Early Lung Cancer Screening: An Update of the Current Evidence Simon Martel, MD IUCPQ Quebec, Canada

No conflict of interest

Lung Cancer Epidemiology Most frequent cause of cancer death In 2020 = 5th cause of death In 2010 (Canada) = 11200 deaths in men and 9400 deaths in women (27% of all cancer deaths) Overall survival at 5 years around 15% 90% of cases attributable to smoking and 50% of new cases in former smokers

Fundamentals of Screening The purpose of screening is to detect a disease at a stage when cure or control is possible At risk population for a specific disease is submitted to a test to identify asymptomatic persons having the disease Persons with a positive result will then be evaluated to determine whether they actually have the disease

Fundamentals of Screening Characteristics of a good screening test and program: Reasonable sensitivity and specificity Accessible with a low cost Low associated morbidity There should be an effective treatment at an early stage of the disease

Screening Bias Patz EF et al. New Eng J Med 2000

Screening Bias Patz EF et al. New Eng J Med 2000

Screening Bias Black WC. Cancer 2007

Fundamentals of Screening A good lung cancer screening program should reduce lung cancer mortality and overall mortality in the screened group compared to the unscreened group

1950-1990 Randomised and non randomised controlled trials: John Hopkins Lung Project Memorial Sloan Kettering Lung Project Mayo Lung Project Czechoslovakian Study North London Cancer Study Erfurt County Study Kaiser Permanente Study Chest radiograph ± sputum cytology every 4 to 12 months compared to less frequent or no screening over 3 to 16 years 52000 subjects in intervention groups and 48000 in control groups

1950-1990 Intervention groups: No reduction in lung cancer mortality More lung cancers More early stage lung cancers More resectable lung cancers No reduction in lung cancer mortality

Recommendations Bach BP et al. Chest 2007

Are we done with chest X-ray in lung cancer screening? J Natl Cancer Inst 2005

Radiation « Persons at risk for repeated radiation exposure, such as workers in health care and the nuclear industry, are typically monitored and restricted to effective doses of 100 mSv every 5 years (i.e. 20 mSv per year), with a maximum of 50 mSv allowed in any given year. » Fazel R et al. New Eng J Med 2009

Radiation Procedure Effective dose (mSv) Chest radiograph (PA view) 0.02 Radiograph of abdomen 0.7 Mammography 0.4 Nuclear bone imaging 6.3 Chest CT 7 Abdomen CT 8 Chest angio-CT 15 Diagnostic cardiac cath.

Radiation Low dose CT Baldwin DR et al. Thorax 2011

CT lung cancer screening Black WC. Cancer 2007

CT lung cancer screening Black WC. Cancer 2007

CT lung cancer screening Black WC. Cancer 2007

CT lung cancer screening What have we learned from these studies? Management of small pulmonary nodules CT can detect early stage lung cancer Excellent survival in a majority of screened cases More epidemiology More and more adenocarcinomas… Overdiagnosis? Slow growing tumors?

Follow-up of nodules MacMahon H et al. Radiology 2005

Thorax 2011

Early stage detection New Eng J Med 2006

Overdiagnosis?

Growth Model of Lung Cancer Bach BP et al. Chest 2007

CT Randomised Controlled Trials DEPISCAN (France) ITALUNG trial (Italy) 3 206 participants Active and former smokers 55-69 years old Chest CT annually for 4 years vs no screening NELSON Trial (Dutch-Belgian) 15 248 participants (2004-2006) Chest CT at 0, 1 and 3 years vs no screening Active and former smokers 50-75 years old

CT Randomised Controlled Trials DANTE Trial (Italy) 2472 participants, male, 60-75 years old (2001-2006) Chest X-ray and sputum cytology at baseline (all) Chest CT at 0, 1, 2, 3 and 4 years vs annual medical visit Active and former smokers of at least 20 pack-years

DANTE trial Infante M et al. Am J Respir Crit Care Med 2009

CT Randomised Controlled Trials NLST (USA) 53 456 participants (2002-2004) Chest CT vs radiograph at 0, 1 and 2 years Active and former smokers 55 to 74 years-old Results 20.3% reduction in lung cancer mortality (354 deaths vs 442 deaths) All-cause mortality lower by 7% in the CT group

NLST Participants CT X-ray Total 26723 26733 M / F 59 / 41 % Age (55 – 74) 43 / 30 / 18 / 9 % Race W / B / A 91 / 4 / 2 % Cur / For Smokers 48 / 52 % Quit (4 / 10 / 15) 15 / 17 / 20 % 15 / 17 / 19 %

Pan-Canadian Early Detection of Lung Cancer Study Validate a low cost risk modeling to select a population with a higher risk of lung cancer Evaluate the add-on impact of spirometry, blood biomarkers and AFB in a screening strategy Evaluate the impact of the screening modalities on the quality of life Evaluate the cost of implementing a lung cancer screening in Canada

Pan-Canadian Early Detection of Lung Cancer Study Enrolled N=2533 AFB = 1252 66 lung cancers confirmed

478 Normal CT Scans at Baseline (20%)

Pan-Canadian Early Detection of Lung Cancer Study Nodules of course Other findings: Kydney cyst or mass Adrenal nodule Interstitial lung disease Coronary calcifications Thoracic aorta aneurism Thyroid nodule …

Conclusions We are not ready for lung cancer screening Low dose CT might be an interesting tool but many questions to answer Lung cancer mortality reduction? Overall mortality reduction? Magnitude of overdiagnosis? Morbidity associated with screening? Cost of this type of screening? SMOKING CESSATION is still a priority!

Screening Bias Black WC. Cancer 2007

1950-1990 Manser RL et al. Thorax 2003

1950-1990 Manser RL et al. Thorax 2003

1950-1990 Manser RL et al. Thorax 2003

Radiation Brenner DJ et al. New Eng J Med 2006

Radiation Brenner DJ et al. New Eng J Med 2006

New Engl J Med 2009

Coûts-Bénéfices? Am J Respir Crit Care Med 2008

Coûts-Bénéfices? Étude PLuSS 3 642 sujets avec TDM de base 3 423 sujets avec TDM répété à 1 an 1 477 sujets avec nodules au TDM initial 821 sujets ont eu une ou des études supplémentaires (TDM et/ou TEP) avant le TDM à 1 an

Coûts-Bénéfices? Wilson DO et al. Am J Respir Crit Care Med 2008

Coûts-Bénéfices? Bach PB et al. Chest 2007

Overdiagnosis?

Follow-up of nodules FU CT Solid <5mm 12 months 24 months Nonsolid <8mm Any size semisolid 3 months Solid 5-9 mm/nonsolid 8-10mm Any lesions ≥ 10mm immediate assessment for either investigation or FU 2-3 months

Lung Cancer Risk Assessment Model Age Smoking history History of COPD (self-reported) Chest X-ray in last 3 years Family history Education Body mass index M Tammemagi & PLCO Study Group

66 Confirmed Cancers *Normal at baseline 1 Invest. 2+ Invest. CA at baseline 1 Invest. 2+ Invest. CA on Visit 2 CA on AFB Normal Baseline (no nods) Total Vancouver 3 6 1* 1 13 Calgary 2 Toronto 8 Hamilton 10 15 Ottawa 7 Quebec 12 Halifax 4 Total 30 46% 19 29% 9 14% 4 6% 3 5% 65 plus 1 incidence Case *Normal at baseline