Transcript Lung Cancer Screening Are We Any Closer in 2002?

Lung Cancer Screening in 2013
Cheryl Czerlanis, MD
Loyola University Medical Center
March 02, 2013
The scope of the problem



An estimated 29% of the global population older
than 15 years smokes tobacco.
75% of patients with lung cancer present with
symptoms due to locally advanced or metastatic
disease.
Overall five-year survival for lung cancer is 16%.
Fry WA. Cancer 1999;86:1867-76.
Ten Leading Cancer Types for the Estimated
New Cancer Cases and Deaths by Sex, 2013
From Seigel,R et al.
CA Cancer J Clin 2013; 63(1): 14.
Five-year overall survival by stage (percent)
Goldstraw, P, et al. J Thorac Oncol 2007; 2:706.
Screening Test Principles
1.
2.
3.
4.
The disease must be prevalent
There must be an advantage to early detection
Screening must be safe, sensitive, and have an
acceptable rate of false positives
Cost to society must be acceptable
Reduce mortality, improve
quality of life, or both.
Henschke CI. Radiol Clinic No Amer 2000;38(3):287-95.
Screening Rationale: Early diagnosis
5–year Survival
Stage Distribution
Wagner H. Cancer Screening 1996;118-49.
Mountain CF. Chest 1997;111:1710-17.
Inoue K. Thorac Cardiovasc Surg 1998;116:407-11.
Outcomes to be assessed in lung
cancer screening trials
Cancer detection rates
 Stage at detection
 Disease–specific mortality
 Overall survival

Mortality rate is the number of persons who die of a
certain cause in a time period per population.
Survival rates calculate the percentage of persons with a
disease who are still alive a set amount of time after
diagnosis.
Methodological biases

Bias related to apparent effects of early diagnosis
and treatment that may inflate the benefit seen by
screening
 Measured
in terms of how screen-detected cases
compare to cases detected by signs and symptoms
 Lead
time bias
 Length time bias
 Overdiagnosis bias
 Volunteer bias
Prior Attempts

1950’s
Four nonrandomized uncontrolled studies
Philadelphia Pulmonary Neoplasm Research Project
 VA Trial
 Tokyo Metropolitan Government Study
 South London Lung Cancer Study


Two nonrandomized but controlled studies
North London Cancer Study
 Erfurt County Study

Patz, EF Jr. NEJM 2000;343(22):1627-33.
Four randomized trials of CXR and
Sputum Cytology (SC)
1970’s
Mayo Lung Project (MLP)
Czechoslovakian Study
Memorial Sloan-Kettering Lung
Project
Johns Hopkins Study
Results

Increased
Number of early stage cancers
 Number of resectable cancers

NO Reduction in Lung Cancer Mortality
 Why?

Screened patients had a higher likelihood of being
diagnosed and living longer from the time of diagnosis.
 But equal numbers of patients in both groups ultimately died
of cancer.

Patz, EF Jr. NEJM 2000;343(22):1627-33.
Low-dose screening CT


No Contrast
Low Radiation Dose
 Average
effective dose varies between 0.6 mSv and
1.5 mSv
 Equivalent to 2 to 5 chest x-rays or a transatlantic flight


Less than a minute
$150-400
Rationale for CT screening
Onset of
tumor
Detectable
by CT
Detectable
by CXR
Onset of
symptoms
Increased window of opportunity
Early Lung Cancer Action Program (ELCAP)



Cornell and NYU
1000 patients
Entry Criteria
 Age
> 60
 ≥ 10 pack year smoking history

Actual Mean Patient
 Age
= 67
 45 pack years

Plain film and CT imaging
Henschke CI. Lancet 1999;354(173):99-105.
ELCAP Protocol

If Negative
 Recommend

If Diffuse disease
 Recommend

annual repeat CT
Pulmonary Evaluation
If Positive
 <5mm
– Follow-up CT scan at 3, 6, 12, 24 months
 6 – 10 mm – Investigator discretion
 > 10 mm – Biopsy or Surgery
Henschke CI. Lancet 1999;354(173):99-105.
ELCAP Data

233 “Positive” Scans (23.3%)
 33
also seen on CXR
 Conversely, less than half of the “nodules” seen on CXR
were confirmed on CT

27 Malignant NCN (2.7%)
 CXR
missed 20 of these
 Mainly adenocarcinoma
 (Plus 4 other malignancies: 2 endobronchial lesions and
2 mediastinal adenopathy)
Henschke CI. Lancet 1999;354(173):99-105.
233 Patients with non-calcified nodules
Size of Largest NCN
%
Number of NCN’s/Scan
70
70
60
60
50
50
40
40
30
% 30
20
20
10
10
0
0
2-5
6-10
11-20
mm
>20
1
2-3
4-6
number
Henschke CI. Lancet 1999;354(173):99-105.
Chance of Malignancy
Size of Largest NCN
Number of NCN’s/Scan
1%
70
70
60
60
24%
50
%
12%
50
40
%
33%
30
20
80%
10
10%
40
30
14%
20
10
0
0
2-5
6-10
mm
11-20
>20
1
2-3
4-6
number
Henschke CI. Lancet 1999;354(173):99-105.
Characteristics of the 27 lung cancers
Stage distribution
Results


II
III

85% were stage I
83% missed by CXR
96% were resectable
I
Henschke CI. Lancet 1999;354(173):99-105.
CT scan versus CXR

More sensitive
 Non-calcified
nodules (23 versus 7 percent)
 Malignancy (2.7 versus 0.7 percent)
 Benign nodules (20.6 versus 6.1 percent)

BUT no stage shift
 3.0/1000
versus 2.1to 3.8/1000 with advanced
disease
Patz, EF Jr. NEJM 2000;343(22):1627-33.
Other results

The rate of biopsy for benign disease was 1.7%
4


of 233 patients
No patient underwent a thoracotomy for a benign
lesion in the ELCAP study
ELCAP had no control group
 Mortality
inferences are subject to bias
Meta-analysis of baseline findings of
randomized, controlled trials
Name
Screening
Duration
Control
Arm
Garg/Colorado
University
2001
50-80
DANISH
2004-2006
49-74
NELSON
2004-
50-75
ITALUNG
2004-2006
55-69
LSS
2000-2004
CXR
55-77
DEPISCAN
2002-2004
CXR
50-75
DANTE
2001-2006
CXR
60-74
Age
CT Screening for lung cancer
Odds Ratio
95% CI
Higher number of
stage 1 cancers
3.9
2.0 – 7.4
Higher total lung
cancers
4.1
2.4 – 7.1
Detection of falsepositive nodules
3.1
2.6 – 3.7
Thoracotomies for
benign lesions
Event rate 3.7 3.5 – 3.8
per 1000
Gopal M. J Thorac Oncol. 2010;5:1233-1239.
National lung cancer screening trial


More than 53,000 current or former smokers were
enrolled in NLST at more than 30 study sites across
the country (2002–2004)
Examined the risks and benefits of spiral CT scans
compared to chest X-rays.
 Repeated

at one and two years after the first scan.
Powered to detect a 20% reduction in mortality due
to screening.
NLST design
Prospective, randomized trial comparing low-dose helical CT screening
to chest x-ray screening with the endpoint of lung cancer specific
mortality in high risk participants
Eligibility





Age 55-74
Asymptomatic current or former smoker; 30 pack year smoking history
Former smokers: quit within preceding 15 years
No prior lung cancer diagnosis
No evidence of other cancer within preceding 5 years
http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full
Slides courtesy of Christine Berg, MD (NIH)
NLST primary endpoint
Helical CT vs. CXR
Lung cancer-specific mortality
20% difference
α
5%
Power
90%
Compliance
85% CT | 80% CXR
Contamination
5% CT | 10% CXR
Size
25,000 / arm
http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full
NLST secondary endpoints
 Secondary endpoints
 All cause mortality
 Lung cancer: prevalence | incidence | interval cancers
 Stage distribution
 Screening test performance
 Medical resource utilization for [+] screen
http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full
Slides courtesy of Christine Berg, MD (NIH)
Comparing NLST with eligible US census population
53,454 participants
NLST
US Census
Male (%)
Age
59.0
58.5
55-59 (%)
60-64 (%)
65-69 (%)
70-74 (%)
Race | Ethnicity
Black (%)
Hispanic (%)
42.8
30.6
17.8
8.8
35.2
29.3
20.8
14.7
4.4
1.7
5.5
2.4
Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.
Comparing NLST with US census population
NLST
US Census
66.6
60.9
< HS
6.1
21.3
≥ College
31.5
14.4
Current smoker
48.2
57.1
Median pack yrs
48.0
47.0
Married
Education
Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.
Comparing NLST with US census population
 Compared with similar US population, NLST cohort has
similar gender distribution and smoking exposure
 However, NLST participants
 Younger
 Better educated
 Less likely to be current smokers
Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.
Screening exam compliance
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%
Helical CT
Chest X-ray
Total
Screen positivity rate by screening round & arm
Low dose helical CT
CXR
Number
screened
Number
positive
%
Positive
Number
screened
Number
positive
% Positive
Screen 1
26,314
7,193
27.3
26,049
2,387
9.2
Screen 2
24,718
6,902
27.9
24,097
1,482
6.2
Screen 3
24,104
4,054
16.8**
23,353
1,175
5.0**
All screens
75,136
18,149
24.2
73,499
5,044
6.9
*
**
Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer.
Abnormality stable for 3 rounds could be called negative by protocol.
True and false positive screens
Screening
Result
Low Dose Helical CT
CXR
Screen 1
N (%)
Round 2
N (%)
Round 3
N (%)
Round 1
N (%)
Round 2
N (%)
Round 3
N (%)
Total Positives
7,193 (100)
6,902 (100)
4,054 (100)
2,387 (100)
1,482 (100)
1,175 (100)
Lung cancer
No lung cancer
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)
Data reflect the final interpretation, including benefit of historical comparison exams.
Interim analysis: lung cancer mortality 10-20-2010
Arm
Person
Years (py)
Lung
cancer
deaths
Lung cancer
mortality per
100,000 py
Reduction in
lung cancer
mortality (%)
Value of
test
statistic
Efficacy
boundary
CT
144,097.6
354
245
20.3
–3.21
–2.02
CXR
143,363.5
442
308
p = 0.0041
Deficit of lung cancer deaths in CT arm exceeds that expected by chance,
even allowing for multiple looks at the data.
Interim analysis: all-cause mortality 10-20-2010
Deaths
All-cause
mortality per
100,000 py
Reduction in
all cause
mortality (%)
Value of
test
statistic
CT 167,389.9
1870
1117
6.9
–2.27
CXR 166,328.2
1996
1200
Arm
Person
Years (py)
p = 0.023
 Lung cancer: 25% of all deaths in NLST
 Lung cancer: 56% of 126 excess deaths in CXR arm
Value for
significance
–1.96
Kaplan-Meier curves for lung cancer mortality
1.00
Probability of survival: ALL participants
0.99
0.98
0.97
0.96
0.95
0.94
0.93
0.92
0.91
0.90
0
1
2
3
4
Years from randomization
5
6
CT arm
CXR arm
7
Kaplan-Meier curves for all-cause mortality
1.00
Probability of survival: ALL participants
0.99
0.98
0.97
0.96
0.95
0.94
0.93
0.92
0.91
0.90
0
1
2
3
4
Years from randomization
5
6
7
8
CT arm
CXR arm
Results

At the time the DSMB held its final meeting on
October 20, 2010:
 356
deaths from lung cancer had occurred among
participants in the CT arm of the study
 443 lung cancer deaths had occurred among those in
the chest X-ray group
 The DSMB concluded that this 20.3 percent reduction in
lung cancer mortality met the standard for statistical
significance and recommended ending the study.
Conclusions





The vast majority of lung nodules detected by either
CT or CXR are benign.
Most CT-detected nodules require some form of
additional follow-up.
CT detects more lung cancers than does CXR.
Most of these excess cancers are early stage
cancers.
Screening programs still uncover late-stage cancers
on initial and interval scans.
Conclusions


Prior to the NLST trial, there had been no evidence
of a mortality benefit for lung cancer-related
mortality with CT screening.
The NLST trial showed a 20% relative risk reduction
in lung-cancer specific mortality.
Cost-effectiveness ratio

Modeling algorithm
 Analysis
based on a model designed prior to
completion of NSLT modeled cost-effectiveness of CT
scan screening for six patient cohorts
 Different
ages and smoking histories
 CT
screening may decrease lung cancer at 10 years by
18 to 25% at a cost ranging from $126,000 to
$269,000 per quality adjusted life year (QALY)
 Cost-effective


ratio for other screened cancers
Colorectal cancer was $47,700 per QALY
Breast cancer was $13,300 to $32,000 per QALY
McMahon PM, et al. J Thorac Oncol 2011; 6:1841.
Number needed to screen




NNS represents the number of patients who must
screened over a given period of time to prevent
one death from the disease in question.
Reflects both the prevalence of the disease and the
effectiveness of therapy.
Does not specifically account for the risks or the
costs of screening.
Reciprocal of the frequency of the reduction in
absolute risk.
Other screening modalities
SCREENING MODALITY
NUMBER NEEDED TO SCREEN
Annual screening mammography of
women ages 40-841
84
Biennial screening mammography of
women ages 50-741
144
Guaiac-based FOBT screening2
1,173 to prevent 1 death over 10 years
Colonoscopy3
200 men with regular screening
Papanicolaou smear screening for
cervical cancer4
1,140 women with regular screening to
prevent 1 death over 10 years
Low-dose CT screening for lung
cancer5
256 persons screened annually for three
years to prevent 1 death over 6 years
1Hendrick
RE, et al. Am J Roentgenol. 2012 Mar;198(3):723-8.
P, et al. Cochrane Database Syst Rev. 2007;(1):CD001216.
3Barrett B et al. Fam Med 2011;43(4):248-53.
4Benedet JL, et al. Am J Obstet Gynecol. 1992;166:1254–9.
5Berg CD, et al. N Eng J Med. 2011;365(5):395-409.
2Hewitson
Recommendations for screening by
expert groups

In 2012, a systematic review was commissioned by
American Cancer Society (ACS), American College
of Chest Physicians (ACCP), American Society of
Clinical Oncology (ASCO), and the National
Comprehensive Cancer Network (NCCN)
 Screening
guidelines supporting low-dose CT scans for
high-risk groups were issued by the NCCN and
ACCP/ASCO
Bach, PB, et al. JAMA. 2012: 307(22): 2418-2429.
Guidelines for lung cancer screening
American Cancer
Society
Recommends that clinicians with access to high-volume, high-quality lung
cancer screening and treatment centers should initiate a discussion about
screening with apparently healthy patients aged 55 years to 74 years
who have at least a 30 pack-year smoking history and who currently
smoke or have quit within the past 15 years.
2013
ACCP/ASCO
Recommends annual low-dose CT screening for high-risk individuals
(ages 55 to 74 years with 30 pack-year history of smoking and current
smoker or quit within past 15 years).
2012
National
Comprehensive
Cancer Network
(NCCN)
Recommends annual low-dose CT screening for high-risk individuals
(ages 55 to 74 years with 30 pack-year history of smoking or 20 packyear history with an additional risk factor).
2011
US Preventive
Services Task Force
Evidence is insufficient to recommend for or against screening
asymptomatic persons for lung cancer with CXR, low-dose CT, or a
combination.
2004;
undergoing
review
Canadian Task Force
on the Periodic Health
Examination
Recommends against the use of chest x-ray in asymptomatic persons.
Evidence is insufficient to recommend for or against screening with spiral
CT in asymptomatic persons.
2003;
undergoing
review
Issues to be addressed






Optimal population for screening
Cost-effectiveness of screening
Optimal management of screen-detected nodules
Optimal screening interval and number of screening rounds
Reimbursement issues
Importance of implementing screening programs only in the
setting of multidisciplinary programs with experience in
evaluation and management of early lung cancers
A proven intervention