have recently reviewed several cohort
studies (without historical controls) [18–24]. The reviewers
reported that CT screening resulted in a threefold
higher detection rate and a fivefold increase in the rate of
resectable cancers relative to chest radiograph screening.
However, CT screening appears to selectively detect adenocarcinomas,
with an approximately twofold to threefold
oversampling of this histologic subtype [17••]. This
may reflect length-biased sampling, overdiagnosis bias,
selection bias, or inadequate detection of endobronchial
squamous cell carcinomas [25,26••].
The specificity of CT screening is poor, ranging between
89% and 49% in high-risk populations at baseline screening
and being lowest with multislice CT [21,26••,27].
There is no standard approach to the evaluation of most
nodules detected by CT, most of which are small (5
mm). Serial imaging can be used to limit the number of
biopsies for benign disease, but benign nodules may
show radiologic evidence of nodule growth, whereas
some cancers have long doubling times [26••,27,28]. In
most studies reported, smaller indeterminate noncalcified
nodules were monitored with repeat CT at 3 or 6
months. Emerging evidence suggests that lesions less
than 5 mm could be reimaged at 12 months to reduce the
number of diagnostic evaluations [29•]. In one study,
follow-up of nodules 5 mm or less was deferred until 12
months [30••]. Six cancers diagnosed at repeat screening
were identified at baseline CT, but all were stage Iat
diagnosis [30••]. In the same study, positron emission
tomography was also used in the diagnostic algorithm,
but this approach did not reduce the rate of benign biopsy
results compared with other studies [30••].
Current methods of evaluation and management of small
nodules detected by CT require validation in long-term
studies. Issues such as the frequency and duration of
follow-up are yet to be resolved. Previous reports based
on chest radiography show that some lung cancers can
appear stable for many years before growth is detected at
serial follow-up [31,32]. Furthermore, slow growth of a
primary tumor does not preclude metastatic spread [33].
Growth can be more accurately detected by CT than by
chest radiography [28]. However, even with serial CT
examinations, it is likely that follow-up of more than 2
years will be necessary for some nodules [34•]. The medicolegal
implications of delayed diagnosis in this setting
are untested but could be similar to the experience reported
for breast cancer [35]. In the future, biomarkers,
in addition to growth patterns, could be used to help
distinguish between benign, premalignant, and malignant
lesions, but the feasibility and validity of such an
approach requires further evaluation [36•].
Although some experts have questioned the role of
RCTs in the setting of screening evaluation, they are
Screening for lung cancer Manser 267
generally considered to be the gold standard [37,38].
Several RCTs of CT screening are being planned or are
in progress [39•]. The National Lung Screening Trial is
a National Cancer Institute—sponsored RCT comparing
annual chest radiography with annual spiral low-dose CT
for 3 years. This trial has enrolled nearly 50,000 exsmokers
and current heavy smokers across multiple centers
in the United States. Enrollment closed in February
2004, and participants will be followed up until 2009
[39a]. A further RCT will be conducted in the Netherlands
and Leuven (Belgium) [40].
Cost-effectiveness of computed
tomography screening for lung cancer
In a cost-effectiveness analysis based on the results of
the Early Lung Cancer Action Project, an incremental
cost-effectiveness ratio of $2500 per life year saved for a
single baseline low-dose CT scan in high-risk individuals
was reported [41•]. These results differ markedly from
those of another cost-effectiveness analysis in which relevant
probabilities were based on the weighted average
of several CT studies and quality-adjusted life years
were assessed in addition to life years saved [42••]. In
this model, current smokers in a hypothetical cohort
were considered who were offered annual low-dose CT
screening compared with a cohort not offered screening.
The model predicted, over a 20-year period, a 13% reduction
in lung cancer–specific mortality, assuming a
50% stage shift. The incremental cost effectiveness ratio
per quality-adjusted life year was $116,300 [42••]. This
analysis was criticized because of the large number of
variables included, some of which were estimated from
limited data [43]. The disparity between the results of
these analyses and others is a reflection of the different
assumptions used in the models and particularly the
level of uncertainty in the estimates of screening efficacy.
Future analyses based on the results of RCTs are
likely to yield more reliable results. Identification of very
high-risk groups is likely to be the most cost-effective
screening strategy [42••]. This could be achieved by the
use of a prediction model or by identifying high-risk
subgroups such as those with chronic obstructive airway
disease [44•,45,46]. However, comorbidity may limit the
potential health gains of screening these populations
[47].
Overdiagnosis: the debate continues
Overdiagnosis may occur if a screening program detects
a case of cancer that would not, even in the absence of
screening and early intervention, have led to death in
that individual’s lifetime. Henschke et al. [48•] consider
overdiagnosed lesions to be those that, although morphologically
malignant, have an indolent natural course and
would not progress to cause death, regardless of competing
causes of mortality. Although it is probable that, according
to this definition, overdiagnosis is uncommon,
slowly growing adenocarcinomas with long doubling

268 Neoplasms of the lung
times are well documented [49–51]. The detection of
such indolent tumors may be more common in low-risk
populations. For example, the detection rate of lung cancer
by CT screening is much higher than expected from
mortality data among nonsmoking women [52•]. Other
experts argue that in any screening program a proportion
of screen-detected cases will be “pseudodisease” simply
because of competing mortality [14]. The findings of the
Mayo Lung Project are consistent with overdiagnosis
bias [8,53]. However, in a recent retrospective review of
tumor doubling times of incident cancers diagnosed in
the Mayo Lung Project and the Memorial Sloan-
Kettering studies, it was reported that only 5% of stage I
cancers had doubling times of more than 400 days [54•].
However, indolent tumors are most likely to be detected
by prevalence screening, and this finding does not exclude
the possibility of overdiagnosis resulting from competing
mortality.
As with any new screening test, it is probable that CT
will detect lesions that have not previously been observed
and have an unknown natural history. Observational
studies in selected populations with unresected
stage Icancer, detected by chest radiography, have reported
poor 5-year survival rates of between 10% and
25% [55–57]. Most recently, a high case-fatality rate was
reported for unresected stage IA lung cancers documented
in the Surveillance, Epidemiology, and End Results
registry [48•]. However, observational studies are
subject to selection bias. For example, in one report
squamous cell carcinoma was overrepresented [55]. In
addition, bias may arise in assigning cause of death [58].
Furthermore, comorbid conditions that contraindicate
surgery could also impair host defenses against the tumor
and increase lung cancer mortality [58]. Because CT can
detect smaller lesions than chest radiography, the potential
for overdiagnosis is greater. In a review of coronial
autopsies, approximately 1 in 300 decedents going to
autopsy had lung cancer detected that was undetected
during life and did not contribute to death [59]. However,
although incidental cancers were uncommon, the
median tumor size of incidental lesions was 3 cm (range
1–10 cm), and it is likely that routine autopsies may not
detect many of the smaller cancers currently detectable
by CT [59,60].
The natural history of lung cancer:
implications for early detection
and treatment
The tendency for CT screening to detect predominantly
adenocarcinomas may be viewed favorably, given that
this is now the predominant histologic type of lung cancer
in many industrialized countries [61]. However, it is
possible that the benefits of early detection and treatment
could differ between different histologic groups.
Squamous cell carcinomas tend to be centrally located
and grow more rapidly than adenocarcinomas but are less
likely to metastasize to distant sites after surgery for localized
disease [62]. Furthermore, lymph node micrometastases
are more common in small peripheral adenocarcinomas,
compared with small peripheral squamous cell
carcinomas, being demonstrable in 36% of adenocarcinomas
1 cm or less in size, but absent or uncommon in
squamous cell carcinomas of 2 cm or less [63]. On the
basis of tumor doubling times, it has been estimated that
an adenocarcinoma takes an average of 13.2 years to
reach 1 cm and a further 2.2 years to reach 3 cm [64]. It
is not surprising that smaller tumors might demonstrate
prolonged disease-free survival when measured from the
point of diagnosis, because it is likely that many will have
been detected at an earlier point in their development
[65•]. The question remains whether the natural history
will be altered by early detection and intervention, particularly
given the long duration of adenocarcinoma prior
to detection with current screening methods.
The benefit of screening is dependent on having effective
therapy for early-stage disease. However, there have
been no reported RCTs of surgery or radiotherapy for
stage Ior stage IInon–small cell lung cancers that have
included an untreated control group [58,66]. In one early
study, pneumonectomy or lobectomy improved survival
at 4 years in patients with squamous cell carcinoma compared
with radiotherapy [67]. Whereas observational data
support the role of surgery for early-stage non–small cell
lung cancer, the magnitude of any benefit and the types
of patients who benefit most is unclear. Some experts
have postulated that non–small cell lung cancer is a biologically
variable disease in which anatomic staging identifies
more indolent tumors that are likely to have a more
favorable clinical course regardless of the intervention
[58,64]. This hypothesis warrants further consideration
in relation to adenocarcinoma, which is particularly heterogeneous,
with a wide range of doubling times reported
[51,68]. In one study of slow-growing tumors, survival
in individuals with adenocarcinoma correlated well
with tumor doubling time, even in those with resected
tumors [50]. Lung cancer studies of gene expression arrays
have identified different subclasses of adenocarcinoma
with particular patterns of gene expression that
correlate with survival [69,70]. What remains unclear is
whether subclasses with different gene expression patterns
have arisen from different precursor cells or whether
the subclass with a more favorable gene expression
pattern is simply at an intermediate point in the development
to the invasive phenotype [70].
Alternative approaches
Although standard sputum cytology lacks sensitivity,
new methods of sputum analysis have now been developed,
such as automated quantitative image cytometry,
immunohistochemical analysis, and molecular approaches
[26••,71•,72]. Blood biomarkers are also being
investigated [73•]. These approaches require validation

in large prospective trials [71•,72]. In a recent study of
automated quantitative image cytometry in conjunction
with low-dose CT screening in high-risk individuals, automated
quantitative image cytometry was shown to enhance
the detection of lung cancer by CT, but specificity
was poor, with 75% of individuals having sputum atypia
detected by automated quantitative image cytometry
[26••]. Only 1 cancer was detected by CT alone’ however,
CT failed to detect 4 of 14 lung cancers. The 4
missed lesions were all squamous cell carcinomas (3
stage 0 and 1 stage IA) identified by autofluorescence
bronchoscopy [26••]. Although this approach has the potential
to reduce the number of initial CT scans by 25%,
nearly three quarters of individuals screened would require
autofluorescence bronchoscopy [26]. However, in
another study, baseline autofluorescence bronchoscopy
findings were predictive of subsequent squamous cell
carcinoma in high-risk patients and therefore may identify
a subgroup requiring closer follow-up [74•].
Molecular approaches are likely to be the most effective
early detection method because they can lead to the
detection of preinvasive changes and therefore provide
the opportunity for intervention at a much earlier point
in the development of cancer. Coupled with noninvasive
chemoprevention, molecular approaches could be more
widely applicable [72]. In the future, noninvasive and
well-tolerated chemoprevention could have a role in
both primary and secondary prevention [75••]. Molecular
targeted agents are currently being evaluated in clinical
trials to assess their ability to prevent the appearance
and progression of premalignant lesions in former or current
smokers with a history of smoking-related cancer
[76•].
Conclusion
Low dose spiral CT screening is a sensitive screening
technique for early-stage lung cancer, particularly adenocarcinoma.
However there is insufficient evidence to
support screening in contemporary practice. In the future,
the results of RCTs will better inform us about
whether the early detection and treatment of cancers
detected by CT leads to a reduction in mortality and if
the potential benefits of screening outweigh the harms
associated with false positive diagnoses or overdiagnosis.
If CT screening has only a small impact on lung cancer
mortality then cost effectiveness will most likely be unfavorable
in the context of current diagnostic and therapeutic
approaches. Alternative approaches to secondary
prevention such as screening with biomarkers, autofluorescence
bronchoscopy and chemoprevention await further
development and evaluation in prospective trials.
Acknowledgments
The author thanks Dr. David Hart for reviewing the manuscript.
Screening for lung cancer Manser 269
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
of special interest
of outstanding interest
1 Lopez A: The lung cancer epidemic in developed countries. In: Adult mortality
in developed countries: from description to explanation. Edited by Lopez A,
Caselli G, Valkonen T. Oxford; 1995: 111–134.
2 Wingo P, Cardinez CJ, Landis SH, et al.: Long-term trends in cancer mortality
in the United States, 1930–1998. Cancer 2003, 97(Suppl):3133–3275.
3 Burns D: Primary prevention, smoking, and smoking cessation: implications
for future trends in lung cancer prevention. Cancer 2000, 89(Suppl):2506–
2509.
4 Sagawa M, Nakayama T, Tsukada H, et al.: The efficacy of lung cancer
screening conducted in 1990s: four case-control studies in Japan. Lung Cancer
2003, 41:29–36.
This report is a meta-analysis of recent case-control trials of lung cancer screening
in Japan.
5 Marcus P: Conflicting evidence in lung cancer screening: randomized controlled
trials versus case-control studies. Lung Cancer 2003, 41:37–39.
This editorial examines the possible reasons for discrepancies between the results
of recent case-control studies and previous controlled trials of lung cancer screening
and discusses some of the limitations of case-control studies.
6 Manser R, Irving LB, Byrnes G, et al.: Screening for lung cancer: a systematic
review and meta-analysis of controlled trials. Thorax 2003, 58:784–789.
Comprehensive overview of controlled trials of lung cancer screening that have
been reported to date.
7 Manser R, Irving LB, Byrnes G, et al.: Screening for lung cancer (Cochrane
Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software;
2001.
8 Fontana RS, Sanderson DR, Woolner LB, et al.: Screening for lung cancer: a
critique of the Mayo Lung Project. Cancer 1991, 67(Suppl):1155–1164.
9 Wilde J: A 10 year follow-up of semi-annual screening for early detection of
lung cancer in the Erfurt County, GDR. Eur Resp J 1989, 2:656–662.
10 Brett GZ: Earlier diagnosis and survival in lung cancer. BMJ 1969, 4:260–
262.
11 Freidman G, Collen MF, Fireman BH: Multiphasic health check up evaluation:
a 16 year follow up. J Chronic Dis 1986, 39:453–463.
12 Kubik A, Parkin DM, Khlat M, et al.: Lack of benefit from semi-annual screening
for cancer of the lung: follow-up report of a randomized controlled trial on a
population of high-risk males in Czechoslovakia. Int J Cancer 1990,
45:26–33.
13 Koyi H, Hillerdal G, Branden E, et al.: The “reservoir” of undetected bronchial
carcinomas in the general population. Lung Cancer 2002, 37:137–142.
14 Black W: Overdiagnosis: an under-recognized cause of confusion and harm
in cancer screening. J Natl Cancer Inst 2000, 92:1280–1282.
15 Gohagan J, Levin DL, Prorok PC, et al.: The prostate, lung, colorectal and
ovarian (PLCO) cancer screening trial. Control Clin Trials 2000,
21(Suppl):249S–406S.
16 Kennedy T, Miller Y, Prindiville S: Screening for lung cancer revisited and the
role of sputum cytology and fluorescence bronchoscopy in a high-risk group.
Chest 2000, 117(Suppl):72S–79S.
17 Bepler G, Carney DG, Djulbegovic B, et al.: A systematic review and lessons
learned from early lung cancer detection trials using low-dose computed tomography
of the chest. Cancer Control 2003, 10:306–314.
Comprehensive and critical overview of early lung cancer detection trials using
low-dose CT. Provides useful summary tables of studies reviewed.
18 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, 222:773–781.
19 Henschke C, Naidich DP, Yankelevitz DF, et al.: Early lung cancer action
project: initial findings on repeat screening. Cancer 2001, 92:153–159.
20 Nawa T, Nakagawa T, Kusano S, et al.: Lung cancer screening using lowdose
spiral CT: results of baseline and 1-year follow-up studies. Chest 2002,
122:15–20.
21 Sobue T, Moriyama N, Kaneko M, et al.: Screening for lung cancer with lowdose
helical computed tomography: Anti-Lung Cancer Association project.J
Clin Oncol 2002, 20:911–920.
22 Sone S, Li F, Yang ZG, et al.: Results of three-year mass screening pro-

270 Neoplasms of the lung
gramme for lung cancer using low-dose spiral computed tomography scanner.
Br J Cancer 2001, 84:25–32.
23 Tiitola M, Kivisaari L, Huuskonen MS, et al.: Computed tomography screening
for lung cancer in asbestos-exposed workers. Lung Cancer 2002, 35:17–22.
24 Swensen S, Jett JR, Hartman TE, et al.: Lung cancer screening with CT: Mayo
Clinic experience. Radiology 2003, 226:756–761.
Update on the results of the Mayo Clinic uncontrolled cohort study of low dose
multislice CT screening.
25 Morrison A: Screening. In: Modern Epidemiology. Edn 2. Edited by Rothman
K, Greenland S. Philadelphia: Lippincott-Raven; 1998:499–518.
26 McWilliams A, Mayo J, MacDonald S, et al.: Lung cancer screening: a different
paradigm. Am J Respir Crit Care Med 2003, 168:1167–1173.
This novel study examines the role of automated quantitative image cytometry of
sputum cells as a potential screening tool and how this might be used in conjunction
with CT screening.
27 Swensen S, Jett JR, Sloan JA, et al.: Screening for lung cancer with low-dose
spiral computed tomography. Am J Respir Crit Care Med 2002, 165:508–
513.
28 Winer-Muram H, Jennings SG, Tarver RD, et al.: Volumetric growth rate of
stage I lung cancer prior to treatment: serial CT scanning. Radiology 2002,
223:798–805.
29 Henschke C, Yankelevitz DF, Naidich DP, et al.: CT screening for lung cancer:
suspiciousness of nodules according to size on baseline scans. Radiology
2004, 231:164168.
30 Pastorino U, Bellomi M, Landoni C, et al.: Early lung-cancer detection with
spiral CT and positron emission tomography in heavy smokers: 2 year results.
Lancet 2003, 362:593–597.
Italian study examining the role of positron emission tomography in the evaluation of
some nodules detected by CT screening for lung cancer in a high-risk population.
31 Davis E, Peabody JW, Katz S: The solitary pulmonary nodule. J Thorac Surg
1956, 32:728–771.
32 Storey C, Grant RA, Rothmann BF: Coin lesions of the lung. Surg Gynecol
Obstet 1953, 97:95–104.
33 Hughes R, Blades B: Stable bronchogenic carcinoma. Postgrad Med 1960,
28:616–622.
34 Kakinuma R, Ohmatsu H, Kaneko M, et al.: Progression of focal pure groundglass
opacity detected by low-dose helical computed tomography screening
for lung cancer. J Comput Assist Tomogr 2004, 28:17–23.
Interesting study that examines patterns of progression of focal pure ground-glass
opacity detected by low-dose spiral CT screening in terms of changes in both size
and density.
35 Brenner R: Breast cancer evaluation: medical legal issues. Breast J 2004,
10:6–9.
36 Zhukov T, Johanson RA, Cantor AB, et al.: Discovery of distinct protein profiles
specific for lung tumours and pre-malignant lung lesions by SELDI mass
spectometry. Lung Cancer 2003, 40:267–279.
Study examining the feasibility of using surface-enhanced laser
desorption/ionization mass spectrometry for detecting “malignant” protein signatures
from lung tumor and premalignant pulmonary epithelium.
37 Barratt A, Irwig L, Glasziou P, et al.: Users’ guides to the medical literature
XVII: how to use guidelines and recommendations about screening. JAMA
1999, 281:2029–2034.
38 Miettinen O, Yankelevitz DF, Henschke CI: Evaluation of screening for a cancer:
annotated catechism of the gold standard creed. J Eval Clin Pract 2003,
9:145–150.
39 Diederich S, Wormanns D, Heindel W: Lung cancer screening with low-dose
CT. Eur J Radiol 2003, 45:2–7.
Comprehensive review that outlines some of the proposed RCTs of CT screening.
39a http://cancer.gov/nlst/, accessed March 2004.
40 van Klaveren R, de Koning HJ, Mali WPTM, et al.: Trial design and first screening
results from the Nederlands-Leuvens Longkanker screening Onderzoek
(NELSON), a prospective randomized clinical trial on lung cancer screening
by spiral CT [abstract]. Lung Cancer 2003, 41(Suppl 2):S158.
41 Wisnivesky J, Mushlin AI, Sicherman N, et al.: The cost-effectiveness of lowdose
CT screening for lung cancer: preliminary results of baseline screening.
Chest 2003, 124:614–621.
Cost-effectiveness analysis based on the results of a single CT screening trial
(Early Lung Cancer Action Project).
42 Mahadevia P, Fleisher LA, Frick KD, et al.: Lung cancer screening with helical
computed tomography in older adult smokers: a decision and costeffectiveness
analysis. JAMA 2003, 289:313–322.
A very comprehensive cost-effectiveness analysis that explores the impact of
changing the assumptions in the analysis in multiway sensitivity analyses. Assumptions
and results are clearly outlined, with a thoughtful discussion of the implications.
43 Chirikos T, Hazelton T, Tockman M, Clark R: Cost-effectiveness of screening
for lung cancer. JAMA 2003, 289:2358.
44 Bach P, Kattan MW, Thornquist MD, et al.: Variations in lung cancer risk
among smokers. J Natl Cancer Inst 2003, 95:470–478.
Useful prediction model of lung cancer risk based on smoking history in addition to
other factors.
45 Mannino D, Aguayo SM, Petty TL, et al.: Low lung function and incident lung
cancer in the United States: data from the First National Health and Nutrition
Examination Survey follow-up. Arch Intern Med 2003, 163:1475–1480.
46 Petty T: Cost-effectiveness of screening for lung cancer. JAMA 2003,
289:2357.
47 Mahadevia P, Powe NR: Cost-effectiveness of screening for lung cancer.
JAMA 2003, 289:2358–2359.
48 Henschke C, Wisnivesky JP, Yankelevitz DF, et al.: Small stage I cancers of
the lung: genuineness and curability. Lung Cancer 2003, 39:327–330.
Examines the 8-year fatality rate of diagnosed but untreated stage IA non–small cell
lung cancers documented in the Surveillance, Epidemiology, and End Results
(SEER) registry in 1988–1994.
49 Araki K, Goto K, Yokose T, et al.: A case of well-differentiated nonmucinous
adenocarcinoma of the lung with an 18-year clinical course before surgery.
Nihon Kokyuki Gakkai Zasshi 2003, 41:708–711.
50 Hayabuchi N, Russell WJ, Murakami J: Slow-growing lung cancer in a fixed
population sample: radiological assessments. Cancer 1983, 52:1098–
1104.
51 Hasegawa M, Sone S, Takashima S, et al.: Growth rate of small lung cancers
detected on mass CT screening. Br J Radiol 2000, 73:1252–1259.
52 Li F, Sone S, Abe H, et al.: Low-dose computed tomography screening for
lung cancer in a general population: characteristics of cancers in nonsmokers
versus smokers. Acad Radiol 2003, 10:1013–1020.
A study of the detection rate of lung cancers by low-dose CT in 7847 Japanese
adults and correlation with clinical, imaging, and pathologic findings in nonsmokers
versus smokers.
53 Patz E, Goodman PC, Bepler G: Screening for lung cancer. N Engl J Med
2000, 343:1627–1633.
54 Yankelevitz D, Kostis WJ, Henschke CI, et al.: Overdiagnosis in chest radiographic
screening for lung carcinoma. Cancer 2003, 97:1271–1275.
Interesting retrospective study examining tumor doubling times of the lung cancers
detected at incidence screenings in the Mayo Lung Project and Memorial Sloan-
Kettering lung cancer screening study.
55 Sobue T, Suzuki T, Matsuda M, et al.: Survival for clinical stage I lung cancer
not surgically treated: comparison between screen-detected and symptomdetected
cases. Cancer 1992, 69:685–692.
56 Motohiro A, Ueda H, Komatsu H, et al.: Prognosis of non-surgically treated
clinical stage I lung cancer patients in Japan. Lung Cancer 2002, 36:65–69.
57 Flehinger BJ, Kimmel M, Melamed MR: The effect of surgical treatment on
survival from early lung cancer. implications for screening. Chest 1992,
101:1013–1018.
58 Lederle F, Niewoehner DE: Lung cancer surgery: a critical review of the evidence.
Arch Intern Med 1994, 154:2397–2401.
59 Manser R, Dodd M, Byrnes G, et al.: Incidental lung cancers identified at
coronial autopsy: implications for overdiagnosis of lung cancer by screening
[abstract]. Respirology 2004, 9(Suppl):A52.
60 Dammas S, Patz EF, Goodman PC: Identification of small lung nodules at
autopsy: implications for lung cancer screening and overdiagnosis bias. Lung
Cancer 2001, 33:11–16.
61 Janssen-Heijnen MLG, Coebergh J-WW. Trends in incidence and prognosis
of the histological subtypes of lung cancer in North America, Australia, New
Zealand and Europe. Lung Cancer 2001, 31:123–137.
62 Sawyer T, Bonner JA, Gould PM, et al.: Patients with stage I non-small cell
lung cancer at postoperative risk for local recurrence, distant metastasis, and
death: implications related to the design of clinical trials. Int J Radiat Oncol
Biol Phys 1999, 45:315–321.
63 Ohta Y, Oda M, Wu J, et al.: Can tumor size be a guide for limited surgical
intervention in patients with peripheral non-small cell lung cancer? Assessment
from the point of view of nodal micrometastasis. J Thorac Cardiovasc
Surg 2001, 122:900–906.
64 Geddes D: The natural history of lung cancer: a review based on rates of
tumour growth. Br J Dis Chest 1979, 73:1–17.

65 Gajra A, Newman N, Gamble GP, et al.: Impact of tumor size on survival in
stage IA non-small cell lung cancer: a case for subdividing stage IA disease.
Lung Cancer 2003, 42:51–57.
Examines the relation between tumor size and survival in stage IA non–small cell
lung cancer, with results that conflict with those in some earlier reports.
66 Sirzen F, Kjellen E, Sorenson S, et al.: A systematic overview of radiation
therapy effects in non-small cell lung cancer. Acta Oncol 2003, 42:493–515.
67 Morrison R, Deeley TJ, Cleland WP: The treatment of carcinoma of the bronchus:
a clinical trial to compare surgery and supervoltage radiotherapy. Lancet
1963, 1:683–684.
68 Aoki T, Nakata H, Watanabe H, et al.: Evolution of peripheral lung adenocarcinomas:
CT findings correlated with histology and tumour doubling time. AJR
2000, 174:763–768.
69 Bhattacharjee A, Richards WG, Staunton J, et al.: Classification of human
lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma
subclasses. Proc Natl Acad Sci USA2001, 98:13790–13795.
70 Garber M, Troyanskaya OG, Schluens K, et al.: Diversity of gene expression
in adenocarcinoma of the lung. Proc Natl Acad SciUSA2001, 98:13784–
13789.
71 Brambilla C, Fievet F, Jeanmart M, et al.: Early detection of lung cancer: role
of biomarkers. Eur Respir J 2003, 39(Suppl):36s–44s.
Comprehensive overview of the role of biomarkers in early lung cancer detection.
Screening for lung cancer Manser 271
72 Tockman M: Advances in sputum analysis for screening and early detection of
lung cancer. Cancer Control 2000, 7:19–24.
73 Sozzi G, Conte D, Leon ME, et al.: Quantification of free circulating DNA as a
diagnostic marker in lung cancer. J Clin Oncol 2003, 21:3902–3908.
Study of the amount of plasma DNA determined through the use of real-time polymerase
chain reaction amplification of the human telomerase reverse transcriptase
gene (hTERT) in 100 patients with non–small cell lung cancer and 100 matched
control participants.
74 Pasic A, Vonk-Noordegraaf A, Risse EKJ, et al.: Multiple suspicious lesions
detected by autofluorescence bronchoscopy predict malignant development
in bronchial mucosa in high risk patients. Lung Cancer 2003, 41:295–301.
Uncontrolled cohort study of individuals at high risk for lung cancer (those with a
history of primary aerodigestive tract tumor or atypical sputum cells on sputum
cytology) examining what suspicious baseline findings at autofluorescence bronchoscopy
might predict the subsequent development of squamous cell carcinoma
in the central airways.
75 Mulshine J, Hirsch FR: Lung cancer chemoprevention: moving from concept
to reality. Lung Cancer 2003, 41:S163–S174.
A comprehensive overview of potential agents for chemoprevention and the challenges
facing further research in this field.
76 Khuri F: Primary and secondary prevention of non-small cell lung cancer: the
SPORE trials of lung cancer prevention. Clin Lung Cancer 2003, 5(Suppl
1):S36–S40.
Outlines current chemoprevention trials involving molecular targeted agents such
as gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase activity.