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. 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

4. 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

5. 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

6. Prior Lung Ca Screening Trials Mayo Clinic Study Czech Study Sloan Kettering study Johns Hopkins study CXR + Sputum cytology CXR + Sputum cytologyvs. Usual Care Usual Care CXR + Sputum cytology vs. vs. CXR alone

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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. Total Lung Cancer Cases  LDCT – 1060  CXR – 941  RR 1.13

17. All Stages Stage Number of Patients NLST – NSCLC Stage Distribution

18. Lung Cancer Mortality

19. NLST – Results Lung CA specific mortalityLung 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 mortalityAll 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 CXRStage distribution more favorable for CT than CXR CT 70.2% vs. 56.7% were stage I-IICT 70.2% vs. 56.7% were stage I-II NLST Research Team, NEJM 2011

20. “Formal” guidelines  American College Chest Physicians  American Society of Clinical Oncology  National Comprehensive Cancer Network  Society of Thoracic Surgeons –55-74 yo –> 30 pk-yrs tobacco use  US Preventive Services Task Force –August 2013 provided positive recommendation

21. Remaining questions What happens if we screen for more than 3 years?What happens if we screen for more than 3 years? Do benefits or harms increase?Do benefits or harms increase? Is annual screening the best interval?Is annual screening the best interval? If we screen less frequently, we will detect a greater proportion of indolent cancers, possibly miss aggressive cancersIf we screen less frequently, we will detect a greater proportion of indolent cancers, possibly miss aggressive cancers

22. Implementation challenges  Cost-effectiveness  Patient selection and access Institutions offering screening CT regardless of re-imbursementInstitutions offering screening CT regardless of re-imbursement Will the pressure to recoup costs via ↑ procedures be overwhelming?Will the pressure to recoup costs via ↑ procedures be overwhelming? Patient navigationPatient navigation Provider workforceProvider workforce Pulmonary, radiology, etc.Pulmonary, radiology, etc. Associated services (tobacco cessation, COPD care)Associated services (tobacco cessation, COPD care)

23. Ensuring Quality What if compliance (with screening) is poor?What if compliance (with screening) is poor? How important is scan quality/interpretation?How important is scan quality/interpretation? Rate of biopsy for benign lesions varies extensivelyRate of biopsy for benign lesions varies extensively Rate of biopsy complications in US varies extensively by regionRate of biopsy complications in US varies extensively by region Quality of thoracic surgery in US varies extensivelyQuality of thoracic surgery in US varies extensively

24. LDCT Randomized Trials NELSON * 15,822 NLST 53,454 Depiscan LSS Garg DANTE ITALUNG DLCT

25. Conclusions  The NLST has shown that CT screening –Decreases lung CA specific mortality –Has a high false positive rate  Further analyses ongoing  Biomarker identification will likely play an important role  Smoking prevention and cessation are still critical to reduce lung CA incidence and mortality rates

26. 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