1. Lung Cancer Screening Update 29 th Annual Denali Oncology Group Reginald F. Munden MD, DMD, MBA I have no conflicts of interest to report

2. National Lung Screening Trial National Cancer Institute National Lung Screening Trial National Cancer Institute T S L N

3. NLST - ACRIN Randomized 1:1 Experimental Arm 1 Control Arm 2 Spirometry Baseline Low-Dose Helical CT Baseline PA CXR (Baseline samples blood, urine, sputum) Annual incidence screen x 2 (Low dose helical CT) (PA CXR) Questionnaires: Interval Health Q6 months: Interval health status x 6- 8 years

4. NLST - ACRIN CT Protocol Single breath hold kVp 120-140 mAs40 – 100 Collimation10 mm, 20mm Reconstruction slice thickness2.5mm interval1.25mm algorithmsoft tissue and high spatial frequency

5. NLST – ACRIN Interpretation Nodule classification ·benign – calcified; fat; or < 4mm micronodule ·abnormal - >10mm, enlarging > 7mm ·indeterminate - 4 – 10mm; enlarging < 7mm

6. NLST – ACRIN Interpretation 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

7. NLST – ACRIN Interpretation 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

8. NLST - Recommendations No intervention – continue screening Comparison with historical Thin section CT: 3, 6, 12 months Diagnostic CT CT nodule densitometry PET Biopsy

9. NLST Design Arms Helical CT vs. CXR Difference in lung cancer-specific mortality 20% α5% Power90% Compliance85% CT | 80% CXR Contamination 5% CT | 10% CXR Size25,000 / arm

10. 33 participating sites LSS si

11. NLST Cumulative Accrual

12. 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.orgwww.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

13. NLSTUS Census Male (%)59.057.6 Age 55-59 (%)42.834.6 60-64 (%)30.627.6 65-69 (%)17.820.9 70-74 (%)8.816.9 Race/ethnicity Black (%)4.54.1 Hispanic (%)1.72.4 Comparison: NLST with US census population

14. NLSTUS Census Married66.660.9 Education < HS6.120.4 ≥ College31.514.4 Current smoker 48.258.4 Median pack years 48.047.0 Comparison: NLST with US census population

15. Family history Helical CTX-RayTotal %% Any first degree relative21.821.7 Two or more first degree relatives3.3

16. Screening Exam Compliance Study Year Helical CTChest X-rayTotal Expected ScreenedExpectedScreenedExpected Screened T0 26,71598.5%26,72397.5%53,43898.0% T1 26,28794.0%26,40191.3%52,68892.6% T2 25,94292.9%26,10189.5%52,04391.2%

17. t ime 9/02 9/03 9/04 9/05 9/06 9/07 9/08 9/09 9/10 10/20/10 T0T0 T1T1 T2T2 NLST Timeline 1 st Interim Analysis 2 nd Interim Analysis 3 rd Interim Analysis 4 th Interim Analysis 5 th Interim Analysis 6 th Interim Analysis

18. Screen Positivity* Rate by Screening Round and Trial Arm CTCXR Number screened Number positive % Positive Number screened Number positive % Positive Screening round 1 26,3147,19327.326,0492,3879.2 Screening round 2 24,7186,90227.924,0971,4826.2 Screening round 3 24,1044,05416.8**23,3531,1755.0** All screening rounds 75,13618,14924.273,4995,0446.9 *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

19. Lung Cancer Screening NLST Arm Person years (py) Lung cancer deaths Lung cancer mortality per 100,000 py Reduction in lung cancer mortality (%) Value of test statistic Efficacy boundary CT 144,097.6354245.7 20.3 –3.21–2.02 CXR 143,363.5442308.3 Interim Analysis of Primary Endpoint - Oct. 20, 2010 Deficit of lung cancer deaths in CT arm exceeds that expected by chance

20. Lung Cancer Screening:NLST Arm Person years (py) DeathsAll-cause mortality per 100,000 py Reduction in all-cause mortality (%) Value of test statistic Value for signifi- cance CT 167,389.918701117.2 6.9 –2.27–1.96 CXR 166,328.219961200.0 All-cause mortality

21. Lung Cancer Screening: NLST Results CT CXR (%)Positive Clin sig Positive Clin sig TO271093 T128662 T217651

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Lung Cancer CT Screening

29. 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

30. 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?

31. 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 2 nd hand smoke); radon, occupational, family hx, COPD Category 1 - based on high level evidence, uniform NCCN consensus Category 2A - based on lower level evidence, uniform NCCN consensus Category 2B - based on lower-level evidence, NCCN consensus

32. Guidelines 55 - 74 yrs of age Smokers and former smokers (< 15 yrs) 30 pack year smoking AATS –55 – 79 –Lung cancer survivors

33. 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

34. 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

35. Lung Cancer Screening False positive/negative NLST: 26% - false negative - “missed rate”

36. False Negative

37. False Positive Baseline3 months follow-up

38. Positive – not cancer

39. Lung Cancer Screening 62y.o. male 38 pk yrs

40. Fleischner Recommendations Nodule sizeLow- riskHigh risk < 4mmNo follow-up12 months >4-6 mm12 monthsinitial 6-12 months then 18, 24 months >6-8mminitial 6-12initial 3-6 months then + 1 yrthen + 6 months, final @ 2 yrs >8mm3, 9, and 24Same as for low risk or dynamic,PET,bx Subsolid – longer follow-up MacMahon et al, Radiology 237: 395-400, 2005

41. 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

42. Lung Cancer Screening One Year

43. Lung Cancer Screening 52 y.o. smoker (high risk)

44. Lung Cancer Screening 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

45. Lung Cancer Screening Solitary Lesion GGO < 5-mmNo follow-up 5-10mm3-6 mos (then annual for 3-5 yrs?) >10mmResect (provided persistence or growth) Mixedany sizelikely malignant – PET/CT, ? biopsy Multiple lesions GGO<5mm1 yr follow-up 5-10mmlikely AAH or RB > 10mmresect/PET/CT Godoy & Naidich. Radiology December, 2009

46. Lung Cancer Screening 3 months

47. Lung Cancer Screening Non - Cancer Findings

48. Lung Cancer Screening Non Cancer Findings

50. Lung Cancer Screening MDACC Lung Cancer Screening Program Radiology, Prevention, Surgery, Pulmonary Activate – spring/summer 2010 Establish standard for screening - multidisciplinary Advance science of screening/prevention Model - mammography

51. Lung cancer screening works! Now what and who? Thank you