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Lung Cancer Screening


Leading cause of cancer mortality ... The American Cancer Society estimates 169,500 new cases of lung cancer will be ... Non-small Cell Lung Cancer, By Stage ... – PowerPoint PPT presentation

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Title: Lung Cancer Screening

Lung Cancer Screening
  • Caryn Gee Morse, MD
  • March 20, 2001

Lung Cancer the problem
  • In the United States, the second most common
    cancer in men and women
  • Leading cause of cancer mortality
  • Accounts for more deaths from than cancer than
    breast, prostate and colorectal cancer combined

Common and Lethal
  • The American Cancer Society estimates 169,500 new
    cases of lung cancer will be diagnosed in 2001
  • Overall 5-year survival remains poor,
    approximately 15
  • ACS anticipates 157,400 deaths from lung cancer
    in 2001

Estimated U.S. Cancer Deaths10 Leading Sites, by
Gender 2001
Age-adjusted cancer death rates by siteUS males,
Age-adjusted cancer death rates by siteUS
females, 1930-1997
Prognosis of Non-small Cell Lung Cancer, By Stage
Table 4. Current guidelines for lung cancer
Adapted from Mandel, J, Weinberger, S.
Screening for lung cancer. UpToDate 2000 81-2.
Mandel, J, Weinberger, S. Screening for lung
cancer. UpToDate 2000 81-2.
Presentation overview
  • History of lung cancer screening
  • Trials of the 1950-60s
  • National Cancer Institute Cooperative Early Lung
    Cancer Project
  • Mayo Lung Project
  • Memorial Sloan-Kettering
  • Johns Hopkins
  • Czechoslovakian Trial
  • Lost interest

Presentation Overview Cont.
  • Renewed interest and new directions
  • Chest radiographs
  • Computed tomography
  • PET
  • Biomarkers
  • Fluorescence bronchoscopy
  • Conclusions and recommendations

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Screening Principles
  • Successful cancer screening program
  • needs to detect disease in the preclinical stage
  • when it is amenable to curative treatment
  • reduce mortality by preventing progression of

Lung cancer screening
  • A successful randomized trial of screening for
    lung cancer
  • Enhances detection of lung cancers, particularly
    asymptomatic, early stage cancers, in the study
    group when compared to a control group during the
    screening phase
  • As the trial progresses, the number of lung
    cancers in the two groups should equalize as
    asymptomatic, early stage cancers undetected in
    the control group grow, spread, and present as
    symptomatic, advanced stage cancers
  • If treatment is more effective for asymptomatic,
    early stage cancers compared with symptomatic,
    more advance lung cancers, fewer deaths would be
    expected in the screened group compared to
    non-screened controls
  • Model assumes that the bulk of early stage lung
    tumors progress to lethal disease without
    detection and early treatment and assumes that
    early detection reduces mortality

Screening mortality and survival
  • No randomized, controlled trial has demonstrated
    that lung cancer screening leads to a reduction
    in disease-specific mortality
  • Mortality vs. survival
  • Mortality(death rate) cancer deaths /
    patients screened, expressed as deaths per 1000
    persons screened per year
  • Survival patients alive following cancer
    diagnosis / cancers detected, expressed as a
    percentage over time

  • Mortality can be influenced by selection bias in
    nonrandomized trials, however, in a RCT, a
    statistically significant mortality reduction is
    considered proof of screening effectiveness or at
    least best evidence for efficacy

Screening bias
  • All other measures of outcome can be affected
    bias, including
  • Selection bias error in patient assignment
    between groups that permits a confounding
    variable to arise from study design rather than
    by chance alone usually eliminated by
  • Lead-time bias mistakenly attributing increased
    survival of patients to a screening intervention
    when longer survival is only a reflection of
    earlier detection in the preclinical phase of
  • Length-sampling bias Slow growing tumors are
    detectable longer than fast growing ones and will
    be preferentially identified by any early
    diagnosis strategy. Fast growing tumors, with
    shorter survival, will be left for routine
  • Over-diagnosis a portion of detected cancers may
    have remained indolent and undetected because of
    patient death from other causes

Early, early trials
  • In the 1950s and 1960s a number of uncontrolled
    and nonrandomized controlled studies were
    performed to evaluate combinations of chest x-ray
    and sputum cytology screening at various time
    intervals, ranging up to once every 6 months
  • Three nonrandomized, uncontrolled trials
  • Philadelphia Pulmonary Neoplasm Research Project
  • Veterans Administration Lung Cancer Screening
  • South London Lung Cancer Study
  • Two randomized controlled trials
  • North London Cancer Study
  • Kaiser Foundation Health Plan Study

Early, early trials cont.
  • All of these studies failed to demonstrate a
    statistically significant mortality benefit from
    lung cancer screening.
  • Small cohorts with limited follow-up periods,
    limiting demonstration of small-moderate
    improvements or longer-term benefits in mortality

NCI Cooperative Early Lung Cancer Group
  • In 1971, the National Cancer Institute (NCI)
    sponsored three large-scale, long-term,
    randomized controlled trials created to determine
  • whether a program of lung cancer screening
    might lead to earlier detection, that is, to
    finding a larger proportion of lung cancers at a
    localized, potentially curable stage, and whether
    with appropriate treatment this would result in a
    substantial reduction of lung cancer deaths in
    the screened group.

NCI Cooperative Early Lung Cancer Group, cont.
  • Specifically, the trials sought to establish if
    detection of early lung cancer could be improved
    by the addition of sputum cytology to routine
    chest x-ray and if lung cancer mortality could be
    reduced by this screening and appropriate
  • The trials, completed in 1984, were conducted at
    Mayo Clinic, Johns Hopkins Medical Center and the
    Memorial-Sloan Kettering Cancer Center and the
    participating institutions were designated the
    Cooperative Early Lung Cancer Group.

Mayo Lung Project
  • From late 1971 to mid-1976, enrolled
  • 10,933 male volunteers
  • Age 45 years or older
  • At least one pack per day cigarette use in the
    previous year
  • Referred for participation by their primary care
    physician during routine physical examination
  • All participants were offered an initial
    prevalence screen including chest x-ray and
    sputum cytology.

Mayo Lung Project Prevalence
Mayo Lung Project
  • 91 prevalent cancer patients removed from the
    initial volunteers
  • 978 patients ruled ineligible because of serious
    underlying medical problems and predicted life
    expectancy of less than 5 years
  • 653 volunteers refused participation
  • Remaining 9211 participants were randomized to
    two groups, screening and control
  • Screening group participants received chest x-ray
    and sputum cytology examination every 4 months
    for 6 years
  • Control group participants were advised to seek
    annual chest x-ray and sputum cytology, standard
    Mayo advice at the time and no reminders were
  • Study group was followed for a total of 9 years,
    6 years of screening and 3 years of follow-up

MLP Incidence and Mortality
MLP Staging and 5-year survival
MLP Late stage cancers, nonresectable cases and
number of deaths
MLP Extended follow-up
Memorial Sloan-Kettering
  • From 1974 to 1978, enrolled
  • 10,040 male volunteers
  • Age 45 years or older
  • At least 1 pack per day cigarette use currently
    or in the preceding year
  • On initial intake all participants received PA
    and lateral chest films and pooled sputum cytology

Memorial Sloan-Kettering
  • Following the initial prevalence screen
  • 5072 men randomized to the chest x-ray only
  • 4985 men randomized to the dual-screened group
  • Both groups received annual chest x-rays.
  • The dual-screened group additionally received
    3-day pooled sputum cytology every 4 months.

Memorial Sloan-KetteringIncidence
M S-K Conclusions
  • There was no statistically significant difference
    in early stage lung cancers identified, 5-year
    survival or mortality between the dual-screen
    group and the chest x-ray only group
  • Sputum cytology, even as often as q4 months, does
    not improve mortality compared to CXR alone

Johns Hopkins
  • Uncanny-ly similar to Memorial Sloan-Kettering
  • From 1973 to1977 enrolled
  • 10,387 male volunteers
  • Age 45 years or older
  • At least one pack per day smoking history in
    preceding year
  • Volunteers were randomly allocated to two groups
  • Control, or single-screen group, received annual
    radiographic screening only
  • Dual-screen group received annual radiography
    plus annual sputum cytologic examination

Johns Hopkins Incidence
  • Lung cancer detected in 396 participants
  • 194 in the dual-screen group
  • 202 in the control group
  • Over half (51) of the cancers identified were
    detected incidentally by chest x-ray or sputum
    cytology performed outside of the screening
  • Compared with clinical diagnosis by symptoms,
    screening by both chest x-ray and sputum cytology
    identified a greater proportion of the lung
    cancer cases at an earlier stage
  • Addition of sputum cytology improved detection of
    squamous cell lung cancer but did not effect
    disease-specific mortality

NCI Cooperative Lung Conclusions
  • Demonstrated improvements in stage distribution,
    resectability and survival in screened groups
  • No improvement in disease-specific mortality with
  • Cooperative authors recognize the potential
    effects of bias, lead-time, length-sampling and
  • Role of control contamination, screening
  • However, they hedge,
  • It is probable that some patients who had
    lung cancers detected by screening would have
    died of their malignancies had they not been
    detected at earlier stages.

NCI Cooperative LungRecommendations, 1984
  • 1. If screening for lung cancer is to be carried
    out, it should be done within the framework of
    general health care that is, in the private
    practitioner's office, HMO, or general medicine
  • 2. The chest x-ray is the most sensitive method
    for detection of lung cancer currently available.
  • 3. Sputum cytology is the most effective and
    specific method of detecting early squamous cell
    lung carcinoma. Patients with positive sputum
    cytology in the setting of radiologically occult
    malignancy have good 5 year survival.
  • 4. Data do not indicate if prolonged survival in
    prevalent cases of lung cancer represented
    decreased mortality from disease or reflects one
    or more screening artifacts.

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Czechoslovakian Lung Cancer Study
  • Began in Czechoslovakia in 1976
  • Designed to evaluate semi-annual screening by
    chest x-ray and sputum cytology
  • 6364 males, ages 40-64, with a greater than 20
    pack year history of tobacco abuse, were
    screened with PA chest x-ray and 24-hour sputum
    cytology to identify prevalent cases

Czech study cont.
  • After the prevalence screen, remaining
    participants were randomized to a screening group
    or a control group
  • 3172 randomized to screening received PA chest
    x-ray and sputum cytology every 6 months for 3
  • 3174 randomized to control received a single
    screening chest x-ray at the end of the 3 year
  • All participants received annual chest x-ray for
    an additional 3 years following the screening

Czechoslovakian Lung Cancer Study
  • Prevalence
  • Initial screen identified 19 cancers, 9 squamous
    cell carcinomas and 7 small cell lung cancers
  • Overall prevalence was 3/1000 examinations
  • 5-year survival for prevalent cases was 25

Czechoslovakian Lung Cancer Study
  • During the three year screening period, 55
    confirmed lung cancers were identified
  • 36 cases were identified in the screening group.
    26(75) cancers found in asymptomatic
  • 19 cases were identified in the control group. 4
    (25)found incidentally or at autopsy
  • Following the screening period, annual CXR
    surveillance revealed an additional 35 cases of
    lung cancer in the screening group and 38 cases
    in the control group
  • Overall mortality after nine years was 3.6/1000
    person/years in both the screened and control

Randomized control trials, summary
RCT, summary cont.
  • Four RCTs collectively screened 37,724
  • All studies demonstrated improvements in stage
    distribution, resectability and survival in
    screened groups
  • No improvement in disease-specific mortality with

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Interest lost, found
  • With failure to demonstrate mortality benefits
    from screening, all major advisory organizations
    adopted recommendations against screening for
    lung cancer
  • Research funding waned
  • But,with emergence of new diagnostic and
    therapeutic modalities, new interest in lung
    cancer screening arose in the mid-1990s

New directions in early lung cancer detection
  • Chest x-ray reexamined
  • PLCO
  • Low-dose spiral CT
  • PET
  • Biomarkers
  • hnRNP expression
  • Fluorescence bronchoscopy

Chest x-ray reexamined PLCO
  • The National Cancer Institute is readdressing the
    use of periodic chest x-ray screening in the
    Prostate, Lung, Colorectal and Ovarian Cancers
    Trial (PLCO)
  • Currently in progress, PLCO seeks to enroll
    150,000 Americans, age 55-75, for randomization
    to various screening or no screening strategies
  • 14 years follow-up planned

Computed Tomography
  • In the 1990s a number of population-based trials
    demonstrated increased sensitivity of CT scan for
    the detection of resectable lung cancer vs. CXR
  • Majority of reports come from Japan where a
    government sponsored screening program with CXR
    and sputum cytology has been in place since
    mid-1980s. The addition of low-dose spiral CT
    to screening programs there lead to higher
    detection rates of early stage non-small cell
    lung cancers.
  • A number of studies are currently underway to
    evaluate the use of low-dose spiral CT for early
    lung cancer detection.

What is low-dose spiral CT?
  • Takes 15-30 seconds to perform
  • Allows complete chest imaging in one breath hold
    using wide slices
  • Radiation exposure equivalent to mammography
  • Can detect lesions as small as 2mm

Computed tomography ELCAP
  • ELCAP Early Lung Cancer Action Project
  • On-going study begun in 1992
  • Single cohort, non-comparative design
  • Aims to establish a cure rate based on lung tumor
    size to be used subsequently to assess other
    screening protocols or novel tests
  • Compared with a randomized controlled trial, this
    design is less costly and allows more rapid
    acquistion of data

  • Enrolled 1000 symptom-free volunteers from New
    York Hospital-Cornell University and NYU Medical
    Center hospitals, associated physicians' offices
  • 60 years of age or older
  • Both men and women!!
  • 10 pack-year history of cigarette abuse or
  • No prior history of malignancy, no
    contraindications to thoracic surgery.

  • All participants underwent PA and lateral chest
    radiographs and low-dose helical CT
  • Positive results were defined as CT evidence of 1
    or greater non-calcified nodules.
  • When nodules were identified parameters were
    recorded including number of nodules, size,
    location (lobe and distance from pleura,) shape
    (round, non-round,) edge (smooth, non-smooth,)
    and benign calcification (present or absent.)

  • Patients with CT evidence of non-calcified
    pulmonary nodules underwent standard-dose high
    resolution diagnostic CT scan of the chest
  • If standard CT demonstrated benign calcifications
    in a nodule with smooth edges, nodule was classified as benign
  • Suspicious nodules were evaluated according to
    ELCAP protocol
  • months. If no growth noted _at_ 24 months the
    lesion was considered benign.
  • 6-10mm biopsy recommended. If contraindications
    to biopsy exist, follow-up serial CTs as
    described above.
  • 11mm biopsy strongly recommended

ELCAP Conclusions
  • Compared with CXR, low-dose CT greatly increases
    the likelihood of detection of small
    non-calcified nodules, and, thus, of lung cancer
    at earlier, more curable stages
  • CT vs CXR
  • detected 3x as many non-calcified nodules
  • 4x as many malignant tumors
  • 6x as many stage I cancers

ELCAP Conclusions
  • High false positive rate of 233 suspicious
    nodules only 27 malignant tumors were confirmed.
    Only 4 patients underwent biopsy for benign
    disease and no biopsy complications were noted.
  • Risks of cumulative radiation likely low
  • Cost-effectiveness ???

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PETPositron Emission Tomography
  • Utilizes metabolic activity of a pulmonary lesion
    to provide information about the malignant
    potential of a pulmonary nodule
  • Allows imaging of structures by virtue of their
    ability to concentrate specific molecules that
    have been labeled with a positron-emitting
  • In evaluation of solitary pulmonary nodules some
    studies suggest a 95 sensitivity and 70
    specificity for the detection of malignancy

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Biomarkers Introduction
  • Screening with conventional sputum cytology
    failed to decrease mortality as demonstrated in
    the Johns Hopkins and Memorial Sloan-Kettering
  • However, new techniques and immunostaining for
    biomarkers promises much greater sensitivity for
    sputum cytology evaluation.

  • Lung cancer results from an interaction between
    genetic predisposition and environmental causes.
  • Exposure of the respiratory epithelium to
    carcinogens triggers mutation in specific genes,
    proto-oncogenes, and tumor suppressor genes.
    Once epithelial cells undergo malignant
    transformation, cell proliferation depends on
    tumor promoters, cellular growth factors.
  • Several genetic abnormalities have been
    identified in association with lung cancer
    (table13.) Mutations and molecular products can
    be identified from sputum and tissue samples
    using polymerase chain reaction (PCR) and other
    techniques in molecular biology.

Biomarkers cont.
Prospective Detection of Preclinical Lung Cancer
Results from studies of heterogeneous nuclear
ribonucleoprotein A2/B1 overexpression
  • Lung Cancer Early Detection Working Group, a
    cooperative NCI-sponsored group
  • Earlier studies identified potentially useful
    lung CA biomarkers expressed in archieved sputum
  • Initiated to address
  • Does hnRNP A2/B1 overexpression correctly detect
    preclinical lung cancer?
  • Does overexpression precede dysplastic
    morphological changes in sputum epithelial cells?

hnRNP overexpression study, cont.
  • Prospective, case-cohort design
  • Monitored Chinese tin workers over age 40 with
    annual sputum cytology and immunocytochemistry
  • Blinded investigators at Johns Hopkins analyzed
    sputum samples from participants with clinically
    detected and confirmed non-small lung cancers and
    from age-matched controls

Immunodetection of preclinical primary lung
cancer by hnRNP overexpression hnRNP test
  • Primary lung cancer risk 56/62850.9
  • Sensitivity82 (CI 68-92)
  • Specificity65(CI 50-78)
  • Relative risk1480/432, 3.4

Biomarkers conclusions
  • May be possible to use biomarkers to identify an
    early clonal phase of progression of lung cancer
    in high-risk populations, enabling cancer
    detection earlier than visualization by spiral
  • May be used to complement spiral CT to ?
    sensitivity and specificity for malignancy.
  • May be used to identify targets for treatment
    allowing chemical, radiation or pharmacological
    targeting of minute primary lung cancers.

Contemporary Screening for Lung Cancer,
Pre-malignancy and Malignancy Project
  • Recruitment underway now
  • Multicenter, randomized controlled trial
  • Aims to address whether a screening program using
    lung cancer associated molecular markers in
    sputum combined with low-dose helical CT can
    improve lung-cancer specific survival in
    individuals at high risk for lung cancer.

Contemporary Screening for Lung Cancer,
Pre-malignancy and Malignancy Project cont.
  • With enrollment, participants will undergo chest
    x-ray and sputum cytologic evaluation to select
    out prevalent cases of lung cancer prior to
    randomization. Enrollees without evidence of
    lung cancer will be randomized to screening and
    control groups.
  • Screening group will undergo sputum (cytologic
    and biomarker evaluation) and radiographic (chest
    x-ray and low dose spiral CT) at 6 month
    intervals. The control group will undergo no
    screening but will complete annual health
  • NC Baptist/Wake Forest University Medical Center
    is one of thirteen participating institutions for
    this study.

Fluorescence Bronchoscopy
  • Undergoing early multi-center trials for
    screening in smokers with established obstructive
    lung disease and abnormal sputum cytology
  • Utilizes differences in the fluorescence
    properties of normal and abnormal bronchial
    epithelium to identify dysplasia and metaplasia

Fluorescence bronchoscopy
  • Demonstrated ability to enhance detection of
    severe dysplasia and carcinoma in situ over
    white-light bronchoscopy
  • May be most useful in localization of sputum
    cytology positive, CXR/CT (-) malignancies and in
    determination of endobronchial involvement by
  • Technology and technique remain under development
  • Anticipate improved sensitivity and specificity
    with future systems

  • No randomized controlled trial to date has
    demonstrated reduced mortality from a lung cancer
    screening program
  • Trials demonstrate improvement in stage at
    diagnosis, resectability and survival with
    screening programs
  • No evidence to support the use of chest x-ray or
    sputum cytology for routine lung cancer screening
    in asymptomatic patients

Conclusions, cont.
  • New diagnostic techniques may prove promising for
    use alone or together in early lung cancer
  • Low-dose spiral CT looks promising for detection
    of early stage lung cancer however high false
    positive rate could lead to unnecessary morbidity
    and mortality in disease-free patients

Conclusions, conclude
  • PET and biomarkers may improve sensitivity and
    specificity of other diagnostic tests especially
  • Not sure what to expect from fluorescence
    bronchoscopy, sounds neat

Should you screen?
  • 1. Does the burden of disability from the disease
    warrant action?
  • 2. Are at-risk populations well-defined?
  • 3. Does early diagnosis really lead to improved
    clinical outcomes (in terms of survival, function
    and quality of life)?
  • 4. Are the cost and accuracy of the screening
    test acceptable?
  • 5. Can you manage the additional clinical time
    required to confirm diagnosis and provide
    long-term care to those who screen positive?
  • 6. Will patients in whom an early diagnosis is
    achieved comply with subsequent recommendations
    and treatment regimens?
  • Adapted from Sackett et al. Clinical
    Epidemiology. A Basic Science for Medicine.
    1991 391.

  • At this time, would hold on screening of
    asymptomatic high-risk patients
  • Could consider lowering your threshold for
    screening in patients with documented airflow
  • Lung Health Study found a 1 cancer mortality at
    5 years in patients with COPD
  • Eagerly await the results of pending trials (that
    do indeed include women)

Recommendations, cont.
  • Anticipate screening will have greater mortality
    benefit as lung cancer therapy advances
  • Above all, emphasize to patients that the
    greatest reduction in lung cancer mortality comes
    from smoking cessation