CT Screening for Lung Cancer: International Early Lung Cancer Action Program

What we know nowWhy is screening controversial?

We know

Only 15% of lung cancers are found in early stageMost of these because of CXR or CT done for other reasonsAlmost all with lung cancer die of it 164,000/174,000 = 95%

Prior randomized controlled studiesThree studies in US in the 1970sMayo Lung ProjectMemorial Sloan Kettering Lung ProjectJohns Hopkins Lung ProjectNone showed a benefit of sputum cytologyMayo Lung Project did not show a benefit of CXRAs a result the USPSTF recommended against screening for lung cancerHowever, the negative interpretation was highly controversial and physicians continued to provide CXR for their high-risk patients

Prior case-control studiesJapan has provided CXR screening for all men and women 40 years and olderFive studies in Japan All showed a benefit of CXR screeningConsidered timing of dx relative to CXRThe USPSTF revised their recommendation from against screening for lung cancer to: not enough evidence for or against screening

Early Lung Cancer Action Project After reviewing prior trials, we decided to study CT screening and planned this in 1991-2We invited the statisticians and pathologists from the prior studies to discuss study design issues with usWe asked them to use their prior data and model to predict the potential value of CT screening

THE ELCAP APPROACHDx, then compare prompt treatment with alternatives

EveryoneScreened Lung Cancer Distribution (Stage/Size)Rx No Rx or Delay in RxDeaths*Deaths** specific to stage and size Baseline and annual repeat 0 years 2 Diagnostic Mission Prognostic MissionClinical Imaging 1994:18: 16-20

Early Lung Cancer Action Project Enrollment of participants at high-risk of lung cancer started in 1993New York University Medical Center and Cornell Medical CenterBaseline and 1 annual repeat Reported results, separately for Baseline in Lancet in 1999Annual repeat in Cancer 2001

The ELCAP RegimenKey to finding lung cancer early Baseline: Workup protocol

Repeat: Different workup protocol

Recommended biopsy if growth was at a malignant rate

Lancet 1999; 354: 99-105I-ELCAP Protocol is on www.IELCAP.org

Annual Repeat ScreeningNew noduleImages 1999, ELCAP Lab, Weill Medical College of Cornell University

Annual Repeat Screening Growth in 1 monthImages 1999, ELCAP Lab, Weill Medical College of Cornell University74-Day Doubling Time

Fine needle aspiration

Adenocarcinoma in a solid nodules: Obscures the parenchyma within the nodule

Early Lung Cancer Action Project Created great excitement around the world as it showed that lung cancer can be found early stage in 85% of the people diagnosed with lung cancerWhile in the absence of screening, early stage cancer is only found in 15%It was estimated that 60-80% of the deaths from lung cancer would be prevented

ELCAP providedNew knowledge Usefulness of growth assessmentIdentification of part-solid and nonsolid nodules and the frequency with which they are malignantNeed different assessment of growthA paradigm for rapid assessment of technology advancesSingle slice to multislice scannersPET scanners

New York- ELCAP Expanded ELCAP to diverse medical settings in New York State using updated regimenEnrollment of same high-risk participants started in 2001-2003 in 12 institutionsBaseline and 1 annual repeat Confirmed the results of ELCAP and the importance of the regimen of screening Delay in diagnosis in 31% of cancers Cancer grew in size and progressed in stageRadiology 2007; 239-249

I-ELCAP Expanded to 8 countries, 44 institutionsExpanded enrollment criteria to lower risk participants Common regimen of screeningReported results in N Eng J Med on October 26, 2006

I-ELCAP InstitutionsWeill Medical College of Cornell University Azumi General Hospital, Nagano, Japan Queens College, Dept of Energy, Queens, NY University of Toronto, Toronto, Canada Clinica Universitaria de Navarra, Navarra, Spain LungenZentrum Hirslanden, Zurich, SwitzerlandNational Cancer Institute Regina Elena, Rome, Italy Christiana Care Health System, Newark DE Swedish Hospital, Seattle, WA H. Lee Moffitt Cancer Center, Tampa FLColumbia University, NY Hadassah Medical Organization, Jerusalem, Israel

I-ELCAP InstitutionsNew York University, NY SUNY, Stonybrook, NYMaimonides Hospital, NYRoswell Park Cancer Center, Buffalo, NYHoly Cross Hospital, Silver Springs, MDSUNY Upstate Medical Center, Syracuse, NYLong Island Jewish, NY5th Aff. Hospital of Sun Yat-Sen Uni., Zuhai, ChinaJackson Memorial Hospital, Miami FlGeorgia Institute for Lung Cancer, Atlanta, GAMt. Sinai Medical Center, NYSt. Agnes Healthcare, Baltimore, MD

I-ELCAP Institutions Eisenhower Memorial Hospital, Luci Curci Cancer Center, Palm Springs, CAMills-Peninsula-D.E.Schneider CC,San Mateo CA Memorial Sloan-Kettering Cancer Center NY Medical College, NY Mt. Sinai, Miami, FL Oconomowoc Regional CC, Milwaukee, WI Evanston Northwestern Healthcare, Evanston IL City of Hope, Los Angeles, CA Our Lady of Mercy, NY Greenwich Hospital, Greenwich CT Karmanos Cancer Institute, Detroit, MI St. Joseph Health Center, St. Charles Mo

I-ELCAP InstitutionsSharp Memorial Hospital, San Diego, CANebraska Methodist Hospital, Omaha, NEComprehensive Cancer Centers of the Desert, Palm Springs, CA Glens Falls Hospital, Glens Falls, NYSouth Nassau Community Hospital, Long Island, NYSylvester Comprehensive Cancer Center, Miami, FLAurora St. Lukes Medical Center, Milwaukee WISUNY Downstate, Brooklyn, NY

I-ELCAP PerformanceEveryonescreenedStage I lung cancer in 85% of diagnosesRx No Rx Curability rate of 92% All died of LC within 5 yrs Baseline and annual repeat screenings!Diagnostic Mission Prognostic MissionNEJM 2006; 355: 1763-71

10-year Kaplan-Meier survival and deathsnow have followed these for almost 5 years

All cases 484 433 356 280 183 90 50 28 16 9 2 Resected Stage I 302 280 242 191 120 59 34 18 12 7 1Resected clinical Stage I: 92% (95% CI: 88%-95%)All cases: 80% (95% CI: 74%-85%)No. at risk1230Number of lung cancer deaths 0102030161331*Deaths includes 6 stage I patients who had no treatment who all died

We know that with CT screening using the I-ELCAP protocol

Lung cancer can be found early85% found in early stageLung cancer when found early and when removed in a timely fashion, it can be cured92% estimated curability rateThese facts are not disputed

Emphysema and Coronary Artery Disease on low-dose CTDetermine extent of emphysemaDetermine extent of coronary artery calcificationsThese findings are predictive of death from the coronary artery disease and chronic obstructive pulmonary disease

528527522521516526525523520519518517515514513512511510508507504505503502501500499498497496495494493492491490489488ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ

ZZZYZZZZZZYYYYYYYYYYYYYYYXYYXYYXYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYWYYYYYYYXYYYYYYXYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYWYYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYWYYYYYYYYYYXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXYXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXZXXXXXXXXXXXXXXXXXXXXXXXXXXXWWWWWWWWWWWWWWWWXWWWWWWWWWWcircle color : 30, 40mm:purple 40, 50mm:blue 50, 60mm: brown; alphabet :

528 527522521516526523520519518515514513512511502508507504505503494501500499498497496495486492491490497488Z493ZZZ

525517510ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZYZZZZZZYYYYYYYYYYYYYYYYXYYXYYXYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYWYYYYYYYXYYYYYYXYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYWYYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYYYXYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYWYYYYYYYYYYXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXYXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXZXXXXXXXXXXXXXXXXXXXXWWWWWWWWWWWWWWWWXWWWWWWWWWWXYX

Low-dose CT provides screening for the entire chestLung cancerCoronary artery diseaseChronic obstructive pulmonary diseaseOther regions in the future

Consistent results in 7 CT cohort studies in the past 10 years when consistent definitions are usedELCAP, Nagano, Tokyo, Italy, Mayo Clinic, Hitachi, I-ELCAPStage I ranged between 77% - 100% when using the same definitionsLong-term survival of Stage I > 90%Few interim cancersThe cancer rate on annual repeat varied between 0.3% - 0.6% depending on risk indicators for lung cancer (age, smoking history) in accordance with usual care

What more do we need to do?

Some advocate a RCT butThose who cannot remember the past are condemned to repeat it Reason in Common Sense by George Santayana

Look at Breast CancerEight randomized screening trials of over 500,000 women All but 2 considered severely flawedStill controversies about the results of those trials 2001 and again 2006Some European countries stopped supporting screening for breast cancerIn the US, this led to congressional hearings in 2002

February 28, 2002

Breast Cancer: Congressional hearings chaired by Senator MulkulskiA. von Eschenbach, Director of NCI said that more trials would be unethicalwe know we can find it early and earlier treatment is better than later treatmentEchoed by Peter Greenwald, Head of Prevention at NCI

Dr Harmon EyreAmerican Cancer Society

Breast CancerV. Jackson in her award winning article in Radiology stated the tide began to turn with the publication by Miettinen, Henschke and othersNeiderhuber, now the Director of NCI stated that the Cornell group showed the problems with the randomized trialsMiettinen, Henschke, Smith et al. Lancet 2002

Dr John Niederhuber Miettinen, Henschke, Libby et al. Lancet 2002

Miettinen et al. Lancet research letter Showed that for breast cancer the deaths prevented by mammography would have occurred 8+ years in the future

Conclusion of the breast controversyThe results of the 8 randomized trials were ignoredScreening continued becauseMammography found it earlyEarlier treatment is better than later treatment

What do we know about lung cancer?Screening using low-dose CTFinds lung cancer early andEarly treatment is better than than later treatment and this has been known for 20+ yearsThese facts are not disputedWe knew this once ELCAP was published

Quotes from RSNA News Letterby Bach, June 2007 Until we figure out whether going through that chain of events is something that is helpful or harmful, it probably makes more sense not to be screened Stopping smoking, managing body weight, exercising and wearing a seat belt are among more important steps people can undertake to improve their health

Have this been proven by an RCT?Stopping smoking, managing body weight, exercising and wearing a seat belt are among more important steps people can undertake to improve their health Bach, RSNA Newsletter June 2007Have these been proven by an RCT?Lets consider proving that smoking cessation reduces deaths from lung cancer

RCT to show that smoking cessation reduces the mortality rate of lung cancer RandomizeDeathsDeaths

Smoking CessationContinue smoking 0 Time (years) 10 15+When would deaths in smoking cessation arm decrease?


Smoking CessationContinue smoking 0 Time (years) 10 15+When would deaths in smoking cessation arm decrease?

Certainly not in the first 5 yearsOnly after many years of quitting smoking


Smoking CessationContinue smoking 0 Time (years) 10 15+But, if smoking is only stopped for 3 years,Would deaths in smoking cessation arm ever decrease?

Illustrates problemsConsequence of regimenProtocol non-adherenceDeaths prevented occur long in the future

Ongoing randomized controlled trials for CT screening

National Lung Screening Trial (NLST)Nelson Trial in the Netherlands and Belgium and Denmark

It is important to identifylimitations of any design and to address them

Issues to be addressed by any screening trial- ELCAP or RCT Overdiagnosis biasLead time biasNo comparison groupLength biasNo reduction in late stage cancers

Overdiagnosis biasRequire growth prior to biopsy for small nodulesAll resected cases reviewed by an International Pathology PanelThose who delay diagnosis or treatment progressAll with Stage I lung cancer without treatment died of lung cancer

No lead time bias in the 10-year Kaplan-Meier survival rate

All cases 484 433 356 280 183 90 50 28 16 9 2 Resected Stage I 302 280 242 191 120 59 34 18 12 7 1Resected clinical Stage I: 92% (95% CI: 88%-95%)All cases: 80% (95% CI: 74%-85%)No. at risk1230Number of lung cancer deaths 0102030161331*Deaths includes 6 stage I patients who had no treatment who all died

Stage I comparison group: Dx and prompt Rx vs. no Rx (no lead time bias)Resected within 1 month92% (95% CI: 87%-95%)Untreated 0%NEJM 2007; 356:743-747

Length biasSlower growing cancers are more frequently diagnosed in the baseline rounds, butThe cancers in the baseline rounds are found later in their natural course than the cancers found in repeat rounds of screeningTherefore baseline and repeat screenings should be reported separately

Baseline vs. Annual CancersCell-type distribution illustrates length bias Baseline cancers Annual cancersLung Cancer 2007; 56: 193-199

Chart3

19

29

153

Baseline

Neuroendocrine 29(14%)

Adenocarcinoma 153(77%)

Squamous cell 19(9%)

Sheet1

All cases

BaselineAnnualAnnual

Adenocarcinoma141.022.0Adenocarcinoma22.0

Squamous cell16.07.0Squamous cell7.0

Neuroendocrine+Other17.08.0Neuroendocrine+Other8.0

BaselineAnnualAnnual

Nonsolid19.013.0Nonsolid13.0

Part-solid29.03.0Part-solid3.0

Solid52.084.0Solid84.0

BaselineAnnual

Issues to be addressed by any screening trial- ELCAP or RCT Overdiagnosis biasLead time biasNo comparison groupLength biasNo reduction in late stage cancers

Repeat screening is key,baseline is just the entry into itor 27 per 1000 screenedPERCENTAGE

Chart1

2.70.20.5900.5900.59

Baseline

B-Interim

1st Annual

A- Interim

2nd Annual

A-Interim

3rd Annual

Sheet1

BaselineB-Interim1st AnnualA- Interim2nd AnnualA-Interim3rd Annual

Years2.70.20.5900.5900.59

Differences between baseline and annual repeat rounds of screeningBaseline rateCT is much better than CXR Annual rate should reflect rate in absence of screening CT CXRCT CXRELCAP vs. Mayo Lung Project

Chart1

2.70.83

ELCAP

MLP

Sheet1

ELCAPMLP

Baseline2.70.83

To resize chart data range, drag lower right corner of range.

Chart1

0.590.55

ELCAP

MLP

Sheet1

ELCAPMLP

Annual0.590.55

To resize chart data range, drag lower right corner of range.

Late Stage Cancers: CT vs. CXRMarked reduction in late stage cancer (in black)0.08 0.290.05 0.220.59 0.55 0.33 0.37

Chart1

0.080.51

0.290.26

Late stage

Early Stage

Sheet1

Late stageEarly Stage

ELCAP0.080.51

Mayo LP0.290.26

Chart1

0.050.28

0.220.15

Late Stage

Early Stage

Sheet1

Late StageEarly Stage

NY-ELCAP0.050.28

MSK LP0.220.15

What more do we need to do?

We think that we should move to provide screening on a wider scaleWe should not wait for RCTsFocused discussions of RCT problemsWe should screen on a wider scale using the ELCAP approachCombine with smoking cessation programsThis will provide ongoing evaluation and incorporation of new technologies

The END

**Why is it so controversial? WE have all heard about the controversies. We like Dr. Siegels from NYU article in the Wall Street Journal. He called it Stupid Cancer Statistics. Based on our results we think we can state it is beneficial. Others say it is not ready, there are definitely harm from it, and we need to wait for the NLST (2009-2010) and the PLCO (2015).

I think that how to study screening is one of the most important topics in radiology today. Why has it been so controversial? What has a greater potential benefit to save lives?

Screening is a complicated topic requiring much knowledge of radiology, statistics, epidemiology and even when someone is knowlegable in all these areas, it is still complicated. But it is critical for radiologists to develop deeper understanding of these topics this will be the future of much of radiology and they should lead the research. **Low-dose CT positive result work-up algorithm diagnosis of lung cancer*Low frequency vs high frequency - 4 month vs 1 year****Circle color : 30, 40mm:purple; 40, 50mm:blue; 50, 60mm: brown; >6cm: blackalphabet :

Documents

CT Screening for Lung Cancer: International Early Lung Cancer Action Program