Screening in ARDRobert A Smith, PhD

American Cancer SocietyAtlanta, GA

International Conference on Monitoring and Surveillance of Asbestos-Related Diseases

2014

11-13 February 2014, Hanasaari Cultural Center, Espoo, Finland

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”

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

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.

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.

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.

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.

October 28, 2010NCI Announces Low Dose CT Screening was

Associated with Reduced Lung Cancer Deaths

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.

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 group1 0.8 0.8 1.002 2.5 2.6 0.953 4.4 5.2 0.854 6.6 8.3 0.795 9.1 11.7 0.776 11.9 15.3 0.787 15.1 19.1 0.798 18.5 22.9 0.819 22.1 26.8 0.8310 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

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

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

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

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.

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

Management of Lung Nodules Detectedby 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

NELSON Volume and Volume Doubling Time Nodule Management Protocol

NEJM 2009:361;23 Supplementary Appendix

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.

In the ELCAP Study, there were 21,136 participants, 12, 078 with a nodule ≥ 1 cm, and

3,396 with a nodule ≥ 5 cm

Frequency of Positive Test Results (%) and Lung Cancer

16%

10%

7%5%

4%

American Cancer Society & U.S. Preventive Services Task Force Guidelines for LDCT Lung

Cancer Screening, 2013

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

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

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

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

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

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

This slide is from an imaging center in Atlanta, using GROUPON to promote its services

Posted on May 29, 2013

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

European Trials of Lung Cancer Screening

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

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

• 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

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.”

• 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

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)

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.

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.

 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 LungCancer Screening

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).

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.

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 yrsSingle occupation group, exposure by years at work“Definite”10 years / > 20 yrs> 20 yrs, or pleural plaquesAsbestosis, 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 yearsVariable proportions of current and former smokers, and total exposures Combinations: > 10 + asbestos, > 10 if no asbestos, etc.

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)

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 Rnd5 (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%)

• 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

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%)

Lung cancer prevalence and confidence intervals of seven studies.

--Baseline screening detected 49 asymptomatic lung cancers among 5074asbestos-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.

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)

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

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.

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.

Acknowledgements

Tapio Vehmas

Anthony B Miller

Kurt Straif

Nea Malila

Riitta Sauni

Chris Berg (NLST)

Thank you