1. Implications of lung cancer screening in the new millenia Andrew R. Haas, MD, PhD Assistant Professor of Medicine Section of Interventional Pulmonary and Thoracic Oncology Perelman School of Medicine of the University of Pennsylvania arhaas@uphs.upenn.edu

2. Disclosures None

3. Rationale for lung CA screening Lung CA – 2 nd most common cancer in the US – Most common cause of cancer death in the US and world – Prognosis depends primarily upon stage at diagnosis – Early detection with screening may lead to improved outcomes??? Siegel et al, CA Cancer J Clin 2011

4. Rationale for lung CA screening Smoking – ~1 in 5 adults (~46 million people) in US smoke – #1 risk factor for lung CA ~85% of lung CA deaths are due to smoking – > 94 million current and former smokers in US are at increased risk for lung CA http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5935a3.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5844a2.htm

5. Prior Lung Ca Screening Trials CXR vs. usual care CXR vs. CXR with sputum cytology CT scan vs. usual care No benefit until – National Lung Screening trial Fontana et al Cancer 67:1155; Tockman et al Chest 89:324S Kubik et al Int J Ca 45:26; Melamed et al Chest 86:44 Oken et al JAMA 306:1865; Hocking et al J NCI 102:722 Infante et al AJRCCM 180:445;

6. National Lung Screening Trial (NLST)  A collaboration between ACRIN and NCI  The largest and most expensive randomized clinical trial of a single screening test in US medical history $250,000,000

7. NLST – Eligibility criteria Age 55-74 years Current or former > 30 pack-year smoking history – Former smokers quit within last 15 years No history of lung CA No treatment for or evidence of any other cancer within the last 5 years

8. NLST – Study design Enrollment: 8/2002-4/2004 Annual Interim Analyses: 4/2006 - 4/2010 Final: 10/2010 Prospective randomized controlled trial Screening for 3 consecutive years with either CXR or low-dose chest CT

9. NLST – Primary endpoint Lung cancer specific mortality – 20% difference between CT vs. CXR Type 1 error rate (  )  = 5% Power (1 -  ) = 90% Compliance 85% CT | 80% CXR Contamination 5% CT | 10% CXR Size = 25,000 subjects/arm

10. NLST – Secondary endpoints Comparison of CT and CXR regarding – All-cause mortality – Incidence of lung CA – Lung CA stage distribution – Medical resource utilization – Quality of life and psychological impact – Cost-effectiveness

11. NLST – Screen interpretation  Positive screen –Non-calcified nodule(s) > 4 mm –Other findings suspicious for lung CA  Negative screen –Non-calcified nodule(s) < 4 mm –Morphologically benign nodule(s) –Other minor abnormalities –Clinically important abnormalities requiring follow-up but not suspicious for lung CA

12. NLST – Subject accrual and biospecimen collection Recruitment from 33 screening centers Blood, urine, and sputum biospecimens collected at – 15 NLST-ACRIN sites – 10208 subjects total Paraffin blocks of resected tumors collected – Across all NLST sites

13. NLST – Subject accrual NLST Research Team slide set 50,000 40,000 30,000 20,000 10,000 Aug 02 Nov 02 Feb 03 May 03 Aug 03 Nov 03 Feb 04 Total 53,454 - CT 26,722 - CXR 26,732 LSS 34,614 (65%) Month Enrolled Subjects ACRIN 18,840 (35%)

14. NLST – Screen positivity rate NLST Research Team, NEJM 2011 Study year CTCXR Number screened Number positive % Positive Number screened Number positive % Positive Screen 126,3097,19127.326,0352,3879.2 Screen 224,7156,90127.924,0891,4826.2 Screen 324,1024,054 16.8**23,3461,174 5.0** All screens75,12618,14624.273,4705,0436.9 Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer. *Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer. **Abnormality stable for 3 rounds could be called negative by protocol.

15. NLST – Significance of positive screens NLST Research Team, NEJM 2011 Screening result CTCXR Screen 1 N (%) Screen 2 N (%) Screen 3 N (%) Total Screen 1 N (%) Screen 2 N (%) Screen 3 N (%) Total Total Positives 7,191 (100) 6,901 (100) 4,054 (100) 18,146 (100) 2,387 (100) 1,482 (100) 1,174 (100) 5043 (100) Lung CA confirmed 270 (3.8)168 (2.4)211 (5.2)649 (3.6)136 (5.7)65 (4.4)78 (6.6)279 (5.5) Lung CA not confirmed 6,921 (96.2) 6,733 (97.6) 3,843 (94.8) 17,497 (96.4) 2,251 (94.3) 1,417 (95.6) 1,096 (93.4) 4,764 (94.5)

16. NLST – Results Lung CA specific mortality – Relative reduction by 20% (95% CI 6.8-26.7, p=0.004) (87 fewer deaths in CT vs. CXR arm) – The number needed to screen with CT to prevent 1 death from lung CA is 320 All cause mortality – Rate of death reduction decreased by 6.7% (95% CI 1.2-13.6, p=0.02) – Rate of death reduction decreased by 3.2% (p=0.28) when lung CA deaths excluded Stage distribution more favorable for CT than CXR 70.2% vs. 56.7% were stage I-II

17. NLST – Biospecimen bank Intended for validation of promising biomarkers in preliminary testing – Biomarkers for high risk of lung CA – Biomarkers for benign vs. malignant nodules – Biomarkers predictive or prognostic of lung CA behavior

18. NLST – Pending analyses Costs – Direct medical (screening, Dx tests, Rx’s) – Non-medical (travel, lodging) – Opportunity (lost wages) Cost-effectiveness (ICER) Quality of life effects Smoking behavior effects Health care utilization

19. NLST – Pending questions Policy recommendations to implement CT screening in standardized fashion – Starting age? Frequency? # of scans? – How do we integrate prevention, Dx, and Rx algorithms in standardized fashion? – How extrapolate/model to other populations? Younger or older people People with lower smoking history People with family history Non-urban non-3 o community practice settings

20. NLST – Pending questions Who will cover costs of CT screening? – Out-of-pocket? Insurance? Tobacco industry? How can the number of false positive CT screens be decreased? What other factors define very high risk? – Biospecimen analysis

21. “Formal” guidelines American College Chest Physicians American Society of Clinical Oncology National Comprehensive Cancer Netwrok – 55-74 yo – > 30 pk-yrs tobacco use US Preventive Services Task Force – No guideline comments

22. Implications of lung cancer screening 10 – 15 million smokers fulfill screening criteria 2.5 – 4.5 million new pulmonary nodules Cost – $5 – $7.5 billion USD Screen positives that went on to biopsy – estimated deaths

23. Conclusions The NLST has shown that CT screening – Decreases lung CA specific mortality – Has a high false positive rate Further analyses ongoing Additional questions about CT screening need to be answered prior to implementation Smoking prevention and cessation are still critical to reduce lung CA incidence and mortality rates

24. The National Lung Screening Trial has demonstrated which of the following : A) A reduction in all cause mortality of 15.3% B) A modest false positive rate of 9% C) A relative reduction in lung cancer specific mortality of 20% D) Follow up of false positive scans had no patient impact E) A very cost effective approach to reduction in lung cancer mortality

25. Thank you!