1. Lung Cancer Screening Update
Vandana Seeram
Assistant Professor
Division Pulmonary, Critical Care and Sleep Medicine
UF College of Medicine - Jacksonville

2. Lung cancer is the leading cause of cancer-related death among globally

3. Cancer Statistics 2017

4. Prevention
Prevention, rather than screening, is the most effective strategy for reducing the burden of lung cancer in the long term
Most lung cancer is attributed to smoking, including lung cancer in nonsmokers in whom a significant proportion of cancer is attributed to environmental smoke exposure
thought to be causal in 85 to 90 percent of all lung cancer
The smoking rate in the United States remains high, at 15 percent in 2015
A high percentage of lung cancer occurs in former smokers since the risk for lung cancer does not decline for many years following smoking cessation

5. Lung Cancer Survival Based on Stage
Clinical
Pathologic

6. Potential Benefits of Screening
Detect early cancers
Increase the overall cure rate
Allow more limited surgical resection to achieve cure
Screening may not accomplish these goals unless it takes place in the context of a multidisciplinary program to ensure that screening is properly performed and results properly interpreted, and followed up, and that disease, when detected, is managed appropriately

7. Potential Harms of Screening
Consequences of evaluating abnormal findings
Radiation exposure
Patient distress
Overdiagnosis

8. Consequences of evaluating abnormal findings
Detection of abnormalities that require further evaluation, most of which are benign nodules
Evaluation may involve needle biopsy and/or surgery, with associated morbidity and mortality
Most positive studies are resolved with imaging and prove to be false-positive exams

9. National Lung Cancer Screening Trial

10. Methods August 2002 through April 2004
53,454 persons at high risk for lung cancer at 33 U.S. medical centers
Randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732)

11. Results Rate of adherence to screening was more than 90%
Participants were men and women 55 to 74 years of age with a history of at least 30 pack-years of smoking, and included current smokers and those who had discontinued smoking within 15 years of enrollment
The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds
A total of 96.4% of the positive screening results in the low-dose CT group and % in the radiography group were false positive results

12. Results
The incidence of lung cancer was 645 cases per 100,000 person-years ( cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group
There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group,
Relative reduction in mortality from lung cancer with low-dose CT screening of % (95% CI, 6.8 to 26.7; P = 0.004)
The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = 0.02).

13. Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer

14. Caveats
Trial participants had a higher education level and were younger than tobacco users identified in United States census data
A low complication rate of follow-up procedures may reflect the expertise at the participating academic centers
Radiologic performance and interpretation may not be representative of community- based radiology
CT scans were compared to CXR which was shown to be an ineffective screening tool

15. PLCO trial
Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial compared screening with no screening
Data published 2015
large randomized trial (n = 154,942) evaluating the impact of screening individuals aged 55 through 74 for several cancers
Results of the PLCO trial were analyzed for the subset of patients who would meet criteria for participation in the NLST
There was no significant difference in mortality at six-year follow-up for the PLCO trial high-risk subset that was assigned to chest radiograph screening or usual care

16. Other Trials
Seven randomized trials of LDCT screening remain in progress in Europe
The trials differ in recruitment strategies and number of screening rounds, though all include only past or current heavy smokers, and all control groups had no screening (in contrast to the NLST where the control arm had chest radiograph screening)
The only individual trial of large enough size to possibly show a mortality reduction is the NELSON trial (conducted in the Netherlands and Belgium with comparison of length of screening, 1 vs 1.5 vs 2 years)
However, there is a plan to analyze pooled data from the seven trials

17. CXR vs LDCT
Chest radiograph screening does not reduce mortality from lung cancer, although there is limited data in women.
LDCT screening is significantly more sensitive than chest radiograph for identifying small, asymptomatic lung cancers.
Chest radiograph and LDCT screening have high rates of "false-positive" (noncancer) findings leading to additional testing that usually includes serial imaging but may include invasive procedures
The most common incidental findings are emphysema and coronary artery calcifications.

18. Current Limitations
Questions remain regarding the optimal screening frequency and duration, appropriate population targets
Defining criteria for a "positive" finding, and identifying diagnostic follow-up protocols that minimize evaluations of false-positive findings

19. Age
25% of participants in the NLST were ≥65 years and none older than 75
A secondary analysis of the NLST results found that compared with patients <65 years, those ≥65 years were more likely to have false-positive screens
Higher prevalence and positive predictive value for cancer (4.9 versus 3.0 %)

20. Abnormal Result
NLST identified a noncalcified nodule >4 mm as an abnormality with a high false- positive rate of screening
Studies have suggested that the false-positive rate could be decreased with different radiologic criteria, but it is not clear how to define the optimal parameters for screening.
A retrospective interpretation of data from the International Early Lung Cancer Action Program (I-ELCAP) study cohort and NLST suggested that setting a more conservative threshold (eg, >6 mm) would decrease the false-positive rate (resulting in fewer unnecessary procedures or follow-up studies) with minimal impact on the detection of cancers

21. Abnormal Result
Another retrospective study applied the Lung Imaging Reporting and Data System (Lung-RADS) criteria from the American College of Radiology to the NLST data found a decrease in the false-positive rate but also a concomitant decrease in the sensitivity of screening if 6mm was used
Compared with the NLST, the Lung-RADS criteria have a more conservative threshold for a positive baseline screen (>6 mm) and require growth for pre-existing nodules.

22. Abnormal Result
It is possible that a range of nodule sizes should be considered "abnormal," determined by an individual's specific risks for cancer
A predictive tool has been developed and validated to estimate the probability that a nodule is malignant based on characteristics of the patient and the nodule in the Pan-Canadian screening study

23. Pan Canadian Study
In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant
Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively
Predictors of cancer in the model included
older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and speculation

24. Relationship between Nodule Size and Probability That a Nodule Is Lung Cancer
McWilliams A et al. N Engl J Med 2013;369:

25. Distribution of Nodule Variables, According to Lung-Cancer Status, in the Development and Validation Study Data Sets.

26. Cost Effectiveness
Based on the NLST trial, the cost of screening per life saved is unknown but likely to be high, given the high (approximately 95 percent) false-positive rate leading to the need for additional studies, the need for ongoing screening, and the relatively low absolute number of deaths prevented (73 per 100,000 person years)
Modeling studies will be needed to determine actual cost-effectiveness
One analysis, based upon a model designed prior to completion of the NLST, suggested that LDCT screening might decrease lung cancer mortality at 10 years by 18 to 25 percent, at a cost ranging from $126,000 to $269,000 per quality-adjusted life year (QALY)
Additionally, the model found that a smoking cessation program was more cost-effective than LDCT screening alone or LDCT screening combined with smoking cessation
Another model, done after the completion of the NLST, estimated LDCT screening would cost $81,000 per QALY
The model noted that estimates varied widely depending on subgroups, with LDCT screening being more cost-effective in women and in groups with a higher risk of lung cancer

27. Counseling for screening
Screening should only be performed when the clinician and patient are committed to pursuing follow-up investigations, including serial imaging and possible surgical lung biopsy, and where there is expertise in chest radiography and lung cancer management
Providers need to be experienced in the principles of screening and the management of small lung nodules

29. Opt to be screened after appropriate counseling
Are in general good health.
Are at increased risk for lung cancer (similar to the risk of the group participating in the NLST trial)
High-risk criteria for participation in the NLST were age 55 to 74 years, a history of smoking at least 30 pack-years and, if former smoker, had quit within the previous 15 years.
Have access to centers whose radiologic, pathologic, surgical, and other treatment capabilities in the management of indeterminate lung lesions are equivalent to those in the NLST trial.
Understand the possible need for subsequent evaluation of abnormal findings.

30. Other Considerations Are able to manage the cost of annual screening
The role of insurance coverage in screening has not been determined following the NLST results, and insurance may not cover the cost of screening
As of February 2015, Medicare will cover low-dose helical CT scanning for asymptomatic patients age 55 to 77 years with a history of smoking at least 30 pack-years and, if a former smoker, quit within the previous 15 years
Orders for screening must also fulfill specific counseling criteria as outlined by the Centers for Medicare and Medicaid Services
For former smokers, annual screening should continue until 15 years has elapsed from the date of smoking cessation

31. Recommendations by expert groups
AATS – The American Association for Thoracic Surgery
Guidelines in 2012 that recommend LDCT screening for high-risk individuals who meet the NLST criteria
ACP/ASCO/ACS –American College of Chest Physicians (ACP), the American Society of Clinical Oncology (ASCO) and the American Cancer Society (ACS) in 2013
Guidelines incorporating high-risk criteria from the NLST
Canadian Task Force on Preventive Health Care
Screening asymptomatic adults age 55 to 74 years with at least a 30 pack-year smoking history who smoke or quit smoking <15 years ago with LDCT every year for three consecutive years

32. Recommendations by expert groups
NCCN – The National Comprehensive Cancer Network guidelines
Recommend discussion of screening with annual LDCT scan screening for those at high risk; they recommend no routine screening for moderate- or low- risk individuals
High risk was defined as age 55 to 74 years with a ≥30 pack-year history of smoking and, if no longer smoking, smoking cessation within 15 years, or age ≥50 years with a 20 pack-year history of smoking with one additional risk factor (other than secondhand smoke exposure).
Emphasize that lung cancer screening should be done within the context of a multidisciplinary program (that may include radiology, pulmonary medicine, internal medicine, thoracic oncology, and/or thoracic surgery) to manage downstream testing

33. Recommendations by expert groups
USPSTF
A 2013 systematic review for the US Preventive Services Task Force (USPSTF) serves as the basis for revised guidelines for the USPSTF
The USPSTF recommends annual LDCT scan for high-risk adults 55 to 80 years old (30 pack-year smoking history and current smoker or quit within the past 15 years), with discontinuation of screening once the individual has not smoked for 15 years or has a limited life expectancy

35. Future Directions Positron emission tomography
Annual low-dose computed tomography (CT) followed by positron emission tomography (PET) with fluorodeoxyglucose (FDG) for evaluating patients with noncalcified lesions ≥7 mm in diameter
Sensitivity, specificity, positive predictive value, and negative predictive value of FDG-PET for the diagnosis of malignancy were 69, 91, 90, and 71 percent, respectively
When a negative FDG-PET was followed three months later with a repeat CT, the negative predictive value was 100 percent

36. Future Directions Nonradiographic technologies
Including identification of molecular and protein-based tumor biomarkers, may also contribute to the early detection of lung cancer
Detection and treatment of small lung tumors (prior to radiographic visualization) may produce superior outcomes, though the possibility of lead- time and other types of bias influencing the assessment of these technologies is great
Potential biosamples for biomarker analysis include airway epithelium (including buccal mucosa), sputum, exhaled breath, and blood

37. Futrure Directions Technologies under investigation include:
Immunostaining or molecular analysis of sputum for tumor markers. As examples, p16 ink4a promoter hypermethylation and p53 mutations have been shown to occur in chronic smokers before there is clinical evidence of neoplasia
Automated image cytometry of sputum
Fluorescence bronchoscopy
Exhaled breath analysis of volatile organic compounds, which appear to be more common in patients with lung cancer
Genomic and proteomic analysis of bronchoscopic samples
Serum protein microarrays for detecting molecular markers

38. Future Directions Assessing tumor growth patterns
COSMOS study investigated whether estimation of the volume doubling time (VDT) or growth rate of tumors detected by low-dose CT scans could be used to determine which tumors may represent indolent cancers and thus potential overdiagnosis
VDT was estimated on the basis of change in tumor size with serial scans; a tumor with a VDT <400 days was considered to be fast growing, 400 to days as slow growing, and >600 days as indolent

39. Lead Time Bias