Presented by Professor Robert Smith from the American Cancer Society.

1. Screening in ARD
Robert A Smith, PhD
American Cancer Society
Atlanta, GA
International Conference on
Monitoring and
Surveillance of Asbestos-
Related Diseases 2014
11-13 February 2014, Hanasaari
Cultural Center, Espoo, Finland

2. History of Guidelines for Lung
Cancer Screening
• Before 1980, the American Cancer Society
(ACS) recommended annual chest x-ray and
sputum cytology for asymptomatic persons at
high risk for lung cancer.
• In 1980, the ACS concluded “lung cancer
screening….has not been demonstrated to be a
benefit in reducing mortality”

3. The Existing Evidence was Limited
• A review of early lung screening trial
methodology revealed numerous shortcomings,
including:
– High rates of control group contamination
– Low statistical power
– Duration of screening and follow-up was too short
– Possible ascertainment problems…underdiagnosis in
the control group
– But,……there still was not compelling evidence of
reduced mortality associated with screening

4. International Conference on the Prevention and Early
Diagnosis of Lung Cancer, Varese, Italy, 1998
• An important aspect of the
Conference was a review of
new technology that holds the
promise of substantial
mortality reduction from lung
cancer.
• Rigorous and rapid evaluation
of these new technologies is
essential in order to ensure
confidence in their efficacy, and
timely application of their
findings.
• It is especially important that
investigation of new early
detection technologies receive
high scientific and public
health priority.

5. Lung Cancer Screening with Low
Dose Spiral CT, Lancet 1999
• In the New York
ELCAP, low-dose CT was
associated with a 5-fold
difference compared
with chest X-ray in the
detection of early
stage, resectable lung
cancers.
Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project:
overall design and findings from baseline screening Lancet. 1999;354:99-105.

7. American Cancer Society Guidance on Lung
Cancer Screening, 2001
• ACS does not recommend lung
cancer screening
• ACS discourages testing in a
setting that is not linked to
multidisciplinary specialty groups
for diagnosis and follow-up.
• Individuals who choose to
undergo testing should have
access to testing and follow-up
that meet state-of-the-art
standards, with informed
decision-making at every step of
an ongoing process.

8. United States Preventive Services Task Force
Statement on Lung Cancer Screening, 2004
• The USPSTF found fair evidence that
screening with LDCT, chest radiographs, or
sputum cytology can detect lung cancer at
an earlier stage than lung cancer would be
detected in an unscreened population;
however, the USPSTF found poor evidence
that any screening strategy for lung cancer
decreases mortality.
• Because of the invasive nature of
diagnostic testing and the possibility of a
high number of false-positive tests in
certain populations, there is potential for
significant harms from screening.
• Therefore, the USPSTF could not
determine the balance between the
benefits and harms of screening for lung
cancer (I Rating).
Ann Intern Med 2004;140:738-9.

9. October 28, 2010
NCI Announces Low Dose CT Screening was
Associated with Reduced Lung Cancer Deaths

10. There were 20% fewer lung cancer deaths in
the LDCT arm compared with the CXR arm.
There were 6.7% fewer deaths from all causes
in the LDCT arm compared with the CXR arm.

11. Predicted cumulative lung cancer mortality per thousand randomized in
hypothetical study and control groups, with relative risks, by years of
follow-up
Year Cumulative mortality per 1,000
in
RR
Study group Control group
1 0.8 0.8 1.00
2 2.5 2.6 0.95
3 4.4 5.2 0.85
4 6.6 8.3 0.79
5 9.1 11.7 0.77
6 11.9 15.3 0.78
7 15.1 19.1 0.79
8 18.5 22.9 0.81
9 22.1 26.8 0.83
10 25.9 30.7 0.84
After year 5 the
effect of screening
is diluted by
deaths from cases
that arise after
screening has
stopped

12. PLCO Trial of Lung Cancer Screening
with Chest Radiograph
• Randomized controlled
trial, with enrollment from
11/1993 through 7/2001
• 154,901 participants aged 55
through 74 years
• 77,445 invited to 4 rounds of
annual screening
• 77,456 assigned to usual care
• All diagnosed
cancers, deaths, and causes of
death were ascertained through
the earlier of 13 years of follow-
up or until December 31, 2009.
JAMA. 2011;306(17):1865-1873

13. Lung Cancer Mortality in the PLCO by Year
Overall, there was no benefit associated with 4 rounds of CXR in the PLCO.
However, if the comparison is limited to 6 years from randomization, there were 11%
fewer lung cancer deaths in the CXR arm compared with the control group.
JAMA, November 2, 2011—Vol 306, No. 17

14. Management of Positive Findings in Lung Cancer
Screening: Emerging Protocols
• Screening for lung
cancer with LDCT is
challenging due to the
high prevalence of
noncalcified pulmonary
nodules detected in
asymptomatic subjects
who have an increased
risk for lung cancer

15. One of the most significant challenges in the
implementation of lung cancer screening will be the
management of positive findings
Approximately 40% of adults experienced a false positive
finding during 3 rounds of LDCT screening.

16. Nodule Size vs. Volume
• Historically, workup and surveillance has been based
on nodule size and growth.
– Fleishner Society
– IELCAP
– NLST
– Nagano, Japan
– Italian RCTs
– Mayo
– Etc
• Newer nodule management protocols are based on
tumor volume and volume doubling time

17. Management of Lung Nodules Detected
by Volume CT Scanning in the NELSON trial
• The NELSON strategy
for workup entails the
use of the volume and
volume-doubling time
of a noncalcified
nodule as the main
criteria for deciding on
further action.
NEJM 2009:361;23

18. NELSON Volume and Volume Doubling Time
Nodule Management Protocol
NEJM 2009:361;23
Supplementary Appendix

19. Using Lung Lesion Size Alone as the
Definition of a Positive Result
• Objective: Assess alternative
thresholds for the definition
of a positive test.
• Measure the frequency of
solid and part-solid pulmonary
nodules and the rate of lung
cancer diagnosis by using
current (5 mm) and more
restrictive (7 – 8 mm)
thresholds of nodule diameter
Ann Intern Med. 2013;158:246-252.

20. In the ELCAP Study, there were 21,136
participants, 12, 078 with a nodule ≥ 1 cm, and
3,396 with a nodule ≥ 5 cm

21. Frequency of Positive Test Results (%) and Lung
Cancer
16%
10%
7%
5%
4%

22. American Cancer Society & U.S. Preventive
Services Task Force Guidelines for LDCT Lung
Cancer Screening, 2013

23. Comparing ACS & USPSTF Lung Cancer
Screening Recommendations
Recommendation ACS USPSTF
Target Population--Age 55-74 55-80
Target Population—Smoking History ≥ 30 pack years ≥ 30 pack years
Time Since Cessation ≤ 15 years ≤ 15 years
General Health Status Good  
Cessation of Screening Poor health;
Age > 75
Poor health;
Age > 81;
> 15 years since
cessation
Shared Decision Making  
Smoking Cessation  

25. Note that the NCCN Guidelines define 2 high risk groups based on
(1) smoking History, and (2) smoking history & 1 additional risk factor

26. Agents that are identified specifically as carcinogens targeting the lungs:
silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, and nickel.

28. Current Lung Cancer Screening Guidelines
2013
United States
Preventive Services
Task Force (USPSTF
2013 Screen Ages 55-80, ≥ 30 pack years; smoking cessation within previous 15 years, stop screening
when time since cessation > 15 years, make shared decision with physician

29. Lung Cancer Risk in Former Smokers
• Smoking cessation is
beneficial at any age
• Greatest benefit accrues
when cessation occurs at a
young age
• Age at cessation has a
major impact on
subsequent lung cancer
risk

30. Lung cancer deaths by age for never, former
and current smokers (Halpern, et al. JNCI 1993;85(6)
Current Smokers
Never Smokers
Quit age 60-64
Quit age 55-59
Quitting after age 50 reduces the risk of lung cancer death compared with current
smokers, but following a plateau after cessation, risk of lung cancer death rises
significantly

31. This slide is from an imaging center
in Atlanta, using GROUPON to
promote its services
Posted on May 29, 2013

33. Lung Cancer Screening Guidelines are
Likely to Evolve over Time
• Other RCT publications
• Demonstration projects results
• Observational studies will provide data on
service screening outcomes
• Applied research will identify strategies to
improve sensitivity and specificity
• New technology will offer new strategies
• The result…broader spectrum of tailored
protocols based on risk

34. European Trials of Lung Cancer Screening

35. European Randomized Controlled Trials
• 6 Ongoing trials which have enrolled
32,000 people
• ~ 150,000 person-years of FU
• UKLS trial has started (4,000)
• NELSON final results (mortality data) 2015

36. Differences between NLST and European
RCT’s
• NLST : Chest x-ray in control arm
• EUCT: no screening in control arm
• NLST: 1-yr screen interval, 3 rounds
• EUCT: different intervals and number of rounds
• NLST: 2D evaluation
• EUCT: 2D and 3D evaluation

37. • Screening of asbestos-
exposed populations can be
carried out for practical and
scientific purposes. There
are 4 goals of screening: (i)
to identify high risk
groups, (ii) to target
preventive actions, (iii) to
discover occupational
diseases, and (iv) to develop
improved tools for
treatment, rehabilitation
and prevention

38. For many years, we have fought a losing battle
in our efforts to detect lung cancer early
• Helsinki Criteria (1997)
• For lung
diseases, including lung
cancer, “Chest X-ray
examinations can include
frontal and lateral
roentgenograms”
• There was no direct
recommendation for lung
cancer screening
• “Further studies on the
effectiveness of screening
programs are needed.”

39. • Emphasized the limitations of
chest x-ray surveillance for lung
cancer, other than
“Occasionally, a few early-stage
lung cancers are also found.”
• The value of spiral CT is
sufficiently compelling that
clinicians and others should
consider its use for case
evaluation and the clinical
management of those at high
risk of lung cancer.
2000

40. Why consider screening asbestos-exposed
workers with LDCT?
• Screening for occupational disease is mandatory and regulated
by authorities
– X-ray screening for lung cancer is not effective are wastes
resources
– The value of CT screening has now been established
– The asbestos-exposed cohort is aging—window of
opportunity to reduce premature deaths
– Asbestos-induced lung cancer shows its peak incidence
now
– lung cancer screening may also detect beneficial
information regarding COPD and atherosclerosis (and
probably reduce all-cause mortality)

41. Screening for Asbestos Related Lung Cancer
• Area 1: We posed the question: “Is there sufficient
evidence from studies of former and current smokers
that lung cancer screening of asbestos exposed
workers with LDCT can be recommended?
• If so, the fundamental question relates to the risk
threshold for inclusion, caused either by asbestos
exposure alone or by the combination of asbestos
exposure and smoking.

42. Area 1: Screening for Asbestos Related Lung
Cancer--Methodology
• Three SRs of LDCT screening for lung cancer were identified
– Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT
screening for lung cancer: a systematic review. JAMA 2012;307:2418-
29
– Manser R, Lethaby A, Irving LB, Stone C, Byrnes G, Abramson
MJ, Campbell D. Screening for lung cancer (Review). The Cochrane
Library, Issue 6, 2013.
– Humphrey LL, Deffebach M, Pappas M, et al. Screening for lung cancer
with low-dose computed tomography: a systematic review to update the
US Preventive services task force recommendation. Annals of internal
medicine 2013;159:411-20.

43. Comparison
Area 1: Systematic Reviews of Lung Cancer Screening with LDCT
ASCO, Etc. ( 2012) Cochrane (2013) USPSTF (2013)
Main
Conclusions
LDCT screening
may benefit
individuals at an
increased risk for
lung cancer, but
uncertainty exists
about the potential
harms of screening
and the
generalizability of
results.
Annual LDCT is associated
with a reduction in lung
cancer death in high risk
smokers and former smokers.
Further data are required on
the cost effectiveness of
screening, and the relative
harms and benefits of
screening across a range of
different risk groups and
settings. Evidence does not
support lung cancer screening
with CXR or sputum
cytology.
Good evidence shows
LDCT can
significantly reduce
mortality from lung
cancer. However,
there are significant
harms associated with
screening that must be
balanced with the
benefits.
AREA 1: Review of Recent Systematic Reviews of Lung
Cancer Screening

44. Area 1: Screening for Asbestos Related Lung
Cancer--Methodology
• Second systematic review: Identify
literature on CT screening for lung
cancer among asbestos-exposed workers.
158 papers were identified, and 12 met
inclusion criteria (non-review, non cases
series).

45. Studies of Lung Cancer Screening in
Asbestos Exposed Workers
• The published articles of asbestos-exposed persons typically:
– Are case series
– Have limited number of subjects
– Have no control groups
– Have little follow-up data on mortality
• They provide only inferential evidence about the
efficacy of lung cancer screening in adults with a
history of asbestos exposure.
• Therefore, the assessment of how asbestos exposed
workers should be followed up must mainly be based
on risk assessment and the outcome of the RCTs of
LDCT screening for lung cancer.

46. Characteristics of Studies of Lung Cancer
Screening in Asbestos Exposed Workers
Characteristic Findings
Year of Publication 1998 - 2012
Age Range/Median 32 – 86, Mean 57 -66
Asbestos Exposure Highly variable indicators, e.g. “in contact at work”
High (current) > 1 yr. vs. High (not current) ≥ 10 yrs
Single occupation group, exposure by years at work
“Definite”
10 years / > 20 yrs
> 20 yrs, or pleural plaques
Asbestosis, or pleural plaques and > 10 pack years
Smoking Highly variable indicators, ie, pack years, years smoking, median
years smoking, etc.
Highly variable smoking exposure (including no smoking)—years
smoked, median years smoked, mean/median pack years
Variable proportions of current and former smokers, and total
exposures
Combinations: > 10 + asbestos, > 10 if no asbestos, etc.

47. Characteristics of Studies of Lung Cancer Screening in
Asbestos Exposed Workers (continued)
Characteristic Findings
CT Methodology Variable slice thickness (5mm, 10 mm); mA (10 – 125); or no
discussion
Criteria for Positive
Finding
Variable: Any suspicious lesion; ELCAP protocol;
1-6 > 2mm; lesion ≥ 2mm, 5mm, 6mm, 20 mm; variable size if
solid vs. non-solid
Screening Protocol Highly variable: Baseline only (9 studies); 2 rounds/biennial (1
study); baseline—annual repeat screening (1 study); 1-3
rounds/annual (1 study)
Control group No (10 studies); Patient are their own controls CT vs. Chest (2
studies)

48. Select Findings from the Systematic Review of
LDCT Screening for ARD
Study # Screened 1st Screen
Suspicious Finding
Number of Lung
Cancers (%)
Callol, 2007 466 21% 1 (0.2%) 1st Rnd
5 (1%) 2nd Rnd
Clin, 2009 719 23% 18 (2.2%)
Clin, 2011 5,662 17% 50 (0.9%)
Das, 2007 187 87% 9 (4.8%)
Fasola, 2007 1,045 44% 9 (0.9%)
Greenberg, 2012 1,182 52% 30 (2.5%)
Loewen,2007 169 57% 13 (7%)
Lynch, 1988 260 6% 2 (0.8%)
Mastrangalo, 2008 1,119 21% 5 (0.4%)
Roberts, 2009 516 17.6% 4 (0.8%)
Tiitola, 2002 602 18.5% 5 (0.8%)
Vierikko, 2007 633 13.6% 5 (0.8%)

49. • Cohort studies involving chest CT screening for lung cancer in
former asbestos exposed workers.
• Inclusion criteria: asbestos exposure, cohort studies (minimal
number of 10 individuals), non case-study design
• Primary outcome: Number of lung cancer cases at prevalent
screening
• 7 studies met inclusion criteria

50. Select Findings from the Systematic Review of LDCT
Screening for ARD—Common studies identified by
Area 1 workgroup and Olliel, et al. (2014)
Study #
Screened
1st Screen
Suspicious
Finding
Number of
Lung Cancers
(%)
Clin, 2009 719 23% 18 (2.2%)
Das, 2007 187 87% 9 (4.8%)
Fasola, 2007 1,045 44% 9 (0.9%)
Mastrangalo,
2008
1,119 21% 5 (0.4%)
Roberts, 2009 516 17.6% 4 (0.8%)
Tiitola, 2002 602 18.5% 5 (0.8%)
Vierikko, 2007 633 13.6% 5 (0.8%)

51. Lung cancer prevalence and confidence
intervals of seven studies.
--Baseline screening detected 49 asymptomatic lung cancers among 5074
asbestos-exposed workers.
--The prevalence of all lung cancers detected by CT screening in asbestos-
exposed workers was 1.1% (CI 95%: 0.6%-1.8%).
--18 were stage 1, accessible to complete removal surgery.

52. Conclusion
• There already is considerable, and growing
evidence supporting the benefits of LDCT in
detection early lung cancer in high risk (current
and former smokers
• There is considerably less information about the
benefits of LDCT screening in select groups at
equivalent risk
• The challenge--Identification of high risk asbestos
exposed workers who do not meet the minimum
absolute risk for the NLST based on smoking
history alone (1.34% over 6 years)

53. International Conference on Monitoring and
Surveillance of Asbestos-Related Diseases 2014
11-13 February 2014, Hanasaari Cultural Center, Espoo, Finland
Recommendation from Workgroup 1
Based on the lung cancer LDCT screening studies, the dose-
response risk of lung cancer in asbestos-exposed
workers, and the established relationship on interaction of
asbestos exposure and smoking, we recommend the
following groups for LDCT screening
1) Workers with any asbestos exposure and a smoking history equal to
the entry criteria of the NLST study
2) Workers with asbestos exposure with or without a smoking history
which alone or together would yield an estimated lung cancer risk level
equal to the entry criteria of the NLST study

54. Area 1: Recommendation (continued)
• First, existing databases should be assessed for the potential to verify the
generalizability of the Lung Cancer Screening RCT results to asbestos exposed
adults.
• Second, since our recommendations are based on inferential evidence and
modeling, the introduction of lung screening in asbestos exposed workers
must be viewed as a research program in order to verify these assumptions.
We strongly recommend an international multicenter research project on
the effect of LDCT screening among asbestos exposed workers to acquire the
necessary evidence.

55. Conclusion
• It is important to heed the lessons learned from
the implementation of screening for breast,
cervix, colorectal and prostate cancers.
• The combination of insistence on best practices,
on-going program evaluation, and attempts to
maximize benefits and minimize harms is critical
to success.
• There can be no shortcuts.

56. Acknowledgements
Tapio Vehmas
Anthony B Miller
Kurt Straif
Nea Malila
Riitta Sauni
Chris Berg (NLST)

57. Thank you