Transcript MRI Follow-Up Conference September 24, 2001

Implications of lung cancer
screening in the new millenia
Andrew R. Haas, MD, PhD
Assistant Professor of Medicine
Section of Interventional Pulmonary and Thoracic Oncology
Perelman School of Medicine of the University of Pennsylvania
[email protected]
Disclosures
• None
Rationale for lung CA screening
• Lung CA
– 2nd most common cancer in the US
– Most common cause of cancer death in the US
and world
– Prognosis depends primarily upon stage at
diagnosis
– Early detection with screening may lead to
improved outcomes???
Siegel et al, CA Cancer J Clin 2011
Rationale for lung CA screening
• Smoking
– ~1 in 5 adults (~46 million people) in US smoke
– #1 risk factor for lung CA
• ~85% of lung CA deaths are due to smoking
– > 94 million current and former smokers in US are
at increased risk for lung CA
http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5935a3.htm
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5844a2.htm
Prior Lung Ca Screening Trials
• CXR vs. usual care
• CXR vs. CXR with sputum cytology
• CT scan vs. usual care
No benefit until – National Lung Screening trial
Fontana et al Cancer 67:1155; Tockman et al Chest 89:324S
Kubik et al Int J Ca 45:26; Melamed et al Chest 86:44
Oken et al JAMA 306:1865; Hocking et al J NCI 102:722
Infante et al AJRCCM 180:445;
National Lung Screening Trial
(NLST)
 A collaboration between ACRIN and NCI
 The largest and most expensive randomized
clinical trial of a single screening test in US
medical history
$250,000,000
NLST – Eligibility criteria
• Age 55-74 years
• Current or former > 30 pack-year smoking
history
– Former smokers quit within last 15 years
• No history of lung CA
• No treatment for or evidence of any other
cancer within the last 5 years
NLST – Study design
Prospective randomized controlled trial
Screening for 3 consecutive years with either CXR or low-dose chest CT
Enrollment: 8/2002-4/2004
Annual Interim Analyses: 4/2006 - 4/2010
Final: 10/2010
NLST – Primary endpoint
• Lung cancer specific mortality
– 20% difference between CT vs. CXR
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Type 1 error rate (a) = 5%
Power (1 - b) = 90%
Compliance 85% CT | 80% CXR
Contamination 5% CT | 10% CXR
Size = 25,000 subjects/arm
NLST – Secondary endpoints
• Comparison of CT and CXR regarding
– All-cause mortality
– Incidence of lung CA
– Lung CA stage distribution
– Medical resource utilization
– Quality of life and psychological impact
– Cost-effectiveness
NLST – Screen interpretation
 Positive screen
– Non-calcified nodule(s)
> 4 mm
– Other findings
suspicious for lung CA
 Negative screen
– Non-calcified nodule(s)
< 4 mm
– Morphologically benign
nodule(s)
– Other minor
abnormalities
– Clinically important
abnormalities requiring
follow-up but not
suspicious for lung CA
NLST – Subject accrual and
biospecimen collection
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Recruitment from 33
screening centers
Blood, urine, and sputum
biospecimens collected at
– 15 NLST-ACRIN sites
– 10208 subjects total
•
Paraffin blocks of resected
tumors collected
– Across all NLST sites
NLST – Subject accrual
Total 53,454
- CT 26,722
- CXR 26,732
50,000
Subjects
40,000
LSS 34,614
(65%)
30,000
20,000
ACRIN 18,840
(35%)
10,000
Aug 02
Nov 02
Feb 03
May 03
Month Enrolled
Aug 03
Nov 03
Feb 04
NLST Research Team slide set
NLST – Screen positivity rate
Study
year
CT
CXR
Number
screened
Number
positive
% Positive
Number
screened
Number
positive
% Positive
Screen 1
26,309
7,191
27.3
26,035
2,387
9.2
Screen 2
24,715
6,901
27.9
24,089
1,482
6.2
Screen 3
24,102
4,054
16.8**
23,346
1,174
5.0**
All screens
75,126
18,146
24.2
73,470
5,043
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.
NLST Research Team, NEJM 2011
NLST – Significance of
positive screens
Screening
result
Total
Positives
Lung CA
confirmed
Lung CA not
confirmed
CT
CXR
Screen 1 Screen 2 Screen 3
N (%)
N (%)
N (%)
7,191
(100)
6,901
(100)
4,054
(100)
Total
N (%)
18,146
(100)
Screen 1 Screen 2 Screen 3
N (%)
N (%)
N (%)
2,387
(100)
1,482
(100)
270 (3.8) 168 (2.4) 211 (5.2) 649 (3.6) 136 (5.7) 65 (4.4)
6,921
(96.2)
6,733
(97.6)
3,843
(94.8)
17,497
(96.4)
2,251
(94.3)
1,417
(95.6)
1,174
(100)
Total
N (%)
5043
(100)
78 (6.6) 279 (5.5)
1,096
(93.4)
4,764
(94.5)
NLST Research Team, NEJM 2011
NLST – Results
• Lung CA specific mortality
– Relative reduction by 20% (95% CI 6.8-26.7, p=0.004)
(87 fewer deaths in CT vs. CXR arm)
– The number needed to screen with CT to prevent 1
death from lung CA is 320
• All cause mortality
– Rate of death reduction decreased by 6.7% (95% CI
1.2-13.6, p=0.02)
– Rate of death reduction decreased by 3.2% (p=0.28)
when lung CA deaths excluded
• Stage distribution more favorable for CT than CXR
• 70.2% vs. 56.7% were stage I-II
NLST – Biospecimen bank
• Intended for validation of promising
biomarkers in preliminary testing
– Biomarkers for high risk of lung CA
– Biomarkers for benign vs. malignant nodules
– Biomarkers predictive or prognostic of lung CA
behavior
NLST – Pending analyses
• Costs
– Direct medical (screening, Dx tests, Rx’s)
– Non-medical (travel, lodging)
– Opportunity (lost wages)
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Cost-effectiveness (ICER)
Quality of life effects
Smoking behavior effects
Health care utilization
NLST – Pending questions
• Policy recommendations to implement CT
screening in standardized fashion
– Starting age? Frequency? # of scans?
– How do we integrate prevention, Dx, and Rx
algorithms in standardized fashion?
– How extrapolate/model to other populations?
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Younger or older people
People with lower smoking history
People with family history
Non-urban non-3o community practice settings
NLST – Pending questions
• Who will cover costs of CT screening?
– Out-of-pocket? Insurance? Tobacco industry?
• How can the number of false positive CT
screens be decreased?
• What other factors define very high risk?
– Biospecimen analysis
“Formal” guidelines
• American College Chest Physicians
• American Society of Clinical Oncology
• National Comprehensive Cancer Netwrok
– 55-74 yo
– > 30 pk-yrs tobacco use
• US Preventive Services Task Force
– No guideline comments
Implications of lung cancer screening
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10 – 15 million smokers fulfill screening criteria
2.5 – 4.5 million new pulmonary nodules
Cost – $5 – $7.5 billion USD
Screen positives that went on to biopsy –
estimated deaths
Conclusions
• The NLST has shown that CT screening
– Decreases lung CA specific mortality
– Has a high false positive rate
• Further analyses ongoing
• Additional questions about CT screening need to
be answered prior to implementation
• Smoking prevention and cessation are still critical
to reduce lung CA incidence and mortality rates
The National Lung Screening Trial has
demonstrated which of the following :
• A) A reduction in all cause mortality of 15.3%
• B) A modest false positive rate of 9%
• C) A relative reduction in lung cancer specific
mortality of 20%
• D) Follow up of false positive scans had no
patient impact
• E) A very cost effective approach to reduction
in lung cancer mortality
Thank you!