lung cancer screening update

Lung Cancer Screening Update

29th Annual Denali Oncology Group

Reginald F. Munden MD, DMD, MBA

I have no conflicts of interest to report

National LungScreening Trial

National Cancer Institute

National LungScreening Trial

National Cancer Institute

TSLN

NLST - ACRIN Randomized 1:1

Experimental Arm 1 Control Arm 2

Spirometry Spirometry

Baseline Low-Dose Helical CT Baseline PA CXR

(Baseline samples blood, urine, sputum)

Annual incidence screen x 2 Annual incidence screen x 2

(Low dose helical CT) (PA CXR)

Questionnaires: Interval Questionnaires: Interval

Health Health

Q6 months: Interval health status x 6- 8 years

NLST - ACRIN

CT Protocol

• Single breath hold• kVp 120-140• mAs 40 – 100• Collimation 10 mm, 20mm• Reconstruction

slice thickness 2.5mminterval 1.25mmalgorithm soft tissue and high

spatial frequency

NLST – ACRINInterpretation

• Nodule classification

· benign – calcified; fat; or < 4mm micronodule· abnormal - >10mm, enlarging > 7mm· indeterminate - 4 – 10mm; enlarging < 7mm


• Negative screen No significant abnormalities

• Negative screen, minor abnormalities not suspicious for lung cancer

Benign nodules, micronodules, atelectasis/scar, coronary artery calcification (?)

• Negative screen, significant abnormalities not suspicious for lung cancer

Aortic aneurysm, mediastinal/thyroid mass, pericardial/pleural effusions, axillary

adenopathy, chest wall lesion, spine lesion


• Positive screen

Nodule 4-10mm or enlarging nodule

• Positive screen

Nodule >10mm, enlarging nodule > 7mm, lung mass, other non-specific abnormality

suspicious for lung cancer

NLST - Recommendations

• No intervention – continue screening

• Comparison with historical

• Thin section CT: 3, 6, 12 months

• Diagnostic CT

• CT nodule densitometry

• PET

• Biopsy

NLST Design

ArmsArms Helical CT vs. CXRHelical 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

33 participating sites

LSS si

0

10000

20000

30000

40000

50000

60000

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

Month Enrolled

Par

tici

pan

ts

Total (53,464)

LSS (34,614)

ACRIN (18,850)

NLST Cumulative Accrual

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 CEA (in conjunction with RAND)

• Effects of screening on smoking behaviors | beliefs− Short and long term

http://www.acrin.org/

NLST US CensusMale (%) 59.0 57.6

Age55-59 (%) 42.8 34.660-64 (%) 30.6 27.665-69 (%) 17.8 20.970-74 (%) 8.8 16.9

Race/ethnicity Black (%) 4.5 4.1 Hispanic (%) 1.7 2.4

Comparison: NLST with US census population

NLST US CensusMarried 66.6 60.9Education < HS 6.1 20.4 ≥ College 31.5 14.4

Current smoker

48.2 58.4

Median pack years

48.0 47.0

Comparison: NLST with US census population

Family history

Helical CT X-Ray Total

% % %

Any first degree relative 21.8 21.7 21.7Two or more first degree relatives 3.3 3.3 3.3

Screening Exam Compliance

Study Year

Helical CT Chest X-ray TotalExpected Screened Expected Screened Expected Screened

T0 26,715 98.5% 26,723 97.5% 53,438 98.0%

T1 26,287 94.0% 26,401 91.3% 52,688 92.6%

T2 25,942 92.9% 26,101 89.5% 52,043 91.2%

time 9/02 9/03 9/04 9/05 9/06 9/07 9/08 9/09 9/10 10/20/10

T0

T1

T2

NLST Timeline

1st Interim

Analysis

2nd Interim

Analysis

3rd Interim

Analysis

4th Interim

Analysis

5th Interim

Analysis

6th Interim

Analysis

Screen Positivity* Rate byScreening Round and Trial Arm

CT CXR

Number screened

Number positive

% Positive

Number screened

Number positive

% Positive

Screening round 1

26,314 7,193 27.3 26,049 2,387 9.2

Screening round 2

24,718 6,902 27.9 24,097 1,482 6.2

Screening round 3

24,104 4,054 16.8** 23,353 1,175 5.0**

All screening rounds

75,136 18,149 24.2 73,499 5,044 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

Lung Cancer ScreeningNLST

Arm Person years (py)

Lung cance

r death

s

Lung cancer

mortality per

100,000 py

Reduction in lung cancer

mortality (%)

Value of test statisti

c

Efficacy bounda

ry

CT 144,097.6 354 245.7 20.3 –3.21 –2.02

CXR 143,363.5 442 308.3

Interim Analysis of Primary Endpoint - Oct. 20, 2010 Deficit of lung cancer deaths in CT arm exceeds that expected by chance

Lung Cancer Screening:NLST

Arm Person years (py)

Deaths

All-cause

mortality per

100,000 py

Reduction in all-cause

mortality (%)

Value of test statisti

c

Value for

signifi-

cance

CT 167,389.9 1870 1117.2 6.9 –2.27 –1.96

CXR 166,328.2 1996 1200.0

All-cause mortality

Lung Cancer Screening:NLST Results

CT CXR

(%) Positive Clin sig Positive

Clin sig

TO 27 10 9 3

T1 28 6 6 2

T2 17 6 5 1

NLST Results:Positive Screens

• CT - 39%

– Clinically significant other than lung cancer – 7.5%

• CXR – 16%– Clinically significant other than lung cancer -2.1%

• > 90% positive = diagnostic evaluations

– 81% - radiology (CXR – 18; CT 73; PET – 10)

– Bx – 2.2; Bronch – 4.3; Surgery – 4.2, other 2.4

NLST Results:Lung Cancers

• CT - 1060– 649 on CT– 44 on negative CT– 367 other (missed or detected after screening ended)

• CXR - 941– 279 CXR– 137 negative CXR– 525 other

NLST Results:Lung Cancer Deaths

• CT - 356– 144,103 person years - 247/100,000 person years

• CXR - 443– 143,368 person years – 309/100,000 person years

* Person years - The total sum of the number of years that each member of a study population has been under observation

NLST Results:Lung Cancer Deaths

• Rate of complication (90 days)

–CT = 1.4%; CXR = 1.6%

• CT - 16– 10 had lung cancer

• CXR - 10– 10 had lung cancer

Lung Cancer Screening New Controversies

– Who gets screened and when?

• Age, how many pack yrs, annually or greater, ex-smokers > 15 yrs

– Who pays?

• CMS, Private payors, tobacco companies, self pay

– Radiation risk

– What to do with incidental findings

• False positives, false negatives – rates acceptable?- 96%?

• Thoracic, extrathoracic non-cancer findings

Lung Cancer Screening New Controversies

– What happens if a scan is positive

– Can any radiologist do these or is there a learning curve

– What about prevention

– Is there any difference in men/women; race

Lung Cancer CT Screening

American Cancer Society shift in screening consensus

• Benefits of detecting many cancers, especially breast and prostate, have been overstated.

• “We don’t want people to panic,” said Dr. Otis Brawley, chief medical officer of the cancer society. “But I’m admitting that American medicine has overpromised when it comes to screening. The advantages to screening have been exaggerated.”

New York Times, Oct 21, 2009

Recommendations?

• NCCN, AACP/ASCO, AATS, ALA

– ?? U.S. Preventive Services Task Force

• What age 50 or 55

• Pack years 20 or 30 pk yrs

• Other factors?

NCCN guidelines

High risk category 1• Age 55-74 y, and

• > 30 pack-year smoking hx, and

• Smoking cessation < 15y

High risk category 2B• Age > 50 y, and

• > 20 pack-year smoking hx, and

• One additional risk factor (other than 2nd hand smoke); radon, occupational, family hx, COPD

Category 1 - based on high level evidence, uniform NCCN consensusCategory 2A - based on lower level evidence, uniform NCCN consensusCategory 2B - based on lower-level evidence, NCCN consensus

Guidelines

• 55 - 74 yrs of age• Smokers and former

smokers (< 15 yrs)• 30 pack year smoking

• AATS – 55 – 79

– Lung cancer survivors

Do no harm!• Radiation: effective dose

– Low dose CT = 0.65 mSv; CT = 5.8 mSv (cody says 7 mSv) CXR = 0.08 mSv; annual recommendation = 1 mSv

– NLST – Ct: 1.4 mSv (std dev 0.5)– 10,000 people exposed 10 mSv = additional 4 deaths; an

increase of 0.2% in cancer mortality rate per 10mSv• 50 yr old screened annually until 75

– increased risk of 0.85% added to expected risk of 17%.• 50% current and former smokers 50 – 75 yr old screened

annually– estimated increase of 36,000 (1.8%) over expected

Brenner, Radiology 2004

Cost Effectiveness of Lung Cancer Screening

Cost/quality adjusted life-year saved:

• MahadeviaModeling analysis

– $ 116,000

• Cornell - actual screening experience

– $ 2,500

• NLST ?

Mahadevia, JAMA 2003; Wisnivesky, Chest 2003

Lung Cancer ScreeningFalse positive/negative

NLST:

• 26% - false negative - “missed rate”

False Negative

False Positive

Baseline 3 months follow-up

Positive – not cancer

Lung Cancer Screening

62 y.o. male

38 pk yrs

Fleischner RecommendationsNodule size Low- risk High risk

< 4mm No follow-up 12 months

>4-6 mm 12 months initial 6-12 monthsthen 18, 24 months

>6-8mm initial 6-12 initial 3-6 monthsthen + 1 yr then + 6 months, final @ 2 yrs

>8mm 3, 9 , and 24 Same as for low riskor dynamic,PET,bx

• Subsolid – longer follow-up

MacMahon et al, Radiology 237: 395-400, 2005

Fleischner Recommendations Compliance

• 13 Case scenarios• 181 members of the Society of Thoracic radiology surveyed

• 27% made appropriate recommendation based on Fleischner• Less likely to follow guidelines

– Longer years in practice– Radiologist outside the US– Endemic areas

Esmaili et al. J Thorac Imaging. In press. epub Jul 9, 2010


One Year


52 y.o. smoker (high risk)


Incidence of malignancy

• Screened population – Subsolid

• pure GGO - 18%

• semisolid - 63%

– Solid - 7%

• Non screened population– Nonsolid persistent lesions - 81% (19% other dz)

Henschke et al. AJR, 2002; Kim et al. Radiology 2007

Lung Cancer ScreeningSolitary LesionGGO < 5-mm No follow-up

5-10mm 3-6 mos (then annual for 3-5 yrs?)

>10mm Resect (provided persistence or growth)

Mixed any size likely malignant – PET/CT, ? biopsy

Multiple lesionsGGO <5mm 1 yr follow-up

5-10mm likely AAH or RB

> 10mm resect/PET/CT

Godoy & Naidich. Radiology December, 2009


3 months

Lung Cancer ScreeningNon - Cancer Findings

Lung Cancer ScreeningNon Cancer Findings

Lung Cancer ScreeningMDACC

Lung Cancer Screening Program

• Radiology, Prevention, Surgery, Pulmonary• Activate – spring/summer 2010• Establish standard for screening - multidisciplinary• Advance science of screening/prevention• Model - mammography

Lung cancer screening works!Now what and who?

Thank you

lung cancer screening update

Documents