Epidemiology./Biostatistics class on lung cancer screening including description of lung cancer, natural history and treatment, lung cancer statistics, lung cancer risk factors, NLST results, NLST follow-on, criteria for a good screening test, USPSTF and CMS lung cancer screening guidelines, and challenges to screening

1. PUBH 5409 - Lung Cancer Screening
Andrea Borondy Kitts
@findlungcancer
April 30, 2015

2. Agenda
• What is Lung Cancer
• Natural History and Treatment
• Lung Cancer Statistics
• Lung Cancer Risk Factors
• National Lung Screening Trial (NLST) Design and Results
• NLST Follow-on Analysis
• Lung Cancer Screening Class Evaluation
– Good Disease for Screening?
– Good Screening Test?
• USPSTF and CMS Recommendations
• Challenges
• Summary
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3. Lung Cancer is a Non-Infectious Chronic Disease
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http://www.nccn.org/patients/guidelines/nscl/index.html#8
Most are carcinomas and initiate in
the lining of the airways
• Bronchi
• Bronchiole
• Alveoli
Today’s smokers are more likely to
develop lung cancer than smokers
50 years ago.

4. 87% Non-Small Cell Lung Cancer (NSCLC); 13%
Small Cell Lung Cancer (SCLC) Histology
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Molecular Challenges in Lung Cancer
Ben Leach Published Online: December 17, 2012
http://www.targetedonc.com/publications/targeted-therapy-
news/2012/November-2012/Molecular-Challenges-in-Lung-Cancer
NSCLC further
characterized
histologically into:
• Adenocarcinoma
• Squamous Cell
• Large Cell

5. Natural History of Lung Cancer
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DNA
damage to
cells
Abnormal
cell growth
Lesion
Pathological
Evidence
Metastasis Diagnosis Treatment Death
Damage
accumulates
with age and
exposure to
agents e.g.
tobacco.
Average age
of diagnosis is
70
Few symptoms
in early stages
Screening test
(LDCT) not
generally
available until
2015
Approximately 80%
of diagnoses at a
late stage
Early stage –
Surgery and
possible adjuvant
chemo/radiation
Late stage –
palliative and life
extension
CT
PET/CT
Biopsy
MRI
Staging
5 year survival 16.8%
Localized – 54%
Distant – 4%
http://seer.cancer.gov/statfacts/html/lungb.html
http://www.nccn.org/patients/guidelines/nscl/index.html

6. Surgical Treatment in Early Stages; Systematic
Treatment in Late Stages
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Surgical Options include wedge resection,
lobectomy, bilobectomy, and
pneumonectomy via traditional,
minimally invasive (VATS) or robotic
surgery
• sometimes preceded by, or followed
with, adjuvant chemotherapy and/or
radiation
Systematic treatments include chemotherapy,
radiation, targeted molecular treatments, and
immunotherapy
• Approximately 67% of NSCLC have an
identified genetic mutation
http://www.onclive.com/publications/Oncology-live/2013/January-
2013/Targeting-Tumors-Early-Trials-Push-Novel-Agents-to-Forefront/2

7. Lung Cancer is the 2nd Leading Cause of Death in the US
• Lung cancer is the leading cause of
cancer deaths in both men and
women in the US
– 160,000 die each year, more than
breast, colon, prostate and
pancreatic cancer combined
– 5 year survival at 16.8% essentially
unchanged since 1975
• Most common cancer worldwide
– 1.6 million deaths in 2012
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10. Lung Cancer Incidence and Mortality Rates Decreasing
in the US
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http://seer.cancer.gov/statfacts/html/lungb.html

11. Overall Lung Cancer Incidence in US is 60.1 cases per 100,000;
Highest in African American Men at 93.0 per 100,000
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http://seer.cancer.gov/statfacts/html/lungb.html
Average age at diagnosis 70

12. Annual Productivity Loss due to Cancer
Lung Cancer Leads with $36 Billion
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13. Over 80% of Lung Cancers are caused by Tobacco
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U.S. Department of Health and Human Services. (2014). The Health Consequences of Smoking – 50 Years of
Progress A Report of the Surgeon General. Retrieved from http://www.surgeongeneral.gov/library/reports/50-
years-of-progress/50-years-of-progress-by-section.html

14. Risk of Lung Cancer Increases with Age and
Dose Tobacco Use
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15. © 2014 Free to Breathe
Other than smoking, what else can cause lung
cancer?
- Secondhand exposure to smoke
- Radon
- Having had smoking related cancer
- Family History
- Environmental pollutants (pollution, dust,
asbestos)
- COPD or Pulmonary Fibrosis
Lung Cancer Risk

16. © 2014 Free to Breathe
• Lung Cancer Risk
94 Million Current and Former Smokers in the US

17. Stigma due to Strong Link with Smoking
Adverse Impacts on Depressive Symptoms, Quality of Life and
Physical Symptoms
People with lung cancer blamed and/or blame themselves for their disease
http://cancergeek.wordpress.com/2013/11/16/cancer-the-harsh-story-of-lung-cancer-vs-breast-cancer/
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18. Stage IV NSCLC
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<1% = 5 year OS
80% of Lung Cancers Diagnosed after the
Cancer has Spread When Chance of Cure Small

19. Annual Low Dose CT Scan Screening Finds Lung
Cancer Early When Chance for Cure High
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92% 5-year Overall Survival
Stage T1AN0
Goldstraw P, Crowley J, Chansky K, et al. (2007) The IASLC Lung Cancer Staging
Project: proposals for the revision of the TNM stage groupings in the forthcoming
(seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol
2:706–714.

20. Smoking Dose and Time Since Quit Key
Considerations for Screening Program Design
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Tammemagi MC, Katkiha HA, Hocking WG, et al. Selection criteria for lung-cancer
screening. N Engl J Med. 2013;368(8):728-236 DOI: 10.1056/NEJMoa1211776
Tammemagi MC, Church TR, Hocking WG, et al. Evaluation of the lung cancer risks at
which to screen ever-and never-smokers: Screening rules applied to the PLCO and NLST
cohorts. PLoS Medicine 2014;11(12):e1001764. doi:10.1371/journalpmed1001764.

21. National Lung Screening Trial Design Overview
• 53,456 participants
– LDCT scan
or
– CXR
• Enrolled 2002 – 2004
• 3 Annual Screenings
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National Lung Screening Trial Research Team (2011) Reduced lung-cancer mortality with low-dose computed
tomographic screening. N Engl J Med 365(5):395–409.

22. National Screening Trial Results
The National Lung Screening Trial Research Team . N
Engl J Med 2011;365:395-409.
More Lung Cancers found in LDCT Arm
• Total Cases
• LDCT 1060
• CXR 941
• Cases per 100k person years
• LDCT 645
• CXR 572
Difference primarily early stage disease
More Lung Cancer Deaths in CXR Arm
• Total Deaths
• LDCT 356
• CXR 443
• Deaths per 100k person years
• LDCT 247
• CXR 309
20% Reduction in lung cancer
mortality with LDCT
6.7% Reduction in all cause mortality
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23. NLST Low Dose CT (LDCT) Lung Cancer
Screening Efficacy
Prevalence = 1 percent (Initial Screen)
Incidence = 0.8 (Following Annual Screens)
For initial screen
Sensitivity =93.5 (90.7-96.3)*
Specificity = 73.4 (72.9-73.9)
False Positives = 26.60 (26.10-27.10)
PPV = 3.80 (3.30 – 4.20)
NPV = 99.90 (99.86-99.94)
NNS = 320
Incidental Findings not suspicious for lung cancer – 7.5%
*Numbers in parentheses 95% Confidence Intervals

24. NLST False Positive Invasive Procedure Tracking
• False positives (Lung Cancer Not Confirmed) (17053)
• Number with:
• No invasive procedure (16596) (97.3%)
• Thoracotomy, thoraoscopy, or mediastinoscopy (164) (0.96%)
• Bronchoscopy (227) (1.33%)
• Needle Biopsy (66) (0.39%)
• Total invasive – (457) (2.68%)
• Positives with lung cancer confirmed (649)
• No invasive procedure (31) (4.77%)
• Thoracotomy, thoraoscopy, or mediastinoscopy (509) (78.43%)
• Bronchoscopy (76) (11.71%)
• Needle Biopsy (33) (5.08%)
• Total invasive – (649) (95.22%)
• Also track complications by procedure and classify as:
• Minor
• Intermediate
• Major

25. Complications after the Most Invasive Screening-Related Diagnostic Evaluation Procedure,
According to Lung-Cancer Status.
The National Lung Screening Trial Research Team . N Engl J Med 2011;365:395-409.
Complications Resulting From False Positives in NLST

26. 5/12/2015 26

27. Reverted to cancers being diagnosed at late stage
once screening stopped
The National Lung
Screening Trial
Research Team . N
Engl J Med
2011;365:395-409.

28. Radiation Exposure
LDCT <1 mSv Years of annual lung
screening
Mammogram .7 mSv
Lumbar Spine Films 2 mSv 2
Diagnostic Chest CT 10 mSv 10
Triphasic CT AB/P 25 mSv 25
Background Exposure
Colorado
3 mSv/year
4.5 mSv/year
3
4.5
Occupational Exposure 50 mSv/year 50
Transatlantic Flight .1 mSv 7 flights = 1 LDCT
10 -30 year latency period to develop secondary malignancies
from exposure
Average age of patients in screening trials is 62

29. An Actuarial Analysis Shows That Offering Lung Cancer
Screening As An Insurance Benefit Would Save Lives At
Relatively Low Cost
• Cost per life-year saved would be below $19,000 (ages 50-64)
Pyenson et al, Health Affairs 31, No.4 770-
779: April 2012
29

30. Adding Smoking Cessation Estimated to Increase
QALY and Lower Cost of Screening by 20 to 45%
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31. NLST Lung Cancer Screening Cost Effectiveness Analysis
$81,000 per QALY
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Black WC et al. N Engl J Med 2014;371:1793-1802

32. Lung Cancer Screening Cost Effectiveness in
Medicare Population
$18,452 per QALY
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33. Lifetime Overdiagnosis for NSCLC (excluding BAC)
with LDCT screening estimated at approximately 3%
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Patz EF, Jr, Pinsky P, Gatsonis C, et al. Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer. JAMA
Intern Med. 2014;174(2):269-274. doi:10.1001/jamainternmed.2013.12738.

34. Is Lung Cancer a “Good” Disease for a Screening
Test?
• Is Disease important to Public Health?
– Leading cause of cancer deaths – 450 a day
– High Mortality; 5 year survival 16.7%
– 93 million current and former smokers in US;
about 10 million in high risk group
– Estimate potential to save 20,000 lives per year
– $36 billion annual lost productivity
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35. Is Lung Cancer a “Good” Disease for a Screening
Test?
• Is there a Long Asymptomatic Period
– Annual screening shown to be effective for NSCLC
• Is There an Effective Intervention?
– If Caught Early Surgery, SBRT and adjuvant
chemotherapy and radiation results in 92% 5 year
survival
– Cost per QALY comparable to other screening tests
• 18,000 – 81,000 (threshold $100,000 per QALY)
5/12/2015 35

36. Is LDCT a Good Screening Test for Lung Cancer?
• Is test effective in correctly identifying those with and without disease?
• Find cases (rule in) or find healthy people (rule out)
– Rule in – SPIN – High Specificity
– Sensitivity 93.5%
– Specificity 73.4% - high false positive rate
– Follow-up over 95% not invasive – mainly imaging
– Screening high risk population
• Is Test Low Cost?
– CT scan fully clothed, No IV, 10 sec breath hold, 15 minutes total
– Annual screen frequency
– Current Medicare reimbursement to provider approx. $250 per scan
– No-copay for participant
– Anxiety due to false positive
– Radiation exposure
– Overdiagnosis estimated at 3% for lifetime
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37. Is LDCT a Good Screening Test for Lung Cancer?
• Reliably reproduce results in many locations?
– NLST 33 screening locations, most major academic or
medical centers
– Lahey Hospital & Medical Center matched NLST results in
clinical application
– American College of Radiology (ACR) accreditation
program, MeVis radiologist training, LungRADS structured
reporting criteria
– Multidisciplinary follow-up may be challenging for some
locations
5/12/2015 37

38. Annual Lung Cancer Screening Recommended For the High
Risk Population
5/12/2015 38
Covered by Insurance and Medicare without a Co-Pay
Age
55 to 80 (age 77 for Medicare)
Smoking History
30 pack years or more
• 1 pack a day for 30 years/2 packs per day for 15 years etc.
Current or Former Smoker Quit within the last 15 years
Asymptomatic
Low Dose CT scan
15 minutes, 10 second breath hold
No IV
Don’t need to change

39. Additional CMS Requirements for Lung Cancer Screening
5/12/2015 39
• Lung cancer screening counseling and shared decision making
dedicated visit prior to initial screen with physician or qualified
non-physician practitioner
• Use of one or more decision aids
• Benefits and harms of screening
• Follow-up diagnostic testing
• Over-diagnosis
• False positive rate
• Total radiation exposure
• Counseling on
• Importance of adherence to annual lung cancer LDCT screening
• Impact of comorbidities
• Ability or willingness to undergo diagnosis and treatment
• Importance of maintaining cigarette smoking abstinence if former
smoker
• Importance of smoking cessation if current smoker
• Furnishing of information about tobacco cessation interventions

40. Elements of shared decision making
• Understands the risk or seriousness of the
disease or condition
• Understands the preventive service, including
the risks, benefits, alternatives and
uncertainties
• Have weighed his/her values regarding the
potential harms and benefits associated with
the service
• Have engaged in decision-making at a level he
or she desires and feels comfortable
Sheridan SL, Harris RP, Woolf SH. Shared Decision making about screening and chemoprevention, a suggested approach from
the U.S. Preventive Services Task Force. American journal of preventive medicine. 2004;26(1):55-56

41. Additional CMS Requirements for Lung Cancer Screening
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• Radiology imaging facility eligibility criteria:
• Performs LDCT with volumetric CT dose index (CTDIvol) of ≤ 3.0 mGy
(milligray) for standard size patients (defined to be 5’ 7” and
approximately 155 pounds) with appropriate reductions in CTDIvol for
smaller patients and appropriate increases in CTDIvol for larger
patients
• Utilizes a standardized lung nodule identification, classification and
reporting system
• Makes available smoking cessation interventions for current smokers
• Collects and submits data to a CMS-approved registry for each LDCT
lung cancer screening performed.

42. LUNG RADS – Lung Cancer Screening Reporting
and Classification System
Lung Number Category
• Category 1: Negative
• Category 2: Negative with
benign pulmonary findings
• Category 3: Positive/likely
benign
• Category 4: Positive/suspicious
for malignancy
• Category 5: Known cancer
“S” Category
• Positive for extra-
pulmonary finding not
suspicious for lung
cancer but requiring
clinical follow-up
– Thyroid mass
– Aneurysm
– Kidney Mass
5/12/2015

43. Additional CMS Requirements for Lung Cancer Screening
5/12/2015 43
• Reading radiologist eligibility criteria:
• Board certification or board eligibility with the American Board of
Radiology or equivalent organization
• Documented training in diagnostic radiology and radiation safety
• Involvement in the supervision and interpretation of at least 300
chest computed tomography acquisitions in the past 3 years
• Documented participation in continuing medical education in
accordance with current American College of Radiology standards
• Furnish lung cancer screening with LDCT in a radiology imaging
facility that meets the radiology imaging facility eligibility criteria
below.

44. On the Horizon
2.Pinsky PF, Gierada DS, Black W,
et al. Performance of Lung-RADS in
the National Lung Screening Trial A
retrospective assessment. Ann
Intern Med Published on-line 10
Feb 2015
1. Brady J. McKee, Shawn M. Regis, Andrea B. McKee, Sebastian Flacke,
Christoph Wald, Performance of ACR Lung-RADS in a Clinical CT Lung Screening
Program, Journal of the American College of Radiology, Volume 12, Issue 3,
March 2015, Pages 273-276, ISSN 1546-1440,
http://dx.doi.org/10.1016/j.jacr.2014.08.004.
(http://www.sciencedirect.com/science/article/pii/S1546144014004736)
44
• Change in Criteria for Positive Findings predicted to reduce
false positives to approximately 10%
• Lahey retrospective analysis of 2180 LDCT scans using “ACR
LungRADS” showed 2.5X increase in PPV with no change in sensitivity
(single screening site - re-analysis done by same team as original
analysis) (1)
• Retrospective analysis of NLST data showed reduction of false
positives with ACR LungRADS from 26.6% to 12.8%, however
sensitivity decreased from 93.5% to 84.9% (33 screening sites, no
standard protocol- re-analysis by NLST team not site radiologists) (2)
• Studies on effective smoking interventions for lung cancer
screening population
• Georgetown/Lahey/Hartford Hospital et al. PCORI proposal RCT
telephone counseling
• Studies to date show 2 to 3X population smoking cessation rates in
lung cancer screening programs

45. Challenges
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• Participation – getting the word out to physicians and the
population at risk
• Multidisciplinary follow-up positive findings including
incidental findings
• Separate Shared Decision Making (SDM) Visit
• Effective Aids to help Physicians with Discussion and
Counseling Session
• Access for all to Physicians for SDM visit
• Radiololgist Training
• MeVis Education Tool has 125 scan module with test
• Site Suitability
• ACR Accreditation program
• Lung Cancer Alliance (LCA) Centers of Excellence
• Screening high risk folks not meeting screening criteria

46. Recent Study Shows Only 1/3 of 1855 Operable
Lung Cancer Patients Met Screening Criteria
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AATS Abstract presented 4/29/2015 Proportionof Newly Diagnosed Non-Small Cell Lung Cancer Patients That Would Have Been Eligible for Lung
Cancer Screening
Geena Wu1, Leanne Goldstein2, Jae Y. Kim1, Dan J. Raz1 1City of Hope National Medical Center, Duarte, CA;2City of Hope National Medical
Center, Duarte, CA

47. • More than 10 million Americans in the recommended population
to screen
• Estimated to save more than 20,000 lives a year
• Additional benefit for smoking cessation
– Published smoking cessation rates in lung cancer screening trials and
studies show 2 to 3 times the cessation rate as compared to the general
population (11 to 22% vs 5 to 7%)
"This has the biggest impact on lung cancer that we have ever seen
in our lifetime," he said. "This will do more to save lives than
anything else we have done to date in lung cancer, from a clinical
perspective.”
Reginald Munden, MD
MD Anderson Cancer Center in Houston
Principal site investigator in the NLST
5/12/2015 Low Dose Lung Cancer Screening 47

48. Lung Cancer Incidence/Mortality: US
Kills 450 People
Every Day

49. Summary
• Lung Cancer is a Non-Infectious Chronic Disease
– More than 80% of cases caused by tobacco use
– 90% of regular tobacco use starts by age 18
– Smoking harder to quit than heroin
– Cigarettes more addictive now than in 1960’s
• Lung cancer is the most common cancer worldwide and the leading cause
of cancer deaths in men and women in the US
– Mortality rate high due late stage at diagnosis
• USPSTF and CMS now recommend LDCT screening annually for the high
risk population
– 10 million Americans eligible
– Estimate more than 20,000 lives saved per year
– Need to raise awareness with primary care physician community and the
population at risk
• Tobacco control efforts, although resulting in some success, have failed
to eliminate smoking
– E-cigarettes threaten to erode smoking incidence reduction achieved to date
• Increased research funding needed for improved screening and
treatment modalities
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