LUNG CANCER SCREENINGmedinfo2.psu.ac.th/pr/chest2012/file/Doc/Nitra.Doc_Lung... · 2012-10-25 · The American Association for Thoracic Surgery (AATS) Recommendation Age 55-79 & a

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


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


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


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



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%



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


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


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


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%



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


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


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


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


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


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

Documents

LUNG CANCER SCREENINGmedinfo2.psu.ac.th/pr/chest2012/file/Doc/Nitra.Doc_Lung... · 2012-10-25 · The American Association for Thoracic Surgery (AATS) Recommendation Age 55-79 & a