Screening for Lung Cancer using Low Dose CT: State of the Art and Controversies

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Screening for Lung Cancer using Low Dose CT
State of the Art and Controversies

• Philippe GRENIER
• University Pierre et Marie Curie (UPMC),
• Pitié-Salpêtrière Hospital, Paris, FRANCE

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Rationale for lung cancer screening

• Lung cancer remains the leading cause of
  cancer-related death among men and women in the
  world
• The 5-year survival rate of 10-15 has been
  roughly unchanged for the past two decades
  despite treatment advances

At diagnosis, most lung cancers are already at
advanced stage
Mountain. Chest 1997.111 1710
Strauss. Surg Oncol Clin N Am 1999 8 747
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Rationale for lung cancer screening

• Early stage lung cancer patients have a much
  higher 5-year survival rate (between 60 and 80)

Changing smoking habits could reduce lung cancer
incidence and deaths
Cessation programs have long-term cessation rates
of only 20 to 35 at one year
The risk for lung cancer does not decrease for
many years after smoking cessation
Pisters. J Clin Oncol 2005 233270
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Lung Cancer Screening with Chest Radiography
with or withoutSputum Cytologic Examination

• Some lower-quality evidence (case-control
  studies) has shown benefit
• Higher-quality evidence (randomized controled
  trials) conducted in the 80s has not (the
  screened groups had the same number of death from
  lung cancer as the control group)

Humphrey. Ann Intern Med 2004 140740
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Early Lung Cancer Action Project (ELCAP)
Uncontrolled observational trial

• 1000 asymptomatic volunteers (gt 60 yo)
• smoking 45 py (median).
• Subjects received both low dose computer
  tomography (LDCT) and chest radiography (CR)
• Non-calcified nodules were detected on 23 of
  LDCT and 7 of CR
• Lung cancer was detected in 2.7 LDCT screens
  (85 were stage I disease) and in 0.7 CR screens

Henschke. Lancet 1999 35499
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Year 0
Year 1
Adenocarcinoma
Year 13 months
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Year 0
Year1
Adenocarcinoma
Year 13 months
9
Initial
3-month Follow-up
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Adenocarcinoma
10
Uncontrolled studies with LDCT
Study years Screening type Screening tests performed Postive test results () Lung cancer () Stage I disease ()
Henschke 1999 Baseline Incidence 1000 1184 24 3.1 0.9 85 67
Nawa 2002 Baseline Incidence 7956 5568 26 0.5 0.1 86 100
Sone 2001 Baseline Incidence 5483 8303 5 0.4 0.6 100 86
Sobue 2002 Baseline Incidence 1611 7891 12 0.8 0.2 77 79
Swensen 2003 Baseline Incidence 1520 2916 51 1.8 0.7 66
Diederich 2002 Baseline 817 43 1.3 58
Pastorino 2003 Baseline Incidence 1035 994 15 1.1 1.1 77
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Uncontrolled studies with LDCT
Prevalence rates of lung cancer have varied
widely (0.44-1.8) , due to different risk
profiles based on age and smoking disease status,
Stage I or II cancers have been 75 to 100
High level of non-calcified benign nodules
detected (15-51) with the risks of invasive
procedures and futile thoracotomies
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False positive rate of screening CT

• Definition number of patients who required
  further evaluation after CT but did not have
  cancer
• Rate of positive tests in prevalence screening
  15-51
• Rate of positive tests in incidence screening
  3-12
• Most are resolved with follow-up CT
• 5 - 14 of those undergoing follow CT were
  referred to biopsy and most (63 - 90 ) then
  received a diagnosis of cancer

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False negative rate of screening CT

• Nodules were missed in 26 of patients on annual
  incidence screening CT scans1
• CT sensitivity for detecting nodules is reduced
  when central versus peripheral, when adjacent to
  the vessels and when small2
• Double reading and CAD may reduce false negative
  rates3

1 Swensen. Am J respir Crit Care Med 2002 165
508 2 Rusinek. Radiology 1998 209243 3 Ko. J
Thorac Imaging 2004 19136
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Computer Aided Diagnosis Detection and Nodule
growth assessment on follow-up CT
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Strategy for indeterminate nodule(more than 50
y.o. smoker)

• Size

McMahon. Radiology. 2005 237 395-400
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Survival of patients with stage I lung cancer
detected on CT screening
31,567 asymptomatic persons at risk for lung
cancer were screened using LDCT (1993-2005)
412/484 (85) had clinical stage I lung cancer
and estimated 10-year survival rate was 88
Among 302/412 who underwent surgical resection
within 1 month after diagnosis, the 10-year
survival rate was 92
The 8 participants with clinical stage I who did
not receive treatment died within 5 years after
diagnosis
Henschke. N Engl J Med. 2006 3551763
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Are Increasing 5-Year Survival Rates Evidence of
Success Against Cancer?
There is little correlation between the change in
5-year survival for a specific tumor and the
change in tumor-related mortality The change in
5-year survival is positively correlated with the
change in the tumor incidence rate
Welch. JAMA 2000 2832975
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Uncontrolled studies with LDCT

• Lung cancer can be diagnosed at a significantly
  earlier stage with CT screening.
• However whether this will translate to a
  mortality benefit is unclear

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CT Screening for Lung CancerFive-year
Prospective Experience
1520 individuals with high risk for lung cancer
68 lung cancers diagnosed (31 initial, 34
subsequent,3 interval) 28 subsequent cases of
non-small cell cancers were detected, of which 17
(61) were stage I tumors
No difference in the observed incidence lung
cancer mortality rate to a historic benchmark
2.8 vs 2.0 per 1000 person-years
Swensen. Radiology 2005 235 259
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CT Screening and Lung Cancer Outcomes
Longitudinal analysis of 3246 individuals current
or former smokers screened for lung cancer in
academic centers with a follow-up of 3.9
years Comparison of predicted with observed
number of new lung cancer cases, lung cancer
resections, advanced lung cancer cases, and
deaths from lung cancer
Bach. JAMA 2007 297 953
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CT Screening and Lung Cancer Outcomes
144 individuals diagnosed with lung cancer
compared with 44.5 expected cases (RR, 3.2
Plt.001)
109 had a lung resection compared with 10.9
expected cases (RR, 10 Plt.001)
No evidence of decline in the number of
diagnoses of advanced lung cancers (42 vs 33.4
expected cases) or deaths from lung cancer (38
observed and 38.8 expected RR, 1 P .9)
Bach. JAMA 2007 297 953
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Cancer screening programmes should do more good
than harmat a financial cost acceptable to
society

• Good
• extend quality years of life (QALY)
• reduce mortality from the tumor
• Harm
• complications of the screening tests
• consequences of false positive diagnoses

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Lead-Time Bias
Survival time
Time
Screened group
Diagnosis confirmed
Patient dies
Lead time
Survival time
Time
Control group
Symptoms Diagnosis Patient

confirmed dies

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Length-Time Bias
Tumor detectable
Onset of tumor
Aggressive tumors
Symptoms
Tumor detectable
Onset of tumor
Symptoms
Tumor detectable
Onset of tumor
Symptoms
Indolent tumors
Time
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Overdiagnosis and consequent overtreatment

• Overdiagnosis bias is the result of slow-growing
  relatively indolent lung cancers that a patient
  dies with and not from
• The high rate of adenocarcinomas raises the
  possibility of overdiagnosis
• Slow-growing adenocarcinomas (bronchioloalveolar
  carcinomas or non-invasive adenocarcinomas) that
  are not lethal may be identified with CT
  screening

Lindell. Radiology 2007 242 555
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Non solid nodules malignant causes
Ground glass opacity
Adenocarcinoma
Bronchioloalveolar cell carcinoma
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Mixed (part-solid) nodules
Adenocarcinomas
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Solid and non-solid nodules growth rate

• Doubling time of nodules from a 3-year screening
  program for lung cancer

Solid nodules 189 days Mixed (part-solid)
nodules 457 days Non solid nodules 813 days
Hasegawa. Br J Radiol 2000 73 1252
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Curative limited resection for small peripheral
lung cancer
146 stage IA peripheral tumors
Type I GGO 90-100 Type II GGO 50-89 Type III GGO 10-49 Type IV GGO lt 10
Nodal metastasis 0 0 20 24
3-year disease-free survival 98 98 86 78
Patients with tumor that have GGO ratio gt 50
are regarded to be possible candidates for
limited pulmonary resection
Nakata. J Thorac Cardiovasc Surg 2005 129 1226
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Overdiagnosis a Substantial Concern in Lung
Cancer Screening
61 cancers reviewed and 48 assessed for
morphologic change
Mean tumor size 16.4 mm (5.5-52.5 mm) 74
prevalence, 37 incidence detected lung cancers
were adenocarcinomas Mean volume doubling time
(VDT) was 518 days 13/48 (27) cancers had a VDT
longer than 400 days (11/13 were in women)
Lindell. Radiology 2007 242 555
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Without screening
10 y later
100
10-y survival
10
1000
With screening
10 y later
4100
10-y survival
82
Welch. Arch Intern Med 2007 167 2289
5000
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Randomized controlled trials eliminate lead-time
and lenght biases
Control group
RDZ
Screened group
Test 4e yr
Test 1e yr
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Randomized controlled trials

• They are very difficult to set up
• Contamination is a major problem
• They take a very long time to produce definitive
  results (enough time to allow for lead time and
  length biases)
• In the interval technology changes and the
  results may not be relevant when trial finally
  reports

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Lung Cancer Study a randomized controlled trial
(LDCT vs CR)
3,318 tobacco-exposed subjects

• Compliance at baseline was 96 in the LDCT arm
  and 93 in the CR arm
• At year one screening compliance was 86 in the
  LDCT arm and 80 in the CR arm

Gohagan. Chest 2004 126 114
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NLST RCT Design
CT Arm
53,476 High-Risk Subjects
Randomize
CXR Arm
time
0 1 2 3 4 5 6 7 8
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The NELSON Trial
15,428 subjects

• LDCT screened arm is beeing compared to a control
  arm without screening

Van Iersel. Int J Cancer 2007 120868
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Conclusion
Screening for lung cancer with LDCT may increase
the rate of lung cancer diagnosis and treatment,
but may not meaningfully reduce the risk of
advanced lung cancer or death from lung
cancer Until more conclusive data are available,
asymptomatic individuals should not be screened
outside of clinical research studies
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Conclusion
Randomized controlled trials are the only way to
reliably determine whether screening does more
good than harm Although expensive and
time-consuming, rigorous trials of cancer
screening are far more cost-effective than
widespread adoption of costly screening
interventions that cause more harm than good
Welch. Arch Intern Med 2007 167 2289
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Genetic abnormalities and biomarkers of
premalignancy or early malignancy
Genomic and proteomic methods may offer a much
easier mass screening as the first step of a
screening strategy

• Detection of biomarkers will have profound
  implications for more precise selection and
  stratification of population at risk for lung
  cancer

Meyerson. J Clin Oncol. 2005 233219
Zhong. Am J Respir Crit Care Med. 2005 1721308
Field. J Thorac Oncol. 2006 1497