Stephen R. Veach, M.D.

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3 Stephen R. Veach, M.D. Memorial Sloan-Kettering Cancer Center International Oncology Programs 160 E. 53 rd Street New York, NY tel fax [email protected]

4 SCREENING AND EARLY DIAGNOSIS OF LUNG CANCER IS IT POSSIBLE?

5 Lung CA: A Major Public Health Problem Tobacco exposure accounts for 50% of premature deaths Lung CA is now the leading cause of tobacco- related death In 2007 ACS F&F Cases: 213,380 Deaths: 160,390

6 Lung Cancer & Tobacco Mortality

7 Cum. Risk of Lung CA in UK Men Data from Sirs Doll & Peto unequivocally demonstrates that the risk of lung CA after smoking never returns to normal

8 Potential For Screening Benefit 5yr Survival ACS CA Facts & Figures ( ) Prostate CA- 99.9% Breast CA- 88.5% Colorectal CA- 64% Lung CA- 15% Premature Mortality Source-SEER Program, 2000 Site YPLL (X 1,000) Average YPLL Lung 2, Breast Uterus

9 Change in U.S. Life Expectancy ( ) Advances in clinical research have significantly increased the lifespan of the average American Lenfant, C: NEJM 349:868, 2003

10 Impact of CT on Lung Cancer Management CT resolution doubling every two yrs for > decade Improved microprocessor capabilities Image processing capabilities evolving rapidly Capability to image and resolve smaller critical nodules (contribution of LIDC & RIDER Databases) Imaging progress drives changes in clinical care

11 Nodule Volume Rendering & Slice Thickness

14 First scan -10mm Slice Thickness (I-ELCAP)

15 Second scan-5mm Slice Thickness (I-ELCAP)

16 Third Scan-2.5mm Slice Thickness (I-ELCAP)

17 Final Scan-1mm Slice Thickness (I-ELCAP)

18 Strategic Importance of Imaging Imaging Technologies Tagged For FDA Drug Development Initiative FDA is commencing an initiative to encourage use of imaging technologies to develop surrogate endpoints for drug submissions. There is tremendous potential for the use of imaging in drug development...from pre-clinical [applications] all the way to using surrogate markers for approval, Center for Drug Evaluation & Research Director Janet Woodcock told participants at the Fifth National Forum on Biomedical Imaging in Oncology in Bethesda, Md. Jan. 29.

19 Mayo Lung Cancer Project 9000 men High risk Randomized Chest x-ray x and sputum cytology 3x year for 6 years Usual medical care

20 Mayo Lung Cancer Project Results published 2000 Frequent xrays found more tumors Large 5 year survival difference Mortality was greatest in the screened arm Follow up in 2006 supported the over diagnosis conclusion

21 Early Lung Cancer Action Project 1000 high risk, > 60 years old, smokers screened All had chest x-ray x and low dose CT CT found > 3x as many suspicious nodules as xrays Malignant disease in 27, 4 x as many with xray 23 had Stage I disease Therefore, CT more sensitive at finding early tumors Henschke, CI et al Lancet 1999; 354:99-105

22 International Early Lung Cancer Action Project 7 countries, mostly smokers, age 40 31,567 patients Screening with LDCT from ,456 annual screening on some patients Found 484 lung cancers 412 in early stage As of May 2006, 75 patients had died of lung cancer NEJM Vol 355: Oct 26, 2006 Number 17

23 Kaplan Meier Survival Curves Henschke, CI et al. NEJM 355:1763, 2006

24 Criticism I-ELCAP patients from Japan who never smoked (some had tumors) probably indolent, skewing statistics year predicted survival based on only 2 patients 3. No mortality statistics 4. No staging (except after Stage I) 5. No pathologic staging

25 Criticism I-ELCAP (2) 6. How many lost to follow up and what % had annual screening? 7. No clear evidence to show benefit 8. No control arm suspicious nodules were investigated, may harm more people than helped

26 I-ELCAP Relevant Statistics Lead time bias: When you find a cancer early by screening, but the patient lives no longer than he would have without screening Length time bias: Screening detects more slow growing cancers as opposed to more aggressive rapidly growing cancers which show up in between screenings.

27 I-ELCAP Screening Risks 4000 suspicious nodules investigated Many benign nodules end up with biopsy 1-4% mortality from lung resection or biopsies No one knows risk of multiple CT scan; some estimates are 5% increase in risk of developing lung cancer.

28 CT and lung Cancer The Media and Public Opinion JCO, Vol 25, No. 36 (Dec 07), pp After publication of I-ELCAPI CBS News Using computerized scan to screen for lung cancer can help save lives and should be part of a regular check-up for people who have a high risk for the disease.

29 Avnnenberg National Health Communication Survey December % had heard or seen media coverage on results of I-ELCAPI Only 5% had heard or seen media coverage and were likely to get a scan.

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32 I-ELCAP Conclusion I-ELCAP detected clinical Stage I lung cancer in a high proportion of persons who were found to have cancer Screening could prevent death from lung cancer Rates of detection 1.3% baseline 0.3% annual comparable to breast cancer.6% to 1% baseline and.2% to 0.4% for annual mammography. Cost effective if one compares treatment for Stage I disease compared to advanced Stage disease

33 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement 1. Background 160,000 die in US 2007 from lung cancer Symptomatic patients present with advanced stage Can screening prevent or delay death? Chest x-ray x screening trials from 70 s s and 80 s s unable to confirm this prevention or delay Cancers found at screening may not be what kills the patient

34 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement 2. Natural History of CT detected lung cancer Consider the growth rate by doubling times More rapid growth more aggressive Have to assume growth rate more or less constant Previous studies estimate 20 doublings to reach 1mm

35 Timeline of lung cancer progression by number of tumor doublings and volume doubling rate Bach, P. B. et al. Chest 2007;132:69S-77S

36 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement 1. Epidemiologic Analysis SEER shows mean survival for clinical detected lung cancer < 1 year Consistent with doubling trial of days 2. SEER shows survival of Stage I lung cancer not treated with surgery is 14 months Consistent with doubling time of 70 days

37 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement 3. If one stops smoking, risk begins to decline within a few years of smoking cessation Consistent with doubling time of days At this rate existing cancers would present in approximately years

38 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement Epidemiologic Analysis 4. Cancers identified by CT screening and followed annually had doubling times of days (Hasegawa) Mayo lung screening with chest xray data suggested only a portion of Stage I with doubling times less than 100 days and 11% > 300 days

39 Screening for Lung Cancer ACCP Evidence Based Clinical Practice Guidelines Bach,, P. et al, Chest, 132/3/Sept 2007 Supplement 5. A portion of lung cancers detected through screening are indolent and are not the cancers that result in death within 1 to 2 years

40 Cost Effectiveness of Screening with CT Measured per Life-Year Gained Source Cohort Regimen Time Cost LYG Mahadavia ,000 current previous > 60 yo > 20 pack year 55% male Annual screening for 20 years 1-4 years $300 Current $116,300 Former $2.3 million Wisnievesky > 60 yo > 10 pack years One time screening 1 year after diagnos is $165 $2,500

41 Summary of Recommendations 1. Do not recommend that low dose computerized tomograph be used to screen for lung cancer except in a clinical trial. 2. Do not recommend the use of serial chest x-ray x to scan for presence of lung cancer. 3. Do not recommend the use of sputum cytology to screen for the presence of lung cancer.

42 What is the Future of Screening 1. New trials for Lung Cancer? National Lung Screening Trial NELSON Trial 2. Refining Risk Prediction 3. Biomolecular Markers Investigational at this time Limits exposure to radiation Cost effectiveness?

43 National Lung Cancer Trial 53,000 people 55 to 74 years old Heavy current or former smokers Randomized Arm A Helical CT scan Arm B Chest x-rayx Initial study then annually x 2 years Closed in 2004 Designed to show 20% mortality reduction by 2009

44 NELSON Trial (Dutch-Belgian Lung Cancer Screening Trial) Launched in ,428 cases aged years old Active and former smokers Randomized CT scan year 1, 2, 4 Smoking cessation advice Conclude 2015

46 The LLP Risk Model for Lung Cancer Risk Cassidy et al, Br. Journal of Cancer 18 Dec Lung cancer cases and 1157 age and sex matched population-based controls Lifestyle risk factors modeled to create profiles 2.5% risk as cut off to trigger increased surveillance equated a sensitivity of 0.62 and specificity of 0.7% A 6% risk cut off would give sensitivity of 0.34 and specificity of 0.90%

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52 Biomolecular Markers 1. Lung Sign Test 370 lung cancer found in 1235 high risk subjects 33% prevalence With sputum DNA cytometry 40% of all lung cancer detected and 31% of Stage I Conventional cytology 16% of lung cancers Possible additional tool for screening *Kemp, R.A., Journal of Thoracic Oncology Vol 2., Number 61, November 2007

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58 Correlation of Lung CA & COPD Emphysema 338 Airway Obstruction 302 E + AO 154 No Airway Obstruction or Emphysema 691 (59%) Total population 1,176 (100%) Airway Obstruction and/or Emphysema 485 (41%) = diagnosis of lung cancer J Zulueta et al. I-ELCAP, 5/07 90% of lung cancers occurred in individuals with airways obstruction, emphysema or both

59 Contribution of the Inflammatory Response in Chronic Injury to Lung CA Carcinogenic Exposure Normal Epithelium Cell Injury Initiated Cell Clonal Expansion Invasion Competence Inflammation 5-LO Cytokines COX-2 Ballaz et al. Clin Lung Ca 5:46, 2003

60 Impact of Steroids for COPD on LCA 10,474 COPD patients followed for 4 years 423 lung cancers developed Lung cancer was 61% less frequent in COPD patients receiving 1.2 mg of inhaled steroids Parimon T, Chien JW, Bryson CL et al. Am J Resp Crit Care Med 175:712, 2007

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62 Global Tobacco Surveillance System 1998 US Center for Disease Control, World Health Organization, Canadian Public Health Association Established Surveys Global Youth Tobacco Survey Global School Personnel Survey Global Health Professions Student Survey Global Adult Tobacco Survey

63 Global Youth Tobacco Survey % smoke % used other than cigarettes % never smokers but susceptible to Boy Girl Boy Girl Boy Girl 2005 Egyptian Students Age

64 Global Youth Tobacco Survey Egyptian Students years old Exposed to smoke from others at home 38.7% Public places 43.7% Favored ban in public places Had object with cigarette logo Offered free cigarette by tobacco company 87.5% 13.2% 10.4%

65 Global Youth Tobacco Survey Egyptian Students years old Desire to stop smoking Usually bought cigarettes at store Were not refused because of age Taught about dangers of smoking at school 76% 42.6% 88% 57.7%