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Screening for Lung Cancer using
Low Dose CT: State of the Art and
Controversies
Philippe GRENIER
University Pierre et Marie Curie (UPMC),
Pitié-Salpêtrière Hospital, Paris, FRANCE
Rationale for lung cancer screening
Lung cancer remains the leading cause of cancerrelated death among men and women in the world
The 5-year survival rate of 10-15% has been roughly
unchanged for the past two decades despite treatment
advances
At diagnosis, most lung cancers are already at
advanced stage
Mountain. Chest; 1997.111: 1710
Strauss. Surg Oncol Clin N Am 1999; 8: 747
Rationale for lung cancer screening
Early stage lung cancer patients have a much higher
5-year survival rate (between 60 and 80%)
Changing smoking habits could reduce lung cancer
incidence and deaths
Cessation programs have long-term cessation rates of
only 20% to 35% at one year
The risk for lung cancer does not decrease for many
years after smoking cessation
Pisters. J Clin Oncol 2005; 23:3270
Lung Cancer Screening
with Chest Radiography with or without
Sputum Cytologic Examination
Some lower-quality evidence (case-control studies) has
shown benefit
Higher-quality evidence (randomized controled trials)
conducted in the 80’s has not (the screened groups had the
same number of death from lung cancer as the control group)
Humphrey. Ann Intern Med 2004; 140:740
Early Lung Cancer Action Project (ELCAP)
Uncontrolled observational trial
1000 asymptomatic volunteers (> 60 yo)
smoking : 45 py (median).
Subjects received both low dose computer tomography (LDCT)
and chest radiography (CR)
Non-calcified nodules were detected on 23% of LDCT and 7%
of CR
Lung cancer was detected in 2.7% LDCT screens (85% were
stage I disease) and in 0.7% CR screens
Henschke. Lancet 1999; 354:99
Year 0
Year 1
Adenocarcinoma
Year 1+3 months
Year 0
Year1
Adenocarcinoma
Year 1+3 months
Initial
3-month Follow-up
+ 30%
Adenocarcinoma
Uncontrolled studies with LDCT
Study years
Screening Screening tests Postive test Lung cancer
Stage I
type
performed
results (%)
(%)
disease (%)
Henschke 1999
Baseline
Incidence
1000
1184
24
3.1
0.9
85
67
Nawa 2002
Baseline
Incidence
7956
5568
26
0.5
0.1
86
100
Sone 2001
Baseline
Incidence
5483
8303
5
0.4
0.6
100
86
Sobue 2002
Baseline
Incidence
1611
7891
12
0.8
0.2
77
79
Swensen 2003
Baseline
Incidence
1520
2916
51
1.8
0.7
66
Diederich 2002
Baseline
817
43
1.3
58
Pastorino 2003
Baseline
Incidence
1035
994
15
1.1
1.1
77
Uncontrolled studies with LDCT
Prevalence rates of lung cancer have varied widely (0.441.8%) , due to different risk profiles based on age and
smoking disease status,
Stage I or II cancers have been 75% to 100%
High level of non-calcified benign nodules detected (1551%) with the risks of invasive procedures and futile
thoracotomies
False positive rate of screening CT
Definition : number of patients who required further
evaluation after CT but did not have cancer
Rate of positive tests in prevalence screening : 15-51 %
Rate of positive tests in incidence screening : 3-12 %
Most are resolved with follow-up CT
5 % - 14 % of those undergoing follow CT were referred to
biopsy and most (63 % - 90 %) then received a diagnosis of
cancer
False negative rate of screening CT
Nodules were missed in 26 % of patients on annual
incidence screening CT scans1
CT sensitivity for detecting nodules is reduced when central
versus peripheral, when adjacent to the vessels and when
small2
Double reading and CAD may reduce false negative rates3
1 Swensen. Am J respir Crit Care Med 2002; 165: 508
2 Rusinek. Radiology 1998; 209:243
3 Ko. J Thorac Imaging 2004; 19:136
Computer Aided Diagnosis: Detection and
Nodule growth assessment on follow-up CT
Strategy for indeterminate nodule
(more than 50 y.o. smoker)
Size
< 4 mm
4 - 8 mm
> 8 mm
CT Follow-up*
12 months
CT Follow-up*
3-6, 6-9, 9-12, 12-24
months
Biopsy
or resection
Alternative: FDG-PET
or contrast enhanced CT
McMahon. Radiology. 2005 ; 237: 395-400
+
Biopsy or resection
Survival of patients with stage I lung
cancer detected on CT screening
31,567 asymptomatic persons at risk for lung cancer were
screened using LDCT (1993-2005)
412/484 (85%) had clinical stage I lung cancer and estimated
10-year survival rate was 88%
Among 302/412 who underwent surgical resection within 1
month after diagnosis, the 10-year survival rate was 92%
The 8 participants with clinical stage I who did not receive
treatment died within 5 years after diagnosis
Henschke. N Engl J Med. 2006; 355:1763
Are Increasing 5-Year Survival Rates
Evidence of Success Against Cancer?
There is little correlation between the change in 5-year
survival for a specific tumor and the change in tumorrelated mortality
The change in 5-year survival is positively correlated
with the change in the tumor incidence rate
Welch. JAMA; 2000; 283:2975
Uncontrolled studies with LDCT
Lung cancer can be diagnosed at a significantly earlier
stage with CT screening.
However whether this will translate to a mortality
benefit is unclear
CT Screening for Lung Cancer:
Five-year Prospective Experience
1520 individuals with high risk for lung cancer
68 lung cancers diagnosed (31 initial, 34 subsequent,3 interval)
28 subsequent cases of non-small cell cancers were detected, of
which 17 (61%) were stage I tumors
No difference in the observed incidence lung cancer
mortality rate to a historic benchmark
2.8 vs 2.0 per 1000 person-years
Swensen. Radiology: 2005; 235: 259
CT Screening and Lung Cancer
Outcomes
Longitudinal analysis of 3246 individuals current or former
smokers screened for lung cancer in academic centers with a
follow-up of 3.9 years
Comparison of predicted with observed number of new lung
cancer cases, lung cancer resections, advanced lung cancer
cases, and deaths from lung cancer
Bach. JAMA: 2007; 297: 953
CT Screening and Lung Cancer
Outcomes
144 individuals diagnosed with lung cancer compared with 44.5
expected cases (RR, 3.2; P<.001)
109 had a lung resection compared with 10.9 expected
cases (RR, 10; P<.001)
No evidence of decline in the number of diagnoses of advanced
lung cancers (42 vs 33.4 expected cases) or deaths from lung cancer
(38 observed and 38.8 expected; RR, 1; P= .9)
Bach. JAMA: 2007; 297: 953
Cancer screening programmes :
should do more good than harm
at a financial cost acceptable to society
Good :
extend quality years of life (QALY)
reduce mortality from the tumor
Harm :
complications of the screening tests
consequences of false positive diagnoses
Lead-Time Bias
Survival time
Time
Screened group
Diagnosis
confirmed
Patient
dies
Lead time
Survival time
Time
Control group
Symptoms
Diagnosis
confirmed
Patient
dies
Length-Time Bias
Onset of
Aggressive tumors tumor
Onset of
tumor
Onset of
tumor
Indolent tumors
Time
Tumor
detectable
Symptoms
Tumor
detectable
Symptoms
Tumor
detectable
Symptoms
Overdiagnosis and consequent
overtreatment
Overdiagnosis bias is the result of slow-growing relatively
indolent lung cancers that a patient dies with and not from
The high rate of adenocarcinomas raises the possibility of
overdiagnosis
Slow-growing adenocarcinomas (bronchioloalveolar
carcinomas or non-invasive adenocarcinomas) that are not
lethal may be identified with CT screening
Lindell. Radiology: 2007; 242: 555
Non solid nodules: malignant causes
Ground glass opacity
Adenocarcinoma
Bronchioloalveolar cell carcinoma
Mixed (part-solid) nodules
Adenocarcinomas
Solid and non-solid nodules: growth rate
Doubling time of nodules from a 3-year
screening program for lung cancer*
Solid nodules: 189 days
Mixed (part-solid) nodules: 457 days
Non solid nodules: 813 days
*Hasegawa. Br J Radiol 2000; 73: 1252
Curative limited resection for small
peripheral lung cancer
146 stage IA peripheral tumors
Nodal metastasis
3-year disease-free
survival
Type I
GGO
90-100 %
Type II
GGO
50-89 %
Type III
GGO
10-49 %
Type IV
GGO
< 10 %
0
0
20 %
24 %
98 %
98 %
86 %
78 %
Patients with tumor that have GGO ratio > 50 % are regarded to be
possible candidates for limited pulmonary resection
Nakata. J Thorac Cardiovasc Surg 2005; 129: 1226
Overdiagnosis: a Substantial Concern in
Lung Cancer Screening
61 cancers reviewed and 48 assessed for morphologic change
Mean tumor size: 16.4 mm (5.5-52.5 mm)
74% prevalence, 37% incidence detected lung cancers were
adenocarcinomas
Mean volume doubling time (VDT) was 518 days
13/48 (27%) cancers had a VDT longer than 400 days
(11/13 were in women)
Lindell. Radiology: 2007; 242: 555
Randomized controlled trials eliminate
lead-time and lenght biases
Control group
RDZ
Screened group
Test
1e yr
Test
2e yr
Test
3e yr
Test
4e yr
Randomized controlled trials
They are very difficult to set up
Contamination is a major problem
They take a very long time to produce definitive
results (enough time to allow for lead time and
length biases)
In the interval technology changes and the results
may not be relevant when trial finally reports
Lung Cancer Study: a randomized controlled
trial (LDCT vs CR)
3,318 tobacco-exposed subjects
Compliance at baseline was 96% in the LDCT arm
and 93% in the CR arm
At year one screening compliance was 86% in the
LDCT arm and 80% in the CR arm
Gohagan. Chest 2004; 126: 114
NLST: RCT Design
CT Arm
53,476
High-Risk
Subjects
F/U
Randomize
CXR Arm
T1
time
0
1
T0
2
3
T2
4
5
6
7
8
The NELSON Trial
15,428 subjects
LDCT screened arm is beeing compared to a
control arm without screening
Van Iersel. Int J Cancer 2007; 120:868
Conclusion
Screening for lung cancer with LDCT may increase the
rate of lung cancer diagnosis and treatment, but may not
meaningfully reduce the risk of advanced lung cancer or
death from lung cancer
Until more conclusive data are available, asymptomatic
individuals should not be screened outside of clinical
research studies
Conclusion
Randomized controlled trials are the only way to
reliably determine whether screening does more good
than harm
Although expensive and time-consuming, rigorous
trials of cancer screening are far more cost-effective
than widespread adoption of costly screening
interventions that cause more harm than good
Welch. Arch Intern Med; 2007; 167: 2289
Genetic abnormalities and biomarkers of
premalignancy or early malignancy
Genomic and proteomic methods may offer a much
easier mass screening as the first step of a
screening strategy
Detection of biomarkers will have profound
implications for more precise selection and
stratification of population at risk for lung cancer
Meyerson. J Clin Oncol. 2005; 23:3219
Zhong. Am J Respir Crit Care Med. 2005; 172:1308
Field. J Thorac Oncol. 2006; 1:497