LUNG CANCER LUNG CANCER SCREENINGSCREENINGThomas R. Nugent, MDThomas R. Nugent, MD

LUNG CANCERLUNG CANCER

Lung cancer is the leading cause of Lung cancer is the leading cause of cancer-related death in the USAcancer-related death in the USA

Third leading cause of cancerThird leading cause of cancer In 2013 it is predicted 224,230 new In 2013 it is predicted 224,230 new

cases of lung cancer and 159,260 cases of lung cancer and 159,260 lung cancer deaths in the USAlung cancer deaths in the USA

75% of present with advanced disease75% of present with advanced disease 5 year survival rates are approx 16%5 year survival rates are approx 16% 0.5- 2.2 % incidence of lung cancer0.5- 2.2 % incidence of lung cancer

What would help most for What would help most for lung cancer?lung cancer?

SMOKING CESSATIONSMOKING CESSATION

U.S. population with direct smoking U.S. population with direct smoking exposure:exposure: 46.5 million former smokers46.5 million former smokers 45.1 million current smokers45.1 million current smokers

CDC MMWR 10/27/06CDC MMWR 10/27/06

Rationale for Lung Cancer Rationale for Lung Cancer ScreeningScreening

Rationale for Lung Cancer Rationale for Lung Cancer ScreeningScreening

Smoking cessation helps, but residual risk Smoking cessation helps, but residual risk remainsremains Quit at age 50 risk by age 75 is 6%Quit at age 50 risk by age 75 is 6%

Improved Improved survivalsurvival with early stage disease with early stage disease 5-Yr Survival all comers: 15%5-Yr Survival all comers: 15% Resected clinical Stage I: 92% per I-Resected clinical Stage I: 92% per I-

ELCAP; 75 % SEERELCAP; 75 % SEER

Why not start screening high-risk Why not start screening high-risk individuals?individuals?

Smoking cessation helps, but residual risk Smoking cessation helps, but residual risk remainsremains Quit at age 50 risk by age 75 is 6%Quit at age 50 risk by age 75 is 6%

Improved Improved survivalsurvival with early stage disease with early stage disease 5-Yr Survival all comers: 15%5-Yr Survival all comers: 15% Resected clinical Stage I: 92% per I-Resected clinical Stage I: 92% per I-

ELCAP; 75 % SEERELCAP; 75 % SEER

Why not start screening high-risk Why not start screening high-risk individuals?individuals?

Effects of stopping smoking at various ages on the cumulative risk (%) of death from lung cancer up to age 75, at death rates for men in UK in 1990. Nonsmoker rates were taken from US prospective study of mortality

Peto R, BMJ, 2000

Distinguishing Distinguishing BenefitBenefit from from BiasBias

In screening, survival endpoints are In screening, survival endpoints are confounded by:confounded by: Lead-time bias:Lead-time bias: Earlier detection prolongs Earlier detection prolongs

survival independent of delay in death survival independent of delay in death

Length bias:Length bias: Screening selects for more Screening selects for more indolent cancers indolent cancers

Overdiagnosis:Overdiagnosis: Detecting cancer that is Detecting cancer that is not lethalnot lethal

Mayo Lung Cancer Screening Mayo Lung Cancer Screening ProjectProject

Lung C ancers=206Stage I & II (resected) 83 (40% )Late-stage (unresected) 123 (60% )

Screened G roupC XR & pooled sputum

q 4 m onths

Lung C ancers=160Stage I & II (resec ted) 4 1 (25% )Late-stage (unresected) 119 (75% )

S tandard care recomm endationat study entry

9211 S tudy Partic ipants

Marcus, JNCI, 2000

Mayo Lung Project Mayo Lung Project Cumulative Lung Cancer Cumulative Lung Cancer

DeathsDeaths

Mayo Lung Project Mayo Lung Project Cumulative Lung Cancer Cumulative Lung Cancer

DeathsDeaths

0

100

200

300

400

0 10 20 30

0

100

200

300

400

0 10 20 30

Screened (n=337)

Usual care (n=303)

Follow-up time (years)

#Deaths

Marcus, JNCI 2000

Mayo Lung Project Mayo Lung Project Lung Cancer SurvivalLung Cancer Survival

Mayo Lung Project Mayo Lung Project Lung Cancer SurvivalLung Cancer Survival

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

0. 0 2. 5 5. 0 7. 5 10. 0 12. 5 15. 0 17. 5 20. 0 22. 5 25. 0

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

0. 0 2. 5 5. 0 7. 5 10. 0 12. 5 15. 0 17. 5 20. 0 22. 5 25. 0

Survival

Prob.

Years Since Diagnosis

Screened (n=206)

Usual care (n=160)

Marcus, JNCI 2000

INTERPRETATIONINTERPRETATION

Overdiagnosis existsOverdiagnosis exists CXR not effective in reducing CXR not effective in reducing

mortalitymortality Problems: Problems:

Study underpowered for a realistic result, Study underpowered for a realistic result, 10% mortality decrease could have been 10% mortality decrease could have been missedmissed

Contamination and complianceContamination and compliance

Prostate, Lung, Colorectal and Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Ovarian (PLCO) Cancer

Screening Trial: Screening Trial: Screening vs. No ScreeningScreening vs. No Screening

Multicenter RCT involving 154,942 men and women aged Multicenter RCT involving 154,942 men and women aged 55-7455-74 1:1 randomization to CXR screening vs. no screening1:1 randomization to CXR screening vs. no screening Smokers: CXR at baseline and then annually for 3 screensSmokers: CXR at baseline and then annually for 3 screens Non-smokers: CXR annually for 3 screensNon-smokers: CXR annually for 3 screens Overall pt population was low riskOverall pt population was low risk

Primary endpoint: lung cancer-specific mortalityPrimary endpoint: lung cancer-specific mortality PLCO Prevalence Screen Results PLCO Prevalence Screen Results

Oken, et al, Oken, et al, JNCI JNCI 20052005

PLCOPLCO

PLCO Cancer screening trial showed only PLCO Cancer screening trial showed only 20% of cancers were detected by screening20% of cancers were detected by screening

No mortality benefit with screening with No mortality benefit with screening with CXR, although when the authors looked at CXR, although when the authors looked at the highest risk pts there was a slight non-the highest risk pts there was a slight non-significant reduction in mortality at 6 and significant reduction in mortality at 6 and 13 years13 years

Conclusion: Conclusion:

Screening for lung cancer with CXR is not Screening for lung cancer with CXR is not recommendedrecommended

Low-Dose Helical CTLow-Dose Helical CT

Allows entire chest to be surveyed in a Allows entire chest to be surveyed in a single breathholdsingle breathhold Time: approximately 7 - 15 secondsTime: approximately 7 - 15 seconds Reduces motion artifactReduces motion artifact Eliminates respiratory misregistrationEliminates respiratory misregistration

Narrower slice thicknessNarrower slice thickness Hourly throughput - 4 patients per Hourly throughput - 4 patients per

hourhour Radiation dose one tenth of diagnostic Radiation dose one tenth of diagnostic

CTCT

What do we see on CT? What do we see on CT?

Definition of termsDefinition of terms GGO (non-solid): Nodule with hazy GGO (non-solid): Nodule with hazy

increased lung attenuation which increased lung attenuation which does not obscure underlying does not obscure underlying bronchovascular markings.bronchovascular markings.

Mixed (part-solid): Nodules Mixed (part-solid): Nodules containing both ground glass and containing both ground glass and solid componentssolid components

Solid (soft tissue): Nodules with Solid (soft tissue): Nodules with attenuation obscuring the attenuation obscuring the bronchovascular structures bronchovascular structures

Downstream Effects of Downstream Effects of CT ScreeningCT Screening

Radiation carcinogenesisRadiation carcinogenesis screening & consequent diagnostic tests: CT, PETscreening & consequent diagnostic tests: CT, PET

Additional minimally invasive proceduresAdditional minimally invasive procedures Percutaneous Lung FNAPercutaneous Lung FNA BronchoscopyBronchoscopy VATSVATS

Thoracotomy for benign disease Thoracotomy for benign disease Is there an acceptable percentage?Is there an acceptable percentage? Potential post-operative morbidity & mortalityPotential post-operative morbidity & mortality Treatment for disease without biopsy?Treatment for disease without biopsy?

Evaluation for other observations: cardiac, renal, Evaluation for other observations: cardiac, renal, liver, adrenal diseaseliver, adrenal disease

International Early Lung International Early Lung Cancer Cancer

Action Project (I-ELAP)Action Project (I-ELAP) Baseline: 31,567Baseline: 31,567

4186 nodules qualifying as positive result (13%)4186 nodules qualifying as positive result (13%) 405 lung cancer405 lung cancer 5 interim diagnoses of lung cancer5 interim diagnoses of lung cancer

Annual repeat: 27,456Annual repeat: 27,456 1460 new nodule (5%)1460 new nodule (5%) 74 lung cancer; no interim 74 lung cancer; no interim

Total lung cancers 484 out of 535 biopsies Total lung cancers 484 out of 535 biopsies 90.5% positivity rate90.5% positivity rate 412 (85%) Clinical Stage I412 (85%) Clinical Stage I Benign diagnoses: 43; Lymphoma or metastases Benign diagnoses: 43; Lymphoma or metastases

from other cancer 13from other cancer 13

I-ELCAP Investigators. NEJM 2006; 355:1763-1771.

Lessons From CT Lessons From CT Observational TrialsObservational Trials

Detected prevalence rate: 0.40 – 2.7%Detected prevalence rate: 0.40 – 2.7% Age is strong risk factor (> 60 years)Age is strong risk factor (> 60 years) Pack year smoking historyPack year smoking history

NoduleNodule detection rate variable on CT: 5.1% - 51.4% detection rate variable on CT: 5.1% - 51.4% Function of [a] definition of “nodule” and [b] CT Function of [a] definition of “nodule” and [b] CT

slice thicknessslice thickness Benign nodules = majority of detected nodules: Benign nodules = majority of detected nodules:

~90%)~90%) CT results in CT results in higherhigher lung cancer detection than CXR lung cancer detection than CXR

≥≥ 3-fold higher detection rate vs CXR; excess 3-fold higher detection rate vs CXR; excess cancers early stagecancers early stage

2-3 fold selective oversampling of adenocarcinoma 2-3 fold selective oversampling of adenocarcinoma Stage shift Stage shift notnot yet been shownyet been shown

NATIONAL LUNG NATIONAL LUNG SCREENING TRIALSCREENING TRIAL

Launched in 2002 followed an Launched in 2002 followed an average of 6.5 yearsaverage of 6.5 years

55,454 pts compared annual low 55,454 pts compared annual low dose with CXR for 3 yearsdose with CXR for 3 years

**estimated additional risk of fatal cancer 1 in 1,000 for adult for estimated additional risk of fatal cancer 1 in 1,000 for adult for regular CT of chest to 1 in 10,000 for low dose CT of chestregular CT of chest to 1 in 10,000 for low dose CT of chest

National Lung Screening National Lung Screening TrialTrial

Determine effect on lung cancer mortalityDetermine effect on lung cancer mortality 90% power, 90% power, αα of of 5%, to detect a 20% difference5%, to detect a 20% difference

Determine magnitude if any of stage shiftDetermine magnitude if any of stage shift Delineate adverse events Delineate adverse events Determine the ratio between risks and Determine the ratio between risks and

benefitsbenefits Thoracotomies for benign diseaseThoracotomies for benign disease Diagnostic radiation exposure in individuals Diagnostic radiation exposure in individuals

without cancer; estimate radiation without cancer; estimate radiation carcinogenesiscarcinogenesis

Definition of High Risk ParticipantsDefinition of High Risk Participants

Males and femalesMales and females 55-74 Yrs55-74 Yrs Asymptomatic current or Asymptomatic current or formerformer smokers smokers ≥≥ 30 pack yrs 30 pack yrs Former smokers must have quit within ≤ 15 yrsFormer smokers must have quit within ≤ 15 yrs No prior Hx lung cancerNo prior Hx lung cancer No Hx No Hx anyany cancer within past 5 years cancer within past 5 years No chest CT w/in prior 18 monthsNo chest CT w/in prior 18 months

NLST Trial DesignNLST Trial Design

53,464High-RiskSubjects

CT Arm

CXR Arm

Randomize

3 annual screens: T0, T1, T2

CT Arm

CXR Arm

Randomize

Follow up

02 03 04 05 06 07 08 09 10

T0

T1

T2

Trial Time postsTrial Time posts

Final A

nalysis

1st In

terim

An

alysis

2n

d Inte

rim A

na

lysis

3rd In

terim

An

alysis

Trial-Wide Participant Trial-Wide Participant DemographicsDemographics

CategoryCategory CTCT## %%

CXRCXR## %%

TotalTotal## %%

GENDERGENDERMaleMale

FemaleFemale

1577157766

1095109511

59.0%59.0%41.0%41.0%

15769157691096810968

59.059.0%%

41.041.0%%

3154315455

2191219199

59.0%59.0%41.0%41.0%

EDUCATIONEDUCATIONHS or LessHS or Less

More than HSMore than HS

7913791318211821

22

29.7%29.7%68.2%68.2%

804780471805318053

30.230.2%%

67.567.5%%

1596159600

3626362655

29.9%29.9%67.8%67.8%

SMOKINGSMOKINGCurrentCurrentFormerFormer

1288128844

1383138377

48.2%48.2%51.8%51.8%

12921129211380513805

48.348.3%%

51.651.6%%

2580258055

2764276422

48.3%48.3%51.7%51.7%

N = 53,464

Screening Exam Screening Exam ComplianceCompliance

(as of June 30, 2006)(as of June 30, 2006)

Study Study YearYear

Spiral CTSpiral CT Chest X-Chest X-rayray TotalTotal

ExpecteExpectedd

ScreeneScreenedd

ExpecteExpectedd

ScreeneScreenedd

ExpecteExpectedd

ScreeneScreenedd

T0T0 26,7126,7155

98.5%98.5% 26,7226,7288

97.5%97.5% 53,4453,4433

98.0%98.0%

T1T1 26,3326,3344

93.9%93.9% 26,4226,4299

91.2%91.2% 52,7652,7633

92.5%92.5%

T2T2 26,0126,0144

91.3%91.3% 26,1626,1600

87.9%87.9% 52,1752,1744

89.6%89.6%

By sex: Female CXR slightly lower than male CXRBy sex: Female CXR slightly lower than male CXR By age group: consistentBy age group: consistent By race/ethnicity: AA, Hispanic is lower than By race/ethnicity: AA, Hispanic is lower than

White at T1,T2White at T1,T2

Results ClassificationsResults Classifications [-] Screen [-] Screen

NoNo significant findings –or – minimal findings not significant findings –or – minimal findings not significant for lung cancersignificant for lung cancer

[-] Screen[-] Screen

SignificantSignificant findings unrelated to lung cancer findings unrelated to lung cancer[Some form of diagnostic recommendation required; e.g., [Some form of diagnostic recommendation required; e.g., echocardiogram for suspected pulmonary hypertension)echocardiogram for suspected pulmonary hypertension)

[+] Screen[+] Screen

Findings potentially related to Findings potentially related to lung cancerlung cancer [diagnostic recommendation of some form required][diagnostic recommendation of some form required]

Diagnostic Pathways for CT Nodules 4-10 mm

1 Pure ground glass nodules can be followed-up at 6-12 months if < 10 mm.2 Some nodules 4-10 mm may go directly to biopsy or other tests in ABNORMAL pathways.3 No growth is defined as < 15% increase in overall diameter OR no ↑ in solid component.

Low DoseThin Section Nodule CTat 4-6 Months1,2

Solid or Mixed Nodule

4-10 mmon Baseline

Screening CT

No Growth3

orResolution

Growth but< 7 mmDiameter

Growth> 7 mmDiameter

Continue Annual Screen

Repeat Low Dose TSCT at 3 to 6 Months[or Abnormal Pathways]

ABNORMAL Nodule Pathways

Solid,Mixed or

GG Nodule >10 mm

Biopsy: Percutaneous, Bronchoscopic, Thoracoscopic, Open

DCE-CT

ABNORMAL Pathways: Nodules >10 mm

1 Reserved for nodules considered highly likely to be BENIGN [polygonal shape, 3D shape ratio > 1.78]

FDG-PET

Biopsy -OR-Definitive Management

No Activity

Enhance 15 HU

Enhance <15 HU

Low Dose TSCTat 3-4 Months1 Per Protocol

TSCT at 6 -12 months

TSCT at 6 -12 months

Activity

Importance of outcomesImportance of outcomes

What happens to screenees.. not just those What happens to screenees.. not just those

with lung cancerwith lung cancer

[+] screens[+] screens Kinds of diagnostic tests, treatments Kinds of diagnostic tests, treatments ComplicationsComplications

[[−] screens−] screens Kinds of diagnostic tests, treatments for Kinds of diagnostic tests, treatments for

otherother findings recorded findings recorded ComplicationsComplications

Lung cancer deathsLung cancer deaths Screening-related deathsScreening-related deaths

What is the balance of risk and benefit to the population screenedWhat is the balance of risk and benefit to the population screened

RESULTS NLST RESULTS NLST

RESULTS NLSTRESULTS NLST

RESULTS NLSTRESULTS NLST

Positive result in 24.2% vs 6.9% of Positive result in 24.2% vs 6.9% of participants in LDCT and CXRparticipants in LDCT and CXR

Cumulative false-positive rate 96.4% Cumulative false-positive rate 96.4% vs 94.5vs 94.5

Overdiagnosis rate of 10-12%Overdiagnosis rate of 10-12% 297 vs 121 false-positives had surgery297 vs 121 false-positives had surgery Sensitivity and specificity 93.8% and Sensitivity and specificity 93.8% and

73.4% vs 73.5% 91.3%73.4% vs 73.5% 91.3%

RESULTS NLSTRESULTS NLST

Mortality reduction with LDCT Mortality reduction with LDCT estimated to range from 15-20%estimated to range from 15-20%

CURRENT CURRENT RECOMMENDATIONSRECOMMENDATIONS

CXR are not recommended as a CXR are not recommended as a screening tool in lung cancerscreening tool in lung cancer

Sputum cytology is not recommended Sputum cytology is not recommended as a screening tool in lung canceras a screening tool in lung cancer

Based on the results of the NLST the Based on the results of the NLST the National Comprehensive Cancer National Comprehensive Cancer Network, the American Cancer Network, the American Cancer Society and the USPSTF (grade B) as Society and the USPSTF (grade B) as well as 40 other societies recommend well as 40 other societies recommend screening with CT screening with CT

CURRENT CURRENT RECOMMENDATIONSRECOMMENDATIONS

Under the Affordable Care Act private Under the Affordable Care Act private insurers are required to cover any insurers are required to cover any procedure receiving a grade B procedure receiving a grade B recommendation from the USPSTFrecommendation from the USPSTF

This being said… recently a Medicare This being said… recently a Medicare advisory panel voted against coverage advisory panel voted against coverage for annual screening of low dose CT of for annual screening of low dose CT of chest in high risk individuals chest in high risk individuals

CURRENT CURRENT RECOMMENDATIONSRECOMMENDATIONS

If Medicare covered low dose CTIf Medicare covered low dose CT 54,900 more lung cancers would be detected 54,900 more lung cancers would be detected

over a 5 year periodover a 5 year period For every 1,000 cancers detected; 50 lives For every 1,000 cancers detected; 50 lives

would be savedwould be saved Over the next 5 years 2,745 Medicare lives Over the next 5 years 2,745 Medicare lives

would be savedwould be saved Cost estimate is $9.1 billion or $3 added to the Cost estimate is $9.1 billion or $3 added to the

premium of every Medicare recipientpremium of every Medicare recipient A draft decision by the Advisory panel is due A draft decision by the Advisory panel is due

in November 2014in November 2014