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LUNG CANCER SCREENINGWHAT’S THE IMPACT?
Nitra Piyavisetpat, MDDepartment of RadiologyChulalongkorn University
Objective
LDCT lung cancer screening (LCS)
Potential Benefits & Harms
Recommendation of LCS
What’s the LDCT?
No strict definition
Usually ~ 10-30% of standard dose CT
Modification of tube current : mainstay of reduced radiation dose
Limited nodule detection in
Large patients
GGOs
What’s the LDCT Screening Protocol?
Parameter ITALUNG DLCST NLST NCCN
Voltage (kVp) 120-140 120120-140
100-120
Tube current time product (mAs)
20-43 40 40-8040/60 (BMI)
Slice thickness (mm)
1-1.25 1.5 1.0-3.2 < 3
Reconstruction interval (mm)
1-1.25 1 1-2.5 < ST
What’s the LDCT Screening Protocol?
3D & CAD application: Collimation < 1.5 mm
Scan interval 50% overlap
Nodule size measurement: affected by Slice thickness
Reconstruction algorithms
Post processing filters
Same technical parameters
National Lung Screening Trial
Randomized trial: 53,454
LDCT: 26,722
CXR: 26,732
Collaborative effort of
Lung Screening Study (LSS)
American College of Radiology Imaging Network (ACRIN)
33 participating medical institutions
Potential Benefits of Screening
National Lung Screening Trial (NLST)
20% decreased lung cancer-specific mortality
6.9% decreased all-cause mortality
The number needed to screen to prevent 1 death from CA lung = 320
Opportunity to Evaluate Other Diseases
Coronary calcium scoring
Chronic obstructive pulmonary disease (COPD)
Osteopenia/Osteoporosis
Mets et al. JAMA 2012
LUNG CANCER SCREENING
THE TIME HAS COME!
NCCN Recommendation of LCS High risk: Category 1
Age 55-74
Smoking > 30 pack year
Smoking cessation < 15 years
High risk: Category 2
Age > 50
Smoking > 20 pack year
1 additional risk factor e.g. Radon exposure, Occupational exposure, COPD, pulmonary fibrosis, cancer Hx or FH of lung cancer
NCCN Recommendation of LCS
Not recommend LCS Not recommend LCS
Moderate risk:
Age > 50
Smoking > 20 pack year
2nd hand smoke
No additional risk factor
Low risk:
Age < 50
Smoking < 20 pack year
The American Association for Thoracic Surgery (AATS) Recommendation
Age 55-79 & a 30 pack year smoking Age > 50 with
a 20 pack year smoking history 5% risk of developing a CA lung over the next 5 years
• COPD with FEV1 < 70%• Environmental & occupational exposure• Any prior cancer / thoracic radiation• A genetic or family history
Lung cancer survivors starting 5 years after treatment
Jaklitsch et al. J thorac Car diovasc Surg 2012
ACCP & ASCO Recommendation
Recommend annual LCS in Age 55-74
> 30 pack year history of smoking
Smoking cessation < 15 years
Not recommend LCS in Age < 55, > 74
< 30 pack year history of smoking
Smoking cessation > 15 years
Severe comorbidities
LUNG CANCER SCREENING
? READY
?? Benefits of Screening
DLCST: screening vs control
Lung cancer mortality: 0.73% vs 0.54%
All cause mortality: 2.97% vs 2.05%
DANTE & DLCST
No difference of lung cancer specific mortality and all-cause mortality between LDCT & usual care
Infante et al. Am J Respir Crit Care Med 2009Saghir et al. Thorax2012
Potential Harms of Lung Cancer Screening
Potential Harms of Screening
High false positive rate
Overdiagnosis
Radiation-induced cancer
Health care costs related to the entire screening process
?? Cost effectiveness
Interpretation: NLST
Positive, suspicious for lung cancer
LDCT: noncalcified nodule > 4 mm
Others: adenopathy, effusion
3rd round of screening (T2)
Stable nodule from T0 – minor abnormalities
False Positive Screening: NLST
LDCT CXR
T0 T1 T2 T0 T1 T2
Positive 7191 6901 4054 2387 1482 1174
CA lung 270 (3.8)
168 (2.4)
211 (5.2)
136 (5.7)
65 (4.4)
78 (6.6)
Positive Rate: 24.2% in LDCT, 6.9% in CXR
False positive: 96.4% in LDCT, 94.5% in CXR
False Positive in LDCT
Avr. nodule detection rate/round 20%
> 90% of positive screening led to a diagnostic evaluation
Further imaging
Invasive procedure
Significant anxiety & expense
> 90% of nodules = Benign
False Positive in LDCT
Further imaging Most often
Management protocol - inconsistent
Increased radiation dose
Invasive procedure Potential risk, particularly in
• Non-specialty care settings
• Population at highest risk i.e. those with smoking-related comorbid conditions
Source No. Noduleat T0
AdditionalNonsurgical
Bx procedureSurgical
procedure
CT PET No. Benign No. Benign
NLST 2011
26722/53454
6561 (25)
8807 (33)
1471 (5.5)
402(1.5)
293(73)
673 (2.6)
164 (24)
NELSON 2009
7557/ 15822
1570 (21)
NR 0 257 (3.4)
138 (54)
153 (2.0)
45(30)
DLCST 2009
2052/ 4104
179(9)
NR NR NR NR 25 (1.2)
8(32)
ITALUNG2009
1406/ 3206
436(30)
NR 59 (4.2)
16 (1.1)
1 (6) 16 (1.1)
1 (6)
? Reduced False Positive
Use different criteria for positive result
Larger nodule diameter
Volume measurement
NELSON: Volume measurement
Baseline scan
Positive: >500 mm3 (>9.8 mm)
Indeterminate:
1. 50-500 mm3 (4.8-9.8 mm)
2. Nonsolid nodule > 8 mm in diameter
Follow-up indeterminate nodule at 3 mo.
• Positive: VDT < 400 days
• Negative: VDT > 400 days
Van Klaveren et al. NEJM 2009
NELSON: Volume measurement
2nd round New nodule: same as baseline
• Positive: >500 mm3 (>9.8 mm)
• Indeterminate nodule: Follow-up at 6 weeks
Previously detected nodule
• Positive:
1. VDT < 400 days
2. Solid component emerging in nonsolid nodule
• Negative: No growth or VDT > 600 days
• Indeterminate: VDT 400-600 days, FU at 1 year
Van Klaveren et al. NEJM 2009
NELSON: Volume measurement
1st round
Positive: 196 (2.6%)
o 70 CA lung (FP 64%)
o 64% stage I
Sensitivity 94.6%
Specificity 98.3%
PPV 35.7%
NPV 99.9%
2nd round
Positive: 128 (1.8%)
o 57 CA lung (FP 56%)
o 73.7% stage I
Sensitivity 96.4%
Specificity 99%
PPV 42.2%
NPV 99.9%
Van Klaveren et al. NEJM 2009
NELSON: Volume measurement
need to follow-up
Chances of findings lung cancer after negative screening test in
o 3 months = 0
o 1st year = 1 in 1000
o 2nd year = 3 in 1000
Van Klaveren et al. NEJM 2009
Pitfalls in Follow-up CT
Mayo Lung Project: 4 of 48 CA lung
Smaller
Decreased in attenuation
More smoothly margin on follow-up
Should not negate follow-up
Lindell et al. Radiology 2007
Overdiagnosis
Detect indolent cancers that would
Never cause symptoms
Never be Dx in the absence of screening
Have no impact on the patients’ life expectancy if undiagnosed
Illusion of a cure
Overdiagnosis
Overdiagnosed cancers: VDT > 400 days
Would not be expected to cause death for 10 years
Mayo Lung Project:
48 lung cancer, mean VDT = 518 days
27% VDT > 400 days, 85% - female
May be substantial concern in lung cancer screening, especially in women
Yankelevitz et al. Cancer 2003Lindell et al. Radiology 2007
Adenocarcinoma
2007 2010Lindell et al. Radiology 2007
Hasegawa et al, Br J Radiology 2000
Mean VDT =533- 746 days
Small cell lung cancer
Jan 2010 Apr 2011
Mean VDT 49 -97 days
Lindell et al. Radiology 2007Hasegawa et al, Br J Radiology 2000
National Lung Screening Trial LDCT (%) CXR (%)
BAC 110 (10.5) 35 (3.8)
Adenocarcinoma 380 (36.3) 328 (35.2)
Squamous cell CA 243 (23.2) 206 (22.1)
Large-cell CA 41(3.9) 43 (4.6)
NSCLC & others 131 (12.5) 158 (17)
Small cell CA 137 (13.1) 159 (17.1)
Carcinoid 6 (0.6) 2 (0.2)
Stage Distribution: NLST LDCT CXR
Stage +ve n 649
-ven 44
Non 367
Total n 1060
+ven 279
-ven 137
Non 525
Total n 941
IA 51.8 11.4 22.7 40 32.7 11.9 17.3 21.1
IB 11.2 4.5 8.6 10 14.9 4.4 8.9 10
IIA 4.1 4.5 1.9 3.4 5.1 1.5 3.1 3.4
IIB 3.1 6.8 4.2 3.7 4 4.4 4.8 4.5
IIIA 9.3 6.8 10.2 9.5 12.7 15.6 10.2 11.7
IIIB 7.7 34.1 16.1 11.7 9.8 17.8 13.7 13.1
IV 12.8 31.8 36.3 21.7 20.7 44.4 42 36.1
Overdiagnosis
Stage LDCT Control
Early stage (I-II) 48 (70) 8 (33)
Late stage (III-IV) 21 (30) 16 (67)
Early stage in LDCT > control 6 times
No significant difference in the absolute numbers of late stage CA in both groups
Saghir et al. Thorax2012
No absolute stage shift
False Negative LDS : NLST
LDCT CXR
Positive screening 649 279
Negative screening 44 137
Missed the screening or after ended screening
367 525
Total 1060 941Negative screen: NOT preclude lung cancer development
Radiation in LDCT
Procedure VS Effective dose (mSv)
Study type Effective dose
PA chest radiograph 0.05
HRCT with 10 mm gap 0.7
Spiral CT pitch 1 7.0
Single low-dose screening 1.5*
Screening mammography 3.0
Annual natural background radiation 2.5
Mayo et al, Radiology 2003*NLST, NEJM 2011
Radiation-Induced Lung Cancer
Only important radiation-related hazard from LDCT
Single LDCT = 2.5-9 mGy to the lung
Avr. 5.2 + 0.9 mGy at setting of 60 mAs
Single baseline CT screening: risk < 0.06%
Lung cancer risk – not negligible
Brenner DJ. Radiology 2004
Estimated excess cancer mortality by age at exposure to a radiation dose of 50 mSv
Brenner DJ. Radiology 2004©2004 by Radiological Society of North America
Radiation-Induced Lung Cancer
Cumulative effects of radiation from multiple CT scans
Radiation damage & smoking damage interact synergistically
Excess risk for radiation-induced lung cancer – highest at age of 55 at exposure
Brenner DJ. Radiology 2004
Lung Cancer Risks: Women VS Men
Smoker with annual screening at 50-75 yrs
Female Male
Expected lung cancer risk 16.9% 15.8%
Estimated excess lung cancer risk
0.85% 0.23%
Increase in risk 5% 1.5%
Brenner DJ. Radiology 2004
Radiation-Induced Lung Cancer
NLST :
The estimated mean 3-year radiation exposure in the screening group = 8 mSv
1 cancer death may caused by radiation from imaging per 2500 persons screened
Occurs 10-20 years later
Benefit in preventing lung cancer death > radiation risk
Bach et al. JAMA 2012
How to Decreased Radiation-Induced Lung Cancer
Radiation dose: Change in technique
to lowest setting possible
Frequency for screening
Minimum age at screening
Brenner DJ. Radiology 2004
Conclusion: LCS
Multidisciplinary expertise in diagnostic workup & treatment
Discussing potential & harms
False positive results
Unnecessary invasive diagnostic procedure and treatments
Complication from screening
Conclusion: LCS
Overdiagnosis, esp. in women
Some lung cancers may not be amenable to detection by CT
Negative screen: not preclude lung cancer development
Conclusion
Tobacco smoke: the single most important etiologic factor in the development of lung cancer
LCS VS Smoking cessation programs : significantly more expensive
Thank You
Bias in Screening
Prospective nonrandomized trials
Lead time bias
Length time bias
Overdiagnosis bias
Randomized control trial
Sticky diagnosis bias
Slippery linkage bias
Lead-Time Bias
Apparent survival advantage
No effect on the disease-specific mortality
Earlier Diagnosis
Earlier detection of slow-growing tumors
Lead Time Bias
Onset of disease
Preclinical Clinical
Screening DevelopS&S
Death
Screening +ve
Survival
SurvivalScreening
No screening
Lead Time
A B C D
Lead-Time Bias
Eliminated by using mortality rather
than survival
I-ELCAP : (n = 31567)
Estimated 10-year lung-cancer-specific
survival rate = 80%
I-ELCAP, NEJM 2006
Length-Time Bias
Screening:
Indolent tumors - more likely to be detected
Aggressive tumors - more likely to be detected by symptoms, not by screening
Intervention in more indolent disease results in the appearance of a survival benefit
Length-Time Bias
I-ELCAP: 484 CA lung (n = 31567)
294 (60.7%) Adenocarcinoma
• 21: BAC
• 273: other subtype
Mayo Lung Project: 61 CA lung (n = 1520)
34 (55.7%) adenocarcinoma
• 9: BAC
• 25: non-BAC adenocarcinoma I-ELCAP, NEJM 2006
Lindell et al, Radiology 2007
Length-Time Bias
Bach et al : 144 CA lung (n = 3246)
67%: stage I
Majority of participants died from CA lung: not detected in an early stage
38 patients died from lung cancer
• 34% - initial stage III, IV non-small cell
• 18% - small cell lung cancer
• 16% - no documented Dx of CA lung prior death
Bach et al. JAMA 2007
Biases Related Disease-Specific Mortality
Disease-specific mortality :
Most widely accepted end point
Fundamental assumption: accurately determine cause of death
Biases related disease-specific mortality
Sticky-diagnosis bias
Slippery linkage bias
Black WC et al. J Natl Cancer Inst 2002
Sticky Diagnosis Bias
Screened gr.: Wrongly attributed deaths from other causes to the target cancer
Control gr.: Wrongly attributed to death from target cancer to other causes
Disease-specific mortality in the screened group
This bias favors the control group
Black WC et al. J Natl Cancer Inst 2002
Slippery Linkage Bias
Deaths from screening-related intervention or treatment falsely attributed to other causes
disease-specific mortality in the screened group
This bias favors the screened group
Black WC. Cancer 2007
Biases affecting disease-specific mortality
Black WC et al. J Natl Cancer Inst 2002
Biases Affecting Disease-Specific Mortality
Net effect of biases: favor screening
Slippery linkage more important than sticky diagnosis
Screening could cause death as well as to prevent it
All-cause mortality: not affected by these biases
Participants
Inclusion: Age 55-74 years Smoking 30 pack-years Ex-smoker – quit within 15 years
Exclusion: Recent hemoptysis Unexplained weight loss > 6.8 kg in
preceding year Previous diagnosed of lung cancer Underwent chest CT within 18 months
Duration
Screening from Aug 2002-Sep 2007
LDCT: 26,722
CXR: 26,732
annual screens: T0, T1 and T2
Follow-up through Dec 31, 2009
Median 6.5 years
Maximum 7.4 years
Results: Positive screening test LDCT CXR
T0 27.3% 9.2%
T1 27.9% 6.2%
T2 16.8% 5.0%
Total in 3 rounds 24.2% 6.9%
> 1 positive in any rounds 39.1% 16.0%
Clinically sig. abnormality other than lung cancer
7.5% 2.1%
Lung Cancer in each Round LDCT CXR
+ve CA lung (%) +ve CA lung (%)
T0 7191 270 (3.8) 2387 136 (5.7)
T1 6901 168 (2.4) 1482 65 (4.4)
T2 4054 211 (5.2) 1174 78 (6.6)
Total 18146 649 (3.6) 5043 279 (5.5)
Histology Type of Lung Cancer LDCT CXR
+ven 649
-ven 44
N0 n 367
Total n1060
+ven 279
-ven 137
N0n 525
Total n 941
BAC 14.7 2.3 3.9 10.5 4.7 0.7 4.0 3.8
AdenoCA 39.9 18.2 31.8 36.3 40.6 27.4 34.4 35.2
Squamous 21.1 29.5 26.3 23.2 25.4 17.8 21.5 22.1
Large cell 4.3 6.8 2.8 3.9 4.3 7.4 4.0 4.6
NSCLC* 11.6 9.1 14.5 12.5 14.5 22.2 16.9 17
Small cell 7.6 34.1 20.4 13.1 10.1 23.7 19.0 17
Carcinoid 0.8 0 0.3 0.6 0.4 0.7 0 0.2
Complication LDCT CXR
At least 1 complication 1.4% 1.6%
Major complication
non lung cancer 0.06% 0.02%
lung cancer 11.2% 8.2%
Death w/i 60 days after invasive Dx procedure
non lung cancer 6 0
lung cancer 10 10
Lung-Cancer-Specific Mortality
20% decrease in mortality in LDCT LDCT:
• 437 deaths
• 247 deaths per 100,000 person-years
CXR• 503 deaths
• 309 deaths per 100,000 person-years
The number needed to screen to prevent one death from CA lung = 320
Lung Cancer VS All-Cause Mortality
20% decrease in mortality in LDCT
LDCT: 437 deaths
CXR: 503 deaths
6.9% reduction in all-cause mortality
LDCT: 1877 deaths
CXR: 2000 deaths
LDCT in Lung Cancer Screening
Many questions ?
Optimal risk populations
Screening frequency & duration
Criteria for positive results
Cost-effectiveness of LDCT screening
Benefits-Harms (FP, overdiagnosis, cost)
California Technology Assessment Forum (CTAF)
Use of LDCT screening cannot currently be recommended outside of the investigational setting
The National Comprehensive Cancer Network (NCCN)
Strongly recommend regular annual
LDCT for heavy smoker 55-74 years of age
Result of 3 Rounds of Screening Much higher rate of positive screening test in LDCT
Histology Type of Lung Cancer LDCT CXR
BAC 110 35
AdenoCA 380 328
Squamous cell CA 243 206
Large cell CA 41 43
NSCLC 131 158
Small cell CA 137 159
Carcinoid 6 2
Unknown 12 10
Overdiagnosis
Overdiagnosed cancers: VDT > 400 days
Mayo Lung Project:
48 lung cancer, mean VDT = 518 days
27% VDT > 400 days; 85% - female
• Would not be expected to cause death for 10
years
Yankelevitz et al. Cancer 2003Lindell et al. Radiology 2007
Overdiagnosis
May be substantial concern in lung
cancer screening, especially in women
May account for the improved survival
rate without improved mortality rate
Lindell et al. Radiology 2007
Overall Mortality
6.7% decrease in mortality in LDCT
LDCT: 1877 deaths
CXR: 2000 deaths
3.2% decreased in mortality in LDCT if excluded death from CA lung
All-Cause Mortality
LDCT (n = 1,276)(%)
Control (n = 1,196)(%)
Lung cancer death 20 (1.6) 20 (1.7)
Other causes 26 (2.0) 25 (2.1)
Total deaths 46 (3.6) 45 (3.8)
Infante et al, AJRCCM 2009
DANTE: (age > 60, exclusively men)
The mortality benefit from lung cancer screening –far smaller than anticipated
Workload
Screened group: 3-folds – diagnosis of lung cancer
10 folds – thoracic resection
Smoking ส ำนกังำนสถติแิหง่ชำตพิ.ศ. 2550
9,486,311 Cigarette smokers• Male 9,068,002 , Female 418,309
• 55.9% บุหรีม่วนเอง, บุหรีข่ีโ้ย
• 2,701,565 คน, Age > 50 years
Bach et al. JAMA 2007
Expected Workload
2,701,565 Cigarette smokers age > 50
120 Thoracic surgeons in Thailand
22500 / surgeon
Expense in Thailand
CT 5000 Baht Screening CT:
• 2,700,000 x 5000 = 13,500 ลำ้นบำท Follow-up CT (13.2%)
• 356,400 x 5000 = 1,782 ลำ้นบำท
Lung Biopsy: 3000+ Baht
Lung resection: 30000+ Baht
Pathology : 500+ Baht
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