Denise R. Aberle, MDDenise R. Aberle, MDProfessor of Radiology and BioengineeringProfessor of Radiology and Bioengineering

David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLANational PI, ACRINNational PI, ACRIN--NLSTNLST

Christine D. Berg, MDChristine D. Berg, MDChief, Early Detection Research GroupChief, Early Detection Research GroupDivision of Cancer Prevention, NCIDivision of Cancer Prevention, NCIProject Officer, LSSProject Officer, LSS--NLSTNLST

National LungScreening Trial

National Cancer Institute

National LungScreening Trial

National Cancer Institute

I have no conflicts of interest. I have no conflicts of interest. I am discussing lung cancer screening with lowI am discussing lung cancer screening with low--dose helical CT and CXR. Neither has been dose helical CT and CXR. Neither has been approved for screening by the FDA. approved for screening by the FDA.

Trial Design and Initial Trial Results FalseFalse--positive Rates and Evaluation of a Positive positive Rates and Evaluation of a Positive ScreenScreen

Quality Assurance | Radiation Dose with LowQuality Assurance | Radiation Dose with Low--Dose Dose Chest CT in the NLST Chest CT in the NLST Important Forthcoming NLST Studies of the Impact Important Forthcoming NLST Studies of the Impact of Screeningof Screening

Prospective, randomized trial comparing lowProspective, randomized trial comparing low--dose helical CT screening dose helical CT screening to chest xto chest x--ray screening with the endpoint of lung cancer specific ray screening with the endpoint of lung cancer specific mortality in high risk participantsmortality in high risk participants

EligibilityAge 55-74Asymptomatic current or former smoker; 30 pack year smoking historyFormer smokers: quit within preceding 15 yearsNo prior lung cancer diagnosisNo evidence of other cancer within preceding 5 years

http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full

NLST design and projected timeline

CT Arm

CXR Arm

1:1High-RiskSubjects

time9/02 9/03 9/04 9/05 9/06 9/07 9/08 9/09 9/10 9/11

T0

T1T2

Annual Interim Analyses : 4/2005 - 4/2010Final: October 2010

http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full

Participating sites

ACRIN 23LSS 10

NLST primary endpoint

Helical CT vs. CXRHelical CT vs. CXR

Lung cancer-specific mortality 20% differenceα 5%

Power 90%Compliance 85% CT | 80% CXR

Contamination 5% CT | 10% CXRSize 25,000 / arm

http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full

Secondary endpointsSecondary endpointsAll cause mortality All cause mortality Lung cancer: prevalence | incidence | interval cancersLung cancer: prevalence | incidence | interval cancersStage distributionStage distributionScreening test performanceScreening test performanceMedical resource utilization for [+] screenMedical resource utilization for [+] screen

Secondary endpointsSecondary endpointsAll cause mortality All cause mortality Lung cancer: prevalence | incidence | interval cancersLung cancer: prevalence | incidence | interval cancersStage distributionStage distributionScreening test performanceScreening test performanceMedical resource utilization for [+] screenMedical resource utilization for [+] screen

NLST cumulative accrual – 33 sites

50,00050,000

40,00040,000

30,00030,000

20,00020,000

10,00010,000

Aug 02Aug 02 Nov 02Nov 02 Feb 03Feb 03 May 03May 03 Aug 03Aug 03 Nov 03Nov 03 Feb 04Feb 04

Total 53,454Total 53,454

LSS 34,614LSS 34,614

ACRIN 18,840ACRIN 18,840

Partic

ipants

Month EnrolledMonth Enrolled

United States Census Dept Tobacco Use Supplement of United States Census Dept Tobacco Use Supplement of Continuing Population Survey for 2002Continuing Population Survey for 2002--20042004

Contains information on 240,000 respondentsContains information on 240,000 respondents

Subset of respondents aged 55Subset of respondents aged 55--74, with 30+ pack year smoking, 74, with 30+ pack year smoking, either current smoker or former smoker who quit within the past either current smoker or former smoker who quit within the past 15 years15 years

Identified smoking status, age, sex, race, ethnicity, marital Identified smoking status, age, sex, race, ethnicity, marital status, and educationstatus, and education

53,454 participants NLSTNLST US CensusUS CensusMale (%) 59.0 58.5Age

55-59 (%) 42.8 35.260-64 (%) 30.6 29.365-69 (%) 17.8 20.870-74 (%) 8.8 14.7

Race | EthnicityBlack (%) 4.4 5.5

Hispanic (%) 1.7 2.4Current smoker 48.2 57.1Median pack yrs 48.0 47.0

Comparing NLST with eligible US census population

JNCI J Natl Cancer Inst (2010) 102 (23): 1771‐1779. 

Institution Location Population of Interest

Emory University Atlanta, GA African American

Jewish Heart and Lung Louisville, KY African American

Johns Hopkins University Baltimore, MD African American

M.D. Anderson Cancer Center Houston, TX Hispanic

St. Elizabeth’s Health System Youngstown, OH African American

UCLA Jonsson Cancer Center Los Angeles, CA African American, Hispanic, Asian

Wake Forest University Winston-Salem, NC African American

University of Alabama Birmingham Birmingham, AL African American

University of Colorado Denver, CO Hispanic

Henry Ford Hospital Detroit, MI African American

Pacific Health Research and Education Institute Honolulu, HI Asian, Pacific-Islanders

Denise R. Aberle, MDDenise R. Aberle, MDProfessor of Radiology and BioengineeringProfessor of Radiology and BioengineeringDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

ACRINACRIN

# of Months from Trial Launch

Screening exam compliance

Study Study YearYear

Helical CTHelical CT Chest XChest X--rayray TotalTotalExpectedExpected ScreenedScreened ExpectedExpected ScreenedScreened ExpectedExpected ScreenedScreened

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%

Screen positivity rate by screening round & arm

Low dose helical CTLow dose helical CT CXRCXR

Number Number screenedscreened

Number Number positivepositive

%%PositivePositive

Number Number screenedscreened

Number Number positivepositive

% Positive% Positive

Screen 1 26,314 7,193 27.3 26,049 2,387 9.2Screen 2 24,718 6,902 27.9 24,097 1,482 6.2Screen 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 Positive screen: nodule ≥≥ 4 mm 4 mm or or other findings potentially related to lung cancer.other findings potentially related to lung cancer.**** Abnormality stable for 3 rounds Abnormality stable for 3 rounds could could be called negative by protocol. be called negative by protocol.

True and false positive screens

Screening Screening ResultResult

Low Dose Helical CTLow Dose Helical CT CXRCXR

Screen 1Screen 1N (%)N (%)

Round 2Round 2N (%)N (%)

Round 3Round 3N (%)N (%)

Round 1Round 1N (%)N (%)

Round 2Round 2N (%)N (%)

Round 3Round 3N (%)N (%)

Total Positives

Lung cancerNo lung cancer

7,193 (100)

270 (4)6,923 (96)

6,902 (100)

168 (2)6,734 (98)

4,054 (100)

211 (5)3,843 (95)

2,387 (100)

136 (6)2,251 (94)

1,482 (100)

65 (4)1,417 (96)

1,175 (100)

78 (7)1,097 (93)

Data reflect the Data reflect the final interpretationfinal interpretation, including benefit of historical comparison exams., including benefit of historical comparison exams.

All death certificates obtainedAll death certificates obtainedIndependent endpoint verification committeeIndependent endpoint verification committeeSelection algorithm includesSelection algorithm includes

All lung cancer deaths | treatmentAll lung cancer deaths | treatment--related deaths related deaths Indeterminate cancers or deathsIndeterminate cancers or deathsDeaths within specific time intervals post screening exams | COPDeaths within specific time intervals post screening exams | COPDDDeaths within 6 months of [Deaths within 6 months of [--] screens with significant ] screens with significant otherother findingsfindings

Chart review of cause of death Chart review of cause of death Review blinded to screening arm and death certificateReview blinded to screening arm and death certificate

Interim analysis: lung cancer mortality 10-20-2010

ArmArm Person Person Years (py)Years (py)

Lung Lung cancer cancer deathsdeaths

Lung cancer Lung cancer mortality per mortality per 100,000 py100,000 py

Reduction in Reduction in lung cancer lung cancer mortality (%)mortality (%)

Value of Value of test test

statisticstatisticEfficacy Efficacy

boundaryboundary

CT 144,097.6 354 245 20.3 –3.21 –2.02

CXR 143,363.5 442 308

Deficit of lung cancer deaths in CT arm exceeds that expected byDeficit of lung cancer deaths in CT arm exceeds that expected by chance, chance, even allowing for multiple looks at the data.even allowing for multiple looks at the data.

CXR arm compared with matched 30,000 cohort in PLCO, no benefit CXR arm compared with matched 30,000 cohort in PLCO, no benefit of of CXR seen.CXR seen.

p = 0.0041p = 0.0041

Lung cancer: 25% of all deaths in NLSTLung cancer: 25% of all deaths in NLSTLung cancer: 56% of 126 excessLung cancer: 56% of 126 excess deaths in CXR armdeaths in CXR arm

p = 0.023p = 0.023

ArmArm Person Person Years (py)Years (py) DeathsDeaths

AllAll--cause cause mortality per mortality per 100,000 py100,000 py

Reduction in Reduction in all causeall cause

mortality (%)mortality (%)

Value of Value of test test

statisticstatisticValue for Value for

significancesignificance

CT 167,389.9 1870 1117 6.9 –2.27 –1.96

CXR 166,328.2 1996 1200

Kaplan-Meier curves for lung cancer mortality

1.00

0.99

0.98

0.97

0.96

0.95

0.94

0.93

0.92

0.91

0.90

00 11 22 33 44 55 66 77

Prob

abilit

y of s

urviv

alPr

obab

ility o

f sur

vival :

ALL

par

ticip

ants

: AL

L pa

rticip

ants

CT armCT armCXR armCXR arm

Years from randomizationYears from randomization

Kaplan-Meier curves for all-cause mortality

1.00

0.99

0.98

0.97

0.96

0.95

0.94

0.93

0.92

0.91

0.90

00 11 22 33 44 55 66 77 88Years from randomizationYears from randomization

Prob

abilit

y of s

urviv

al:

Prob

abilit

y of s

urviv

al: A

LL p

artic

ipan

tsAL

L pa

rticip

ants

CT armCT armCXR armCXR arm

Lung cancer case survival Kaplan Meier curve

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

00 11 22 33 44 55 66 77

Prob

abilit

y of s

urviv

al:

Prob

abilit

y of s

urviv

al: P

artic

ipan

ts w

ith lu

ng ca

ncer

Pa

rticip

ants

with

lung

canc

er

Years from randomizationYears from randomization CT armCT armCXR armCXR arm

NLST imaging standardizationNLST CT Technique ChartNLST CT Technique ChartParameterParameter

kVGantry rotation timemA (Regular patient | Large patient values)mAs (Regular | Large)Scanner effective mAs (Reg | Large)Detector collimation (mm) – TNumber of active channels – NDetector configuration- N x TCollimation (on operator console)Table incrementation (mm/rotation) – IPitch ([mm/rotation]/beam collimation) – I/NTTable speed (mm/second)Scan time (40 cm thorax)Nominal reconstructed slice widthReconstruction intervalReconstruction algorithm# Images/dataset (40 cm thorax)CTDI vol (Dose in mGy)

CT Technique ChartStandardized 18 parameters

14 CT scanners: 4-64 channels

120 kV; mAs < 80 (CTDIvol 2-3mGy)

Nominal slice thickness: ≤ 2.5 mm

Equipment certification annuallyRoutine CT phantom calibration

CXR techniques from CRFs & machine output

mR/mAs vs. kV

Manual & automated review of DICOM headersSubsample had visual QC by radiologists

Cagnon CH. Acad Radiol 2006; 13: 1431Cagnon CH. Acad Radiol 2006; 13: 1431--1441.1441.

Comparison to Standard Chest CTComparison to Standard Chest CT

Acceptable chest CT screening can be Acceptable chest CT screening can be accomplished at a small fraction of the doseaccomplished at a small fraction of the doseof a standard chest CTof a standard chest CT

NLST Effective Dose vs Standard Chest CT

1.4 1.6 1.62.1 2.4

7.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

EURO GROUP CTEXPO & ICRP 60 CTEXPO & ICRP 103 STD CHEST CT

mSv

male female std chest ct

Serial specimen collection for validation of biomarkers (N=10,26Serial specimen collection for validation of biomarkers (N=10,260)0)Plasma | buffy coat; sputum; urine annually x 3 yrsPlasma | buffy coat; sputum; urine annually x 3 yrsResected lung cancer specimensResected lung cancer specimensAvailable to the research community through proposals acrin.orgAvailable to the research community through proposals acrin.org

Quality of LifeQuality of LifeDifferential impact of screening of QoL at T0, T1, T2 (SFDifferential impact of screening of QoL at T0, T1, T2 (SF--36, EQ36, EQ--5D)5D)Differential impact of [+] screen on anxiety (SFDifferential impact of [+] screen on anxiety (SF--36, EQ36, EQ--5D, STAI) 5D, STAI) Administered at T0, 30 days post [+] screen and Q 6 months) Administered at T0, 30 days post [+] screen and Q 6 months)

Formal CEA (in conjunction with RAND)Formal CEA (in conjunction with RAND)Effects of screening on smoking behaviors | beliefsEffects of screening on smoking behaviors | beliefs

Short and long termShort and long term

Acknowledgements

NLST Executive Committee

Denise R. Aberle, MDChristine D. Berg, MDWilliam C. Black, MDTimothy R. Church, PhD, MSRichard M. Fagerstrom, PhDBarbara Galen, MSN, CRNP, CNMTIlana F. Gareen, PhD Constantine Gatsonis, PhD

Jonathan Goldin, MD, PhDBarnett S. Kramer, MD, MPHDavid Lynch, MDIrene Mahon, RN, MPHPamela M. Marcus, MS, PhDDorothy Sullivan Carl J. Zylak, MD

National Cancer Institute: National Cancer Institute: DCP, EDRG, Lung Screening StudyDCP, EDRG, Lung Screening Study

DCTD, Cancer Imaging Program, Bethesda, MDDCTD, Cancer Imaging Program, Bethesda, MDAmerican College of Radiology Imaging Network, Philadelphia, PAAmerican College of Radiology Imaging Network, Philadelphia, PA

ACRIN

Gerald Abbott MD, Denise Aberle MD, Judith Amorosa MD, Richard Barr MD, William Black MD, Phillip Boiselle MD, Caroline Chiles MD, Robert Clark MD, Lynn Coppage MD, Robert Falk MD, Elliot Fishman MD, Jonathan Goldin MD PhD, Eric Goodman MD, Eric Hart MD, Elizabeth Johnson MD, Phillip Judy PhD, Ella Kazerooni MD, Robert Mattrey MD, Barbara McComb MD, Geoffrey McLennan MD, Reginald Munden MD, James Ravenel MD, Michael Sullivan MD, Stephen Swensen MD, Drew Torigian MD, Kay Vydareny MD, John Worrell MD

LSS

Peter Balkin MD, Matthew T. Freedman MD MBA, Kavita Garg MD, David S.Gierada MD, Subbarao Inampudi MD, Howard Mann MB BCh, William Manor DO, Hrudaya Nath MBBS DMR MD, David L. Spizarny MD, Diane C. Strollo MD, John Waltz MD

NLST PhysicistsCT Physics Committee Dianna Cody, PhD MD Anderson Cancer Center

Mike McNitt-Gray, Phd UCLAChristopher Cagnon, PhD UCLAPhilip Judy, PhD Brigham and Women’s HospitalFred Larke, PhD University of ColoradoRandell Kruger, PhD Marshfield ClinicMike Flynn, PhD Henry Ford HospitalXizeng Wu, PhD University of Alabama

CXR Physics Committee J. Anthony Seibert, PhD UC Davis

Chris Cagnon, PhD UCLAPhilip Judy, PhD Brigham and Women’s HospitalRandell Kruger, PhD Marshfield ClinicMike Flynn, PhD Henry Ford Hospital

Endpoint Verification TeamAnthony B. Miller, MB, Chair, Martin J. Edelman, MD, William K. Evans, MD, Robert S. Fontana, MD, Mitchell Machtay, MD

Oversight CommitteeRobert C. Young, MD, Chair, David Alberts, MD, David DeMets, PhD, Peter Greenwald, MD, PhD, Paula Jacobs, MD, Theresa C. McLoud, MD, David P. Naidich, MD, James Tatum, MDData and Safety Monitoring BoardEdward A. Sausville, MD, PhD, Chair, Wylie Burke, MD, PhD, Gene Colice, MD, Brenda Edwards, PhD, Scott Emerson, MD, PhD, John Fletcher*,MD, Sylvan Green*,MD, Russell Harris, MD, MPH, Jeffrey S. Klein, MD, Edward L. Korn, PhD, Robert Mayer, MD, Joe V. Selby, MD, MPH, David W. Sturges, JD, Bruce W. Turnbull, PhD, Thomas J. Watson, MD

* Deceased

National Cancer Institute: Cancer Imaging Program, DCTD Early Detection Research Group, DCP

ACRIN | Westat | IMS | CARE Communications

Our many, many site investigators and research staff

Colleagues NLST ACRIN Tissue Bank & Biomarker Oversight CommitteeNLST ACRIN Research Evaluation PanelACRIN Specimen Biorepository at University of ColoradoACRIN Specimen Biorepository at University of ColoradoUCLA Tissue Microarray LaboratoryUCLA Tissue Microarray Laboratory

Advocates & members of lung cancer community who supported NLSTAdvocates & members of lung cancer community who supported NLST

With appreciationWith appreciation

53,454 trial participants without whom these studies would not have been possible