A Comprehensive Cancer Center Designated by the National Cancer Institute

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1 N C I C C C A Comprehensive Cancer Center Designated by the National Cancer Institute Screening and Early Detection of Lung Cancer: Ready for Practice? David S. Ettinger, MD, FACP, FCCP Alex Grass Professor of Oncology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

2 Disclosure Statement Reported a financial interest/relationship or affiliation in the form of: Consultant, Biodesix, Boehringer-Ingelheim GmbH, Eli Lilly and Company, Gilead, Genentech: A member of the Roche Group

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

5 Medical Cost of Lung Cancer $12.1 billion in the US in 2010, accounting for approximately 10% of the total medical expenditure on cancer. NCI Trends Progress Report 2011/2012 Update, Bethesda, MD

6 Magnitude of Premature Mortality Due to Cancer US deaths from lung cancer in 2009 accounted for 2,373,200 personyears of life lost, more than 3 times the number of years lost to breast cancer (770,700 person-years) and colorectal cancer (765,300 personyears). Howlander N, et al. SEER Cancer Statistics Review NCI, Bethesda, MD

7 Indirect Costs of Lung Cancer Of the $134.8 billion indirect cost (or productivity loss) with cancer deaths in 2005, $36.1 billion (or over 25%) was attributable to premature mortality from lung cancer. NCI Trends Progress Report 2011/2012 Update, Bethesda, MD

8 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;

9 Early Lung Cancer Action Project (ELCAP) Compared Lung Cancer Screening with LDCT and CXR volunteers age 60 and over with at least 10 pack-years. LDCT identified 233 participants with noncalcified nodules and 27 malignancies, 26 of which were resected and 23 were stage I disease. CXR identified 68 non-calcified nodules, 7 were malignant and 4 were stage I disease. Henschke et al., Lancet 1999; 354:99

10 Benefits of Screening for Lung Cancer with LDCT 3 randomized control trials reported mortality results (the NLST, DANTE and DLCST studies). DANTE (Detection & Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays) Obs 3% fewer lung cancer deaths in group screened with no difference in all-cause mortality. DLCST (Danish Lung Cancer Screening Study) found an excess rate of lung cancer mortality in the group screened and no difference in allcause mortality.

11 Smoking Cessation There is a concern that in some smokers, they might use LDCT imaging as an excuse to continue smoking. However, most of these studies have shown high rates of smoking cessation among those choosing to be screened by LDCT than are see in unscreened groups.

12 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

13 NLST Eligibility Criteria Age 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 Aberle DR, et al., N Engl J Med 2011;365:

14 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 Aberle DR, et al., N Engl J Med 2011;365:

15 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 Aberle DR, et al., N Engl J Med 2011;365:

16 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

17 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

18 NLST Subject Accrual and Biospecimen Collection Recruitment from 33 screening centers Blood, urine, and sputum biospecimens collected at 15 NLST-ACRIN sites subjects total Paraffin blocks of resected tumors collected Across all NLST sites

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

20 NLST Screen Positivity Rate Study year Number screened CT Number positive % Positive Number screened CXR Number positive % Positive Screen 1 26,309 7, ,035 2, Screen 2 24,715 6, ,089 1, Screen 3 24,102 4, ** 23,346 1, ** All screens 75,126 18, ,470 5, * 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

21 NLST Significance of Positive Screens Screening result Total Positives Lung CA confirmed Lung CA not confirmed Screen 1 N (%) 7,191 (100) Screen 2 N (%) 6,901 (100) CT Screen 3 N (%) 4,054 (100) Total N (%) 18,146 (100) Screen 1 N (%) 2,387 (100) Screen 2 N (%) 1,482 (100) CXR Screen 3 N (%) 1,174 (100) Total N (%) 5043 (100) 270 (3.8) 168 (2.4) 211 (5.2) 649 (3.6) 136 (5.7) 65 (4.4) 78 (6.6) 279 (5.5) 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) NLST Research Team, NEJM 2011

22 False Positive Results Relatively high rate of identification of benign, non-calcified nodules. Over 3 screening rounds, 39.1% of individuals experienced at least 1 abnormal CT scan. Additional tests based on nodule size and level of suspicion for lung cancer.

23 False Positive Results (Cont d) Prior to resolution, if additional studies needed, false-positive findings can cause anxiety, lead to additional costs, additional radiation exposures and invasive procedures.

24 Invasive Procedures Rate of invasive procedures among participants with abnormal imaging results was low, only 2.7%. Rate of complications from diagnostic procedure following a positive screening test was relatively low (higher in pts. with dx of lung cancer vs. benign nodule (11.2% vs. 0.06% respectively). Few pts. (2.7%) who did not have lung cancer underwent an invasive procedure. Pts. having a positive screen test and underwent a diagnostic procedure ~1.4% experience a complication.

25 Mortality Associated Diagnostic Procedures 21 deaths within 60 days of the most invasive diagnostic procedures in the LDCT group, 16 of which occurred following invasive medical intervention and 5 of which occurred in patients who only underwent additional imaging. 10 of these deaths occurred in pts. found to have lung cancer. In patients without lung cancer, 6 deaths occurred with the first invasive procedure and 5 deaths occurred within 60 days of additional imaging.

26 Mortality Associated Diagnostic Procedures (Cont d) Risk of death and major complications associated with any diagnostic evaluation for benign findings was 4.1 and 4.5 per 10,000 respectively. The risk of death in the non-cancer patients was low (0.024%). Bach PB, et al. JAMA 2012;307:2418

27 Radiation Risk Concerns about radiation exposure from repeat LDCT screening examinations and higher dose evaluations. However, risks are not precisely quantifiable. For individuals at low risk of lung cancer, radiation exposure is more of concern relative to the expected benefit versus potential harm. Brenner DT, et al. Radiology 2004;231:440 Berrington de Gonzalez A, et al. J Med Screen 2008;15:153

28 NLST Results Lung CA specific mortality Relative reduction by 20% (95% CI , 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 , 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

29 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

30 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

31 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

32 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

33 Formal Guidelines American College Chest Physicians American Society of Clinical Oncology National Comprehensive Cancer Network yo > 30 pk-yrs tobacco use American Cancer Society US Preventive Services Task Force No guideline comments

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36 Implications of Lung Cancer Screening million smokers fulfill screening criteria million new pulmonary nodules Cost $5 $7.5 billion USD Screen positives that went on to biopsy estimated deaths

37 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

38 Thank you!