Early Diagnosis of Lung Cancer

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EARLY DIAGNOSIS OF LUNG CANCER
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LUNG CANCER (LC) Epidemiology

• Most common cause of cancer death in
  industrialized world.
• More people die of LC than of colorectal, breast,
  and prostate cancer combined
• LC was diagnosed in an estimated 172000 people in
  USA, and 160000 died of it in 1998

Jain P et al., Cleve Clin J Med 2001 68(1)
74 Henschke CI, Cancer Suppl. 2000 89(11) 2474
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LUNG CANCER (LC) Risk Factors

• 87 of lung cancers are smoking related.
• 50 lung cancers now occur in former smokers.
• Additional risk factors

• Prior surgery for another lung cancer
• Occupational exposure to asbestos
• Prolonged exposure to high levels of radon
• History of other previous forms of cancer
• Radiation therapy

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LUNG CANCER
Small cell lung cancer SCLC
Non-small cell lung cancer NSCLC

• 25 of LC
• usually widespread
• when it firsts presents

• 75 of LC
• gt50 have distant
• metastases at presentation
• Only 25 potentially resectable for cure

SCREENING
Aberle DR, J Thorac Imaging. 2001 16(1) 65
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Definition
Screening can be defined as the systematic
testing of individuals who are asymptomatic with
respect to some target disease. The purpose of
screening is to prevent, interrupt, or delay the
development of advanced disease in the subset
with a pre-clinical form of the target disease
through early detection and treatment.
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SCREENING Some fundamentals

• Goal
• detect disease at a stage when cure or control
  is possible
• Target
• asymptomatic persons at risk for a specific
  disease
• Early intervention
• should change the course of the disease with
  decrease in mortality

Patz EF, NEJM 2000 343(22) 1627
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SCREENING Some fundamentals
Survival from the time of diagnosis of the
disease (commonly reported in clinical trials)
NOT APPROPRIATE MEASURE OF SCREENING TEST
PERFORMANCE
Subject to multiple BIAS

• LEAD-TIME BIAS
• LENGTH-TIME BIAS
• OVERDIAGNOSIS BIAS

Patz EF, NEJM 2000 343(22) 1627
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SCREENING - BIAS
LEAD-TIME BIAS
Diagnosis confirmed
Screened group
Patient dies
Survival time
Time
Lead-time
Survival time
Time
Diagnosis confirmed
Control group
Patient dies
Symptoms
The diagnosis of disease is made earlier in the
screened group, resulting in an apparent
increase in survival time, although the time of
death is the same in both groups.
Patz EF, NEJM 2000 343(22) 1627
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SCREENING - BIAS
LENGTH-TIME BIAS
Aggressive tumors
Symptoms
Onset of tumor
Tumor detectable
Indolent tumors
Time
The probability of detecting disease is related
to the growth rate of tumor. Aggressive, rapidly
growing tumors have a short potential screening
period. More slowly growing tumors have a longer
potential screening period and are more likely
to be detected when they are asymptomatic,
causing an apparent improvement in survival
Patz EF, NEJM 2000 343(22) 1627
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SCREENING - BIAS
OVERDIAGNOSIS BIAS
Diagnosis confirmed
Screened group
Patient dies
Natural death
Time
Natural death
Time
Diagnosis confirmed
Patient dies
Symptoms
Control group
The detection of very indolent tumors in the
screened group produces apparent increases in
the number of cases of lung cancer. But two
patients in the control group died with
undiagnosed lung cancer that did not affect
their natural life span
Patz EF, NEJM 2000 343(22) 1627
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RATIONALE FOR LC SCREENING

• Overall survival at 5 years
• 13-15
• not improved since 1950, despite advances in
  surgery, chemotherapy and radiation oncology.
• Early stage lung cancer 70 curable
• Early Stage IA 80 curable

Jain P et al., Cleve Clin J Med 2001 68(1)
74 Aberle DR, J Thorac Imaging. 2001 16(1)
65 Henschke CI, Radiol. Clin North America 2000
38(3) 479
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SCREENING MODALITIES

• Sputum cytologic examination
• Chest radiographic examination
• Bronchoscopy
• Recent non-imaging methods of early detection
• Low-dose CT

Henschke CI, Radiol. Clin North America 2000
38(3) 479 Patz EF, NEJM 2000 343(22) 1627
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Sputum cytologic examination

• DISADVANTAGES
• Low sensitivity in detecting peripheral
  adenocarcinomas
• Sensitivity depends upon the histotypes
• - squamous 93
• - small cell 89
• - adenocarcinoma 25
• - large cell carcinoma 54

• ADVANTAGES
• Effective at diagnosing very small microscopic
  cancers (Stage O)
• Cost-effective

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Chest radiographic examination

• ADVANTAGES
• Economical
• Easy to use and
• less-time consuming
• (10 minutes)

• DISADVANTAGES
• Detects tumors of at least 1 cm
• Often the quality is poor
• Radiation exposure

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Bronchoscopy

• ADVANTAGES
• In endobronchial visible lesions, it will
  correctly diagnose the lesion in 94 of cases (at
  least 5 samples)
• Flourescence Bronchoscopy

• DISADVANTAGES
• Invasive test
• Reliability seems to depend upon the location of
  the tumor.
• An adequate sampling is critical
• Costly

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Recent non-imaging methods of early detection

• Abnormal patterns of immunostaining
• Genetic mutation (in p53 and K-ras)
• Telomerase activity
• Microsatellite instability
• Abnormal DNA methylation

• DISADVANTAGES
• Sensitivity and specificity suboptimal at this
  moment
• To obtain specimens often invasive procedure are
  needed
• Very expensive at the moment.

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Low-dose CT
The multi slice-low dose spiral CT scanner
improves on the regular CT scanner by offering
faster scanning (15-20 sec), and is able to
achieve better resolution and more diagnostic
detail.

• DISADVANTAGES
• Costly
• Radiation exposure is about 10 times more
  than one for chest x-ray.
• It is not foolproof at the moment
• False-positive results are very common. PPV is
  less than 10.
• Additional high-resolution CT may be needed.

• ADVANTAGES
• Extremely sensitive and reliable able to detect
  LC at early stages
• No contrast media
• Radiation dose of low-dose CT is 1/7th the
  radiation dose of a standard CT

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PRIOR LC SCREENINGS TRIALS
1950s
Four nonrandomized, uncontrolled screening
studies, using chest radiography were performed

• Philadelphia Pulmonary Neoplasm Research Project
• Veterans Administration Trial
• Tokyo Metropolitan Government Study
• South London Lung Cancer Study

RESULTS Some improvement in survival, but
mortality from LC was not adequately
assessed. CONCLUSIONS No benefits from chest
x-ray screening
Patz EF, NEJM 2000 343(22) 1627
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PRIOR LC SCREENINGS TRIALS
1959-1970
Two nonrandomized but controlled trials, using
chest radiography were performed

• North London Cancer Study
• Erfurt Country Study

RESULTS Number of early-stage lung
cancers Number of resectable cancers Survival
rates
HIGHER THAN IN CONTROL GROUP
No clear reduction in mortality was demonstrated
Patz EF, NEJM 2000 343(22) 1627
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PRIOR LC SCREENINGS TRIALS
Early 1970s
Four randomized, controlled trials, using chest
radiography and sputum-cytology were performed

• John Hopkins Lung Project
• Memorial Sloan-Kettering Lung Project
• Mayo Lung Project
• Czechoslovakian Study

• Targeted high-risk male smokers over 45 years age
• 37,000 people enrolled

STUDY DESIGN
Patz EF, NEJM 2000 343(22) 1627 Aberle DR, J
Thorac Imaging. 2001 16(1) 65
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• Johns Hopkins Lung Project
• Memorial Sloan-Kettering Lung Project

Chest x-ray Sputum cytology
Every 4 months
SCREENING GROUP
CONTROL GROUP
Chest x-ray Every year

• Mayo Lung Project

Chest x-ray Sputum cytology
SCREENING GROUP
Every 4 months
CONTROL GROUP
Chest x-ray Sputum cytology
Every year

• Czechoslovakian Study

Chest x-ray Sputum cytology
SCREENING GROUP
Every 4 months
CONTROL GROUP
Chest x-ray Sputum cytology
On 3rd, 4th and 5th year
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RESULTS

• Stage of NSCLC lower in screening group
• Number of resectable cancers higher in screening
  group
• 5-year survival 35 in screening group vs 15
• Disease-specific mortality (3.2/1000) was
  unchanged

-
CONCLUSION
Screening and subsequent therapy did not affect
the outcome of the disease
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PROBLEMS and BIAS

• Lead-time bias
• Overdiagnosis bias the incidence of LC was
  higher
• in the screened group than in control group
• Mayo study had less than 20 power to detect a
  10
• decrease in LC mortality
• Follow-up period was insufficient to show a
  decrease in
• mortality
• In Mayo study only 75 of pts in screening group
  
• and 50 of pts in control group completed the
  program

Patz EF, NEJM 2000 343(22) 1627 Aberle DR, J
Thorac Imaging. 2001 16(1) 65
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OTHER FINDINGS AGAINST SCREENING FROM THESE
STUDIES

• Some LC are very aggressive and even close
  surveillance and early detection will not affect
  the outcome
• The size of the primary lesion is not always
  correlated
• with the ability of the tumor to disseminate
• The number of patients with advanced-stage
  disease was not lower in the screened group than
  in control group

Patz EF, NEJM 2000 343(22) 1627 Miettinen OS,
Radiol Clin North Am 2000 38(3) 479
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CURRENT SCREENING TRIALS
Recent advances in imaging technologies helical-CT
renewed interest in LC screening
1990s

• Two nonrandomized studies from Japan
• - almost 7000 people
• - smokers and non-smokers over 40 years old
• - chest x-ray, sputum cytology and low-dose CT
• Early Lung Cancer Action Project, nonrandomized
  trial
• - 1000 people
• - high smokers over 60 years-old
• - chest x-ray and low-dose CT

Patz EF, NEJM 2000 343(22) 1627 Aberle DR, J
Thorac Imaging. 2001 16(1) 65
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RESULTS - Positive findings

• Low-dose CT detects more cases of lung cancer
  than
• chest x-ray (27/1000 vs 9.1 to 7.6/1000)
• Low-dose CT compared with chest x-ray detected
• - Non-calcified nodules three times as
  commonly (23 vs 7)
• - Malignancies four times as commonly
  (2.7 vs 0.7)
• - Stage I malignancies six time as
  commonly (2.3 vs 0.4)
• The size of malignancies are smaller with
  low-dose CT

Henschke CI, Cancer Suppl. 2000 89(11)
2474 Henschke CI, Lancet 1999354(22)
1627 Henschke CI, Radiol Clin North Am 2000
38(3) 479
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RESULTS - Negative findings

• The prevalence-screening rate for advanced
  disease
• on low-dose CT did not decrease
• True clinical significance of small tumors
  founded by
• screening is unknown
• CT founded at least one indeterminate nodule in
• 23 of patients

Henschke CI, Cancer Suppl. 2000 89(11)
2474 Henschke CI, Lancet 1999354(22)
1627 Henschke CI, Radiol Clin North Am 2000
38(3) 479
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RECOMMENDATIONS FOR LUNG CANCER SCREENING
A Consensus Statement of the Society of Thoracic
Radiology Screening for Lung Cancer with Helical
Computed Tomography Journal of Thoracic Imaging,
16, 1, 65-68, 2001
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SUBJECT SELECTION

• For general population
• - age range between 50 and 80 years
• - cigarette smoking at least 10 or 20 pack/years
• - absence of symptoms (recent coughing, chest
  pain,
• coughing up blood, shortness of breath, and
  wheezing)

• In high-risk group selection criteria may vary
• - occupational exposure
• - Previous NSCLS

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RADIATION DOSE

• Effective radiation dose associated with
  low-dose
• screening examination is 0.65 mSv (mRem).
• Approximative dose for conventional CT is 5.8
  mSv.
• These doses not include any high resolution or
• follow-up CT studies

Aberle DR, J Thorac Imaging. 2001 16(1) 65
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FOLLOW-UP
LOW-DOSE CT
NEGATIVE
POSITIVE
DIFFUSE
1-6 NCLN
gt 6 NCLN
1 YEAR FOLLOW-UP
DEPENDS UPON SIZE
Non Calcified Lung Nodules
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High resolution CT 3, 6, 12 and 24 months If no
growth in 2 ys nodule is benign Biopsy if nodule
increases in size (1 malig.)
2 to 5 mm
Assessment on case-by-case basis for biopsy Or
high resolution CT 3, 6, 12 and 24 months Biopsy
if nodule increases in size (25-30 malig.)
6 to 10 mm
Consider biopsy of all these nodules (30 to 80
malignant)
gt 10 mm
Aberle DR, J Thorac Imaging. 2001 16(1)
65 Henschke CI, Cancer Suppl. 2000 89(11)
2474 Henschke CI, Lancet 1999354(22) 1627
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COSTS

• Low-dose CT requires less than 20 sec of
  scanning and
• does not requires intravenous contrast
  injection
• Low-dose CT costs 1/3 of standard CT
• The cost of low-dose CT is slightly higher than
  that
• of chest x-ray
• Elective thoracotomy of Small stage I LC is less
  costly
• than the treatment cost of a later stage cancer
• Preliminary data indicates that a single
  baseline CT
• screening program costs about 2000 per
  life-year saved

Henschke CI, Cancer Suppl. 2000 89(11) 2474
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COSTS

• If every adult smoker undergo annual CT
  screening
• it would cost 12.22 billion dollars
• Moreover we should examine also a some number
• of former smokers
• Actually almost 50 of cases screened need short
  
• follow-up with an increase of costs

-
Mott FE, Lancet 1999 3541206
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Subtle and Very Subtle Nodules Imaged on CT scan
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Harms from Screening

• Anxiety about cancer
• False positive test, anticipation
• Mortality morbidity from earlier treatment
• Over-diagnosis