Implications of lung cancer screening in the new millenia

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 • 2nd 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 • Mayo Clinic Study • Czech Study • Sloan Kettering study • Johns Hopkins study CXR + Sputum cytology vs. Usual Care CXR + Sputum cytology vs. CXR alone

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

9. NLST – Primary endpoint • Lung cancer specific mortality • 20% difference between CT vs. CXR • Type 1 error rate (a)= 5% • Power (1 - b) = 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 – Screen positivity rate * Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer. ** Abnormality stable for 3 rounds could be called negative by protocol. NLST Research Team, NEJM 2011

14. NLST – Significance ofpositive screens NLST Research Team, NEJM 2011

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

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

17. Lung Cancer Mortality

18. 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 • CT 70.2% vs. 56.7% were stage I-II NLST Research Team, NEJM 2011

19. “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

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

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

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

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

24. 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