Download Screening Lung CT, Update

LUNG CANCER
SCREENING UPDATE
Vandana Seeram
Assistant Professor
Division Pulmonary, Critical Care and Sleep Medicine
UF College of Medicine - Jacksonville
Lung cancer is the leading cause of
cancer-related death among globally
Cancer Statistics 2017
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
Lung Cancer Survival Based on Stage
Clinical
Pathologic
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
Potential Harms of Screening
■ Consequences of evaluating abnormal findings
■ Radiation exposure
■ Patient distress
■ Overdiagnosis
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
National Lung Cancer Screening Trial
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)
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
94.5% in the radiography group were false positive results
Results
■ The incidence of lung cancer was 645 cases per 100,000 person-years (1060
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
20.0% (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).
Cumulative Numbers of Lung Cancers
and of Deaths from Lung Cancer
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 communitybased radiology
■ CT scans were compared to CXR which was shown to be an ineffective screening
tool
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
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
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.
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
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 %)
Abnormal Result
■ NLST identified a noncalcified nodule >4 mm as an abnormality with a high falsepositive 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
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.
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
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
– www.brocku.ca/cancerpredictionresearch
Relationship between Nodule Size and
Probability That a Nodule Is Lung Cancer
McWilliams A et al. N Engl J Med 2013;369:910-919
Distribution of Nodule Variables, According to LungCancer Status, in the Development and Validation
Study Data Sets.
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
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
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.
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
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
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 lowrisk 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
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
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
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 leadtime 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
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
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 599
days as slow growing, and >600 days as indolent
Lead Time Bias