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National Lung Screening Trial
Design Specifications
Ella A. Kazerooni, M.D.
Professor & Director
Cardiothoracic Radiology
Associate Chair for Clinical Affairs
University of Michigan
Lung Cancer Screening Outline
 Background
 NLST Design
 NSLT Results
 What’s next?
Lung Cancer Screening Background
 Leading cause of cancer death in both men & women
Estimated Cancer Cases & Deaths
ACS Facts & Figures 2010
New Cases
Deaths
Breast
209,060 (14%)
40,230 (7%)
Prostate
217,730 (14%)
32,050 (6%)
Colorectal
142,570 (9%)
51,370 (9%)
Lung
222,520 (15%)
157,300 (28%)
All Sites
1,529,560
569,490
5-Year Relative Survival Rates by Stage
1999-2005 (NCI/SEER)
All
Local Regional Distant
Breast
89%
98%
84%
23%
Colorectal
65%
91%
70%
11%
Prostate
100%
100%
100%
31%
Lung/Bronchus
16%
53%
24%
4%
Pancreas
6%
22%
9%
2%
Esophagus
17%
37%
19%
3%
Lung Cancer Screening Background
 Large population at risk due to cigarette smoking and
second hand smoke exposure
• ≈ 60 million current smokers
(19.3% of U.S. adults in 2010; 3
million fewer than 20.9% in 2005
• ≈ 30 million former smokers
• Tobacco: leading cause of
preventable death & illness;
responsible for 1 in 5 deaths
Smoking in the U.S.
CDC. Vital Signs: Current Cigarette Smoking Among Adults Aged ≥ 18 Years ―
United States 2005-2010. Morbidity and Mortality Weekly Report 2011;60(35):1207-1211
Low: Utah & California
High: Kentucky & West Virginia
Smoking in the U.S.
90% of new
smokers begin as
teenagers
every day ≈ 3500
kids aged 12-17
smoke for the first
time
American Academy of Pediatrics
Source: CDC Office of Smoking and Health; National
Center for Tobacco-Free Kids
Second Hand Smoke in U.S.
2006 US Surgeon General Report: The Health Consequences of Involuntary Exposure
to Tobacco Smoke; and ACS Facts & Figures 2010
• > 126 million are exposed to SHS
• 3,400 lung cancer deaths / year
• 46,000 heart disease deaths / year
• SHS exposure is declining
• 84% in 1988-94 to 46% in 1999-2004
• 74% of population is covered by smoke free
policies in work places and restaurants/bars
Lung Cancer Screening Background
 Many single arm prospective cohort studies using
low dose helical CT have demonstrated:
− Smaller size and lower stage of screen detected cancers
(stage shift) compared to symptom detected cancer
CT Lung Cancer Screening Trials
Prevalence Results
Kaneko
Sone
ELCAP
Swensen
Diederich
Fl/Moffitt
Japan
N
nodules
1369
5483
1000
1520
817
1150
7956
13.1%
12.3%
23%
51%
43%
35%
26%
cancer stage I
0.38%
0.48%
2.7%
1.3%
1.3%
3.0%
0.4%
93%
84%
85%
71%
58%
44%
86%
CT Lung Cancer Screening Trials
Prevalence Results
N
Sone
ELCAP
Swensen
Diederich
Nawa
5483
1000
1520
817
7986
cancers (≤ 1cm)
23 (6; 27%)
31 (15; 56%)
27 (9; 34%)
12 (0; 0%)
37 (6; 16%)
mean size
15 mm
15 mm
17 mm
25 mm
17 mm
Lung Cancer Screening Background
 Many single arm prospective cohort studies using
low dose helical CT have demonstrated:
− Smaller size and lower stage of screen detected cancers
(stage shift) compared to symptom detected cancer
− Improved survival
I-ELCAP 10-Year Survival
I-ELCAP Investigators; NEJM 2006;355:1763-1771
31,567 persons screened
1993-2005
27,456 repeat screenings
1994-2005
7-18 m after baseline
484 lung cancers
412 (85%) stage I lung ca
88% 10 yr survival
302 stage I lung ca
resected within 1 m of dx
92% 10 yr survival
Biases of Early Detection
 lead time (earlier diagnosis)
 length (less rapid progression)
 over diagnosis (pseudodisease)
Natural History of Cancer
Preclinical
Clinical
DPCP
disease detectable
onset
by test
signs
& sx
death
DPCP = detectable preclinical phase
Lead Time Bias
disease
disease
Test +
s/sx
death
s/sx
death
lead time
false calculation of improved survival
Length Bias
 slowly progressive disease more amenable to
detection than disease that develops and
progresses quickly between screenings
 screened cases less aggressive than sx cases
diagnosis
disease
DPCP
indolent
aggressive
diagnosis
DPCP
death
death
Pseudodisease – Overdiagnosis Bias
 Inherent in screening
 disease that would have remained
subclinical if not detected at screening
− does not progress to symptomatc disease (DCIS)
− patient dies of something else (prostate ca)
 autopsy prevalence of disease higher than
clinical prevalence of disease
− up to 16% of lung cancer not suspected before death
 pathologic misdiagnosis (hyperplasia vs. ca)
Lung Cancer Screening Background
 Leading cause of cancer death in both men & women
 Large population at risk
 Many single arm prospective cohort studies using
low dose helical CT have demonstrated:
− Improved survival
− Lower stage of screen detected cancers (stage shift)
 No screening test has been shown to
reduce lung cancer mortality
N LST
National Lung
Screening Trial
National Cancer Institute
Denise R. Aberle, MD
Cancer Imaging Program, DCTD | NCI
David Geffen School of Medicine at UCLA
National PI, ACRIN-NLST
American College of Radiology
Imaging Network
Christine D. Berg, MD
Chief, Early Detection Research Group
Division of Cancer Prevention | NCI
Project Officer, LSS-NLST
Lung Screening Feasibility
Study of the PLCO Trial
ACRIN
American College of Radiology Imaging Network
 Funded in 1998 by NCI as a non-member network
 Conducts clinical trials of imaging research to lengthen &
improve the quality of cancer patient’s lives
 First 10 years: enrolled > 76,000 subjects, collected > 20
million images & over 50 publications
 Major trials:
− DMIST – Digital Mammographic Imaging Screening Trial 2001
− NLST – National Lung Screening Trial 2002
− National CT Colonography Trial 2005
− RESCUE 2011
PLCO
Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial
 These 4 cancers account for approx. 40% of new cancers
diagnosed & 45% of cancer deaths in U.S.
 10 site clinical trial to determine if screening reduces
mortality; run by NCI’s Cancer Division of Cancer Prevention
 Half screening tests / half routine health care
 Enrolled 155,000 men & women aged 55-74 years between
1992 and 2001
 Screening ended 2006; 10 year follow up in progress
NLST Design
NLST Design
NLST Research Team. Radiology 2011; 258:243-253





Multicenter, randomized trial
Low dose helical CT vs. CXR
Current and former heavy smokers (≥ 30 pack-yrs)
Age 55-74 years
Does early detection reduce lung cancer specific
mortality?
• 5-year survival stage IA 70%
• 5-year survival stage IV 5%
• > 75% lung cancer patients present with locally
advanced or metastatic disease
NLST Design
Arms
Helical CT vs. CXR
Difference in
lung cancer-specific mortality
20%
α
5%
Power
90%
Compliance
85% CT | 80% CXR
Contamination
5% CT | 10% CXR
Size
25,000 / arm
NLST: Endpoints
 Primary:
 Secondary:
Lung cancer specific mortality
All cause mortality
Lung cancer incidence
Lung cancer stage distribution
Diagnostic performance
Adverse impact of diagnostic
evaluation
NLST-ACRIN: Substudies
 Analyses:
Cost effectiveness analysis
Health care resource use
Effect of screening on quality of life
T0, T1, T2; SF-36, EQ-5D; 16 sites
Effect of (+) screen on anxiety
T0, 30 days post screen & q 6 mths
SF-36, EQ-5D, STAI
Smoking cessation
NLST Biorepository
 15 ACRIN sites collected serial blood, urine &
sputum specimens annually x 3 for validation
of biomarkers (n = 10,260)
 All sites collected lung cancer specimens in
paraffin blocks
 Available to researchers through a peer-review
process
NLST – 33 Participating Sites
LSS si
NLST: CXR Technique
NLST Research Team. Radiology 2011; 258:243-253
 PA Inspiratory CXR
 CR or DR, some film-screen
 Average effective dose 0.02 mSv
NLST: CT Technique
Cagnon CH, et al. Academic Radiology 2006; 13:1431-1441
 Target Technique based on
−
−
−
−
Detect and follow nodules ≥ 4 mm
Single breath-hold
Avoid edge enhancement at nodule borders
Low radiation exposure (av effective dose 1.5 mSv)
 CT Technique Chart
−
−
−
−
Standardized 18 parameters
14 different CT scanner platforms
4 manufacturers: 4-64 channel
Individualized protocols
NLST: CT Technique Chart
GE-VCT(64)
64 slice | 0.5 sec
Siemens
Sensation 64
64 x 0.0.6
Phillips MX8000 16
slice | 0.5 sec
16 x .75
Toshiba Aquillon
16 slice | 0.5 sec
120
120
120
120
Gantry Rotation Time
0.5 sec
0.5 sec
0.5 sec
0.5 sec
mA (Regular-Large Patient)
50-100
50-100
75-15-
80-160
mAs (Regular-Large)
25-50
25-50
37.5-75
40-80
Scanner Effective mAs (Reg-Large)
27-53
25-50
25-50
26.7-53.3
0.625 mm
0.6 mm
.75 mm
2 mm
Number of Active Channels: N
64
32
16
16
Detector configuration: N x T
64 x 0.625 mm
32 x 0.6 mm
16 x 0.75
16 x 2
MODE (Thick/Speed) or Console Collimation1
.625/.984/39.37
64 x 0.6 mm
N/A
N/A
39.37 mm
19.2 mm
18 mm
48 mm
0.984
1.0
1.5
1.5
Table speed (mm/second)
78.74 mm/sec
38.4 mm/sec
36 mm/sec
96 mm/sec
Scan time (40 cm thorax)
5.1 sec
11 sec
11 sec
4.2 sec
Max Nominal Reconstructed Slice Width
2.5 mm
2 mm
2 mm
2 mm
Reconstruction Interval
2.0 mm
1.8 mm
1.8 mm
1.8 mm
Reconstruction Algorithm
STD
B30f
B or C
FC 10
# Images/Data set (40 cm Thorax)
200
223
223
223
2.2-2.4 mGy
1.9-3.8 mGy
1.9-3.8 mGy
2.7-5.4 mGy
Parameter
kV
Detector Collimation (mm): T
Table Incrementation (mm/rotation): I
Pitch ([mm/rotation]/configuration): I/NT
CTDIvol Dose in mGy (Regular-Large)
CT Scanners in NLST: # of Detectors
Cody DD et al. Americam Journal of Roentgenology 2010;194:1539-1546
NLST: Positive CT Screen Definition
 nodule  4 mm
 indeterminate nodule
» new nodule 4-10 mm
» growing nodule < 7 mm
» f/u CT 6, 12, 24 months
 abnormal
»
»
»
»
new nodule > 10 mm
growing nodule > 7 mm
nodule enhancement CT or FDG-PET
(+) nodules: definitive biopsy/diagnosis
NOTE: no trial wide algorithms for evaluation & treatment
NLST Cumulative Accrual
NLST Cumulative Accrual
60000
Total (53,464)
50000
Participants
40000
LSS (34,614)
30000
20000
ACRIN (18,850)
10000
0
Aug-02
Nov-02
Feb-03
May-03
Aug-03
Month Enrolled
Nov-03
Feb-04
NLST Timeline
6th Interim Analysis
5th Interim Analysis
4th Interim Analysis
T2
3rd Interim Analysis
T1
2nd Interim Analysis
time
9/09 9/10 10/20/10
9/07 9/08
9/06
9/05
9/04
9/03
9/02
1st Interim Analysis
T0
National Lung Screening Trial
Design Specifications
Ella A. Kazerooni, M.D.
Professor & Director
Cardiothoracic Radiology
Associate Chair for Clinical Affairs
University of Michigan
NLST: Subjects – Age & Gender
NLST: Subjects – Race/Ethnicity
NLST: Subjects – Smoking History
NLST Demographics vs. US Population
 United States Census Department Tobacco Use
Supplement of Continuing Population Survey for 20022004
 Information on 240,000 respondents
 Reviewed subset of respondents aged 55-74, with 30+
pack year smoking, either current smoker or former
smoker who quit within the past 15 years
 Identified smoking status, age, sex, race, ethnicity, marital
status, and education
NLST Demographics vs. US Population
NLST
US Census
59.0
58.5
55-59 (%)
60-64 (%)
65-69 (%)
70-74 (%)
42.8
30.6
17.8
8.8
35.2
29.3
20.8
14.7
Race/ethnicity
Black (%)
Hispanic (%)
4.4
1.7
5.5
2.4
Male (%)
Age
NLST Demographics vs. US Population
Married
Education
< HS
≥ College
Current smoker
Median pack years
NLST
66.6
US Census
60.0
6.1
31.5
21.3
14.4
48.2
48.0
57.1
47.0
NLST Demographics vs. US Population
 Compared with similar US population, NLST
subjects have:
−similar gender distribution and smoking exposure
−are younger
−better educated
−less likely to be current smokers
NLST: Family History of Lung Cancer
Any first degree relative
Two or more first degree relatives
CT
CXR
Total
21.8 %
21.7 %
21.7 %
3.3
3.2
3.3
Screening Exam Compliance & Crossover
Helical CT
CXR
Total
Study
Year
Expected Screened Expected Screened Expected Screened
T0
26,713 98.5% 26,722 97.5% 53,435 98.0%
T1
26,282 94.0% 26,398 91.3% 52,680 92.6%
T2
25,935 92.9% 26,097 89.5% 52,032 91.2%
Compliance: 95% CT arm & 93% CXR arm
Crossover: 4.3% in LSS CXR arm underwent CT
NLST: Screen Positivity* Rate by
Screening Round and Trial Arm
CT
CXR
Number
screened
Number
positive
% Positive
Number
screened
Number
positive
% Positive
Screening
round 1
26,309
7,191
27.3
26,035
2,387
9.2
Screening
round 2
24,715
6,901
27.9
24,089
1,482
6.2
Screening
round 3
24,102
4,054
16.8**
23,346
1,174
5.0**
All 3 rounds
75,126
18,146
24.1
73,499
5,043
6.9
*A positive screen is one that may be suspicious for lung cancer.
**A suspicious abnormality that has been stable for 3 rounds may be called negative according to protocol.
NLST: Clinically Significant NON lung
cancer by Screening Round & Trial Arm
CT
CXR
Number
screened
Number
%
Number
screened
Number
%
Screening
round 1
26,309
2695
10.2
26,035
785
3.0
Screening
round 2
24,715
1519
6.1
24,089
429
1.8
Screening
round 3
24,102
1408
5.8
23,346
361
1.5
All 3 rounds
75,126
5622
7.5
73,499
1575
2.1
NLST: True and False Positive Screens by
Screening Round and Trial Arm
CT
Total positives
With lung cancer
Without lung cancer
CXR
Round 1
N (%)
Round 2
N (%)
Round 3
N (%)
Round 1
N (%)
Round 2
N (%)
Round 3
N (%)
7,193
(100)
6,902
(100)
4,054
(100)
2,387
(100)
1,482
(100)
1,175
(100)
270 (4)
6,923 (96)
168 (2)
6,734 (98)
211 (5)
3,843 (95)
136 (6)
2,251 (94)
65 (4)
1,417 (96)
78 (7)
1,097 (93)
Results of Interim Analysis of Primary Endpoint
Reported on Oct. 20, 2010
Person
years (py)
Lung
cancer
deaths
Lung
cancer
mortality
per
100,000 py
Reduction
in lung
cancer
mortality
(%)
Value of
test
statistic
Efficacy
boundary
144,097.6
354
245.7
20.3
–3.21
–2.02
CXR 143,363.5
442
308.3
Arm
CT
Deficit of lung cancer deaths in CT arm exceeds that expected by
chance, even allowing for multiple looks at the data
Results of Analysis of All-cause Mortality
(Secondary Endpoint)
Reported on Oct. 20, 2010
Person
years (py)
Deaths
All-cause
mortality
per
100,000
py
Reduction
in all-cause
mortality
(%)
Value of
test
statistic
Value
for
significance
CT
167,389.9
1870
1117.2
6.9
–2.27
–1.96
CXR
166,328.2
1996
1200.0
Arm
Deficit of deaths in CT arm exceeds that expected by chance.
NLST: Cumulative # of Lung Cancers
NLST: Cumulative # of Lung Cancer Deaths
Kaplan-Meier Curves for Lung Cancer Mortality
Table 11.5.3a
Kaplan-Meier Curves for All-Cause Mortality
Table 11.5.6a
Kaplan-Meier Curves for Lung Cancer Case Survival
(Lung Cancer Cause of Death)
Table 11.5.3d
ACRIN-NLST Sub-Studies
 Serial specimen collection for validation of biomarkers
(N=10,260)
− Plasma | buffy coat; sputum; urine annually x 3 yrs
− Resected lung cancer specimens
− Applications to use specimens for research www.acrin.org
 Quality of life
− Differential impact of screening of QoL at T0, T1, T2 (SF-36, EQ-5D)
− Differential impact of [+] screen on anxiety (SF-36, EQ-5D, STAI)
Administered at T0, 30 days post [+] screen and Q 6 months)
 Formal cost effectiveness analysis (in conjunction with RAND)
 Effects of screening on smoking behaviors | beliefs
− Short and long term
Cancer or not?
Radiation Exposure
Brenner DJ et al. Radiology 2004;231:440-445
Radiation Risks Potentially Associated with Low Dose Screening
• assumptions:
 entire US population current/former smokers
 age 50-75 years
 annual CT until age 75 (5.2 ± 0.9 mGy to lung; 60mAs)
 50% compliance rate
 atomic bomb survivor cohort for predicting risk
• expect 1.9 million lung cancers
• 36,000 additional lung cancers attributed to CT
• 1.8% increase in lung cancer (95% CI 0.5-5.5%)
Lung Cancer Screening – what’s the future?
 Awaiting data publication of primary end point and importantly
cost effectiveness analysis necessary when informing
recommendations about screening
 Screening as a public health recommendation
 For CMS, screening requires federal legislation
 Many sites considering or developing high risk screening
programs – what’s a best practice?
 Patient requests for screening CT have not been as large as
expected
 Many interested parties, most taking a cautious approach
American Cancer Society, November 4, 2010
So if you are contemplating getting screened for lung
cancer—and from what I hear there are a fair number of
smokers thinking of doing just that—be certain you
understand what we don’t know about the benefits of
getting such a test (which means we can’t say that it
really saves lives) and what we do know about the
downsides, as reported in this study.
Remember, just because we doctors can do things
doesn’t always means it’s always the best thing to do.
So be cautious, and be informed.
American College of Radiology
As the expert organization in this area of care, the ACR is very
encouraged by the NLST results. The College looks forward to
working with the U.S. Department of Health and Human Services,
the National Cancer Institute, patient advocacy groups, Congress
and other stakeholders in addressing challenges to a potential lung
cancer screening program.
Until and unless a national lung cancer screening program can be
put in place, we encourage all physicians to obtain as much
information regarding the NLST as possible. We also encourage
patients to speak with their doctors regarding the usefulness of CT
scanning to screen for lung cancer in their particular cases.
Lung Cancer Screening
NLST results & next steps
Ella A. Kazerooni, M.D.
Professor & Director of
Cardiothoracic Radiology
University of Michigan