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					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 Deaths
10 Leading Sites, by Gender 2001
Age-adjusted cancer death rates by site
US males, 1930-1997
Age-adjusted cancer death rates by site
US females, 1930-1997
Prognosis of Non-small Cell Lung Cancer, By Stage

     Clinical Stage    N     Five-year survival
                                     %
          IA           687           61
           IB         1189           38
          IIA          29            34
          IIB          357           24
         IIIA          511           13
         IIIB         1030           5
          IV          1427           1
                              Adapted from Mountain, CF, Chest, 1997, 11:1710.
Table 4. Current guidelines for lung cancer screening

Organization                        Recommendation
American Cancer Society             Against routine screening of asymptomatic patients

American College of Radiology       Against the use of chest x-ray in asymptomatic
                                    patients
US Preventive Services Task Force   Against the use of chest x-ray or sputum cytology in
                                    asymptomatic patients

American College of Physicians      Against the use of chest x-ray in asymptomatic persons

American Thoracic Society           Against mass lung cancer screening programs except
                                    as part of well-designed, controlled clinical trials
American Academy of Family          Against the use of chest x-ray or sputum cytology in
Practice                            asymptomatic patients
Canadian Task Force on the          Against the use of chest x-ray and/or sputum cytology
Periodic Health Examination         in asymptomatic persons
                                          Adapted from Mandel, J, Weinberger, S. Screening for lung cancer. UpToDate 2000; 8:1-2.
                                                     Mandel, J, Weinberger, S. Screening for lung cancer. UpToDate 2000; 8:1-2.
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
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 disease
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
Screening
   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
            randomization
           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
            disease
           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 diagnosis.
           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 Study
     – 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 therapy.
   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
      Table 5. Mayo Lung Project Prevalence Screen
  Detection Method     Lung cancers Resection 5-year
                         identified        rate    survival
Chest x-ray alone            59         30 (51%)
Sputum cytology alone        17         16 (94%)
Chest x-ray and sputum       15          3 (30%)
cytology,
combined
TOTAL                    91(0.83%)      49 (54%)    >30%
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 sent
   Study group was followed for a total of 9 years, 6 years of
    screening and 3 years of follow-up observation.
MLP: Incidence and Mortality


                   Table 6. Mayo Lung Project Incidence and Mortality
GROUP       PARTICIPANTS   SCREEN      CANCERS    RESECTABILITY    5-YEAR     DEATH
                                       DETECTED                   SURVIVAL      RATE
Screening       4618          CXR,        206        46% (94)        45%     3.2/1000/yr
                             sputum
                            cytology
                             every 4
                             months
 Control        4593        Based on     160         32% (51)       15%      3.0/1000/yr
                           symptoms
MLP: Staging and 5-year survival


               Table 7. Percentage of Lung Cancers Detected in Stages I and II
                                      Postsurgical Cancer Stage
Cancers identified           Stage I, II           Stage III and nonresected     Total
   Screening group            71 (42%)                     96 (58%)           167 (100%)
   Control group              32 (25%)                     99 (75%)           131 (100%)

5-year survival
    Screening group                   47 (66%)                                         4 (4%)                                   53 (32%)
    Control group                     13 (41%)                                         4 (4%)                                   17 (13%)
                  Fontana, RS, Sanderson, DR, Woolner, LB et al. Lung cancer screening: The Mayo Program. Journal of Occupational Medicine 1986; 28:746.
 MLP: Late stage cancers, nonresectable cases
 and number of deaths


  Table 8. Mayo Lung Project: Late stage cancers, nonresectable cases
                          and number of deaths
                  Result                 Screening group Control group
Late-stage lung cancers                        123            119
Nonresectable lung cancers                     112            109
Lung cancer deaths                             122            115
Lung cancer deaths per 1000 person years       3.2            3.0
MLP: Extended follow-up


    Table 9. Mortality in the Mayo Lung Project, as of 12/31/96
 Group       Deaths from      Mortality rate per 1000 person-years
             lung cancer          (95% confidence interval)
Screening     337 (7%)                    4.4 (3.9-4.9)
Control       303 (7%)                    3.9 (3.5-4.4)
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
        group”
    –   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-Kettering:Incidence


 Table 10. Memorial S-K: total lung cancers detected, resectable, non-resectable and deaths
                                         CHEST X-RAY                                      CHEST X-RAY PLUS SPUTUM
                                            ONLY                                          CYTOLOGY(DUAL-SCREEN)
LUNG CANCERS
   TOTAL                                            144                                                             144
   RESECTABLE                                       73 (51%)                                                         75 (53%)
   LATE STAGE DZ                                    78                                                               77
DEATHS                                              90                                                               92
            Data from Melamed, MR et al. Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York. Chest. 1984; 86:45-46.
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 protocol
   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
    screening
   Cooperative authors recognize the potential effects of bias,
    lead-time, length-sampling and over-diagnosis
   Role of control contamination, screening non-compliance?
   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 Lung
Recommendations, 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 clinic.
 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.
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
    years
   3174 randomized to control: received a single
    screening chest x-ray at the end of the 3 year trial
   All participants received annual chest x-ray for
    an additional 3 years following the screening
    period
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 participants
   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
    groups
 Randomized control trials, summary


         Table 11. Lung cancer screening randomized controlled trials, summary
 RCT    Year   Population     N      Group    Cancers    Prevalent   Incident        Resect-           Survival, %       Mortality
                                              detected     cases      cases         ability, %
MLP     1971   Men, 45+     10933   Prev                 91                         54                40 (5yr)
                            4618    Exp                              206            46                33 (5yr)           3.2
                            4593    Control                          160            32                15 (5yr)           3.0
JHLP    1973   Men, 45+     5226    Exp       194        39          155            47                20 (8yr)           3.4
                            5161    Control   202        40          162            44                20 (8yr)           3.8
MSKLP   1974   Men, 45+     5072    Exp       144        30          114            53                35 (5yr)           2.7
                            4968    Control   144        23          121            51                35 (5yr)           2.7
Czech   1975   Men,         6364    Prev                 19                                           28 (5yr)
               40-64
                            3172    Exp                              36             25                24 (5yr)           1.7
                            3174    Control                          19             16                0 (5yr)            1.5
                                                                                Mortality as deaths/1000 screened/year
RCT, summary cont.

 Four RCTs collectively screened 37,724
  participants
 All studies demonstrated improvements in
  stage distribution, resectability and survival
  in screened groups
 No improvement in disease-specific
  mortality with screening
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-1990’s
New directions in early lung
cancer detection
   Chest x-ray reexamined
    –   PLCO
   Low-dose spiral CT
    –   ELCAP
 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-1980’s. 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
ELCAP

   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 greater
   No prior history of malignancy, no contraindications to
    thoracic surgery.
ELCAP
   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.)
ELCAP
   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, <20mm in size, the nodule was classified as
    benign
   Suspicious nodules were evaluated according to ELCAP
    protocol
     – <5mm: follow-up high-res CT at 3, 6, 12, 24 months. If no
        growth noted @ 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 RESULTS (brief)

                                  Table 12. ELCAP results
                                Low-dose CT                 Chest radiograph
Nodules                         559                         196
Benign calcifications           196 (35%)                   118 (60%)
Individuals identified with     233                         68 (33 correlated with nodules
non-calcified nodules                                       on CT, 35 "nodules"
                                                            determined to be confluent
                                                            shadows)
Nodule-associated malignant     27 (12%)                    7
disease
Stage I disease by pathologic   23 (85%)                    4
or clinical staging
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 ???
PET:Positron 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 isotope
   In evaluation of solitary pulmonary nodules some
    studies suggest a 95% sensitivity and 70%
    specificity for the detection of malignancy
      Biomarkers: Introduction
 Screening with conventional sputum
  cytology failed to decrease mortality as
  demonstrated in the Johns Hopkins and
  Memorial Sloan-Kettering trials.
 However, new techniques and
  immunostaining for biomarkers promises
  much greater sensitivity for sputum
  cytology evaluation.
                    Biomarkers
   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.

       Table 12. ONCOGENES AND MARKERS ASSOCIATED WITH LUNG CANCER
ONCOGENE                    MUTATION                   FREQUENCY OF                                       HISTOLOGY
                                                       OCCURRENCE IN
                                                       NSCLC
Autosomal dominant oncogenes and protooncogenes, promoters of cellular deregulation
         K-ras               Point                     30%                                                Adenocarcinoma
         erb B1 (EGFR        Overexpression            20%                                                Squamous cell
         gene)                                         90%                                                Squamous cell
         EGFR (erb B1                                  20%?                                               Adenocarcinoma
         gene products)
         erb B2 (Her-        Overexpression            25-35%                                             Adenocarcinoma
         2/neu)
Autosomal recessive oncogene or tumor suppressor genes
         p53                 Deletion or point         50-80%                                             All
         3p                  Deletion                  50%                                                All
Tumor associated antigens on sputum epithelial cells
         Hn-RNP              N/A (I’m a glycoprotein)  90%                                                NSCLC
                                               Adapted from Aberle, DR et al. Contemporary Screening for Lung Cancer. Abstract. 2001.
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 characteristics

   hnRNP immunodetection   Confirmed cancers   No cancer
   POSITIVE SCREEN             37(82%)         17(35%)
   NEGATIVE SCREEN              8(18%)         32(65%)
   TOTAL                          45              49

     Primary lung cancer risk 56/6285=0.9%
     Sensitivity:82% (CI 68-92%)
     Specificity:65%(CI 50-78%)
     Relative risk:1480/432, 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 CT.
   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 questionnaires.
   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
    malignancy
   Technology and technique remain under
    development
   Anticipate improved sensitivity and specificity
    with future systems
Conclusions
   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 detection
 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 CT
 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.
Recommendations
   At this time, would hold on screening of
    asymptomatic high-risk patients
   Could consider lowering your threshold for
    screening in patients with documented airflow
    obstruction
     – 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

				
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