LUNG CANCER SCREENING WHAT S THE IMPACT? Nitra Piyavisetpat, MD Department of Radiology Chulalongkorn University

LUNG CANCER SCREENING WHAT S THE IMPACT? Nitra Piyavisetpat, MD Department of Radiology Chulalongkorn 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) 120-140 120 Tube current time product (mas) Slice thickness (mm) Reconstruction interval (mm) 120-140 20-43 40 40-80 100-120 40/60 (BMI) 1-1.25 1.5 1.0-3.2 < 3 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 Moderate risk: Age > 50 Smoking > 20 pack year 2 nd hand smoke No additional risk factor Not recommend LCS 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 2009 Saghir 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 3 rd 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. Nodule at T0 Additional Nonsurgical Bx procedure Surgical 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) ITALUNG 2009 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 mm 3 (>9.8 mm) Indeterminate: 1. 50-500 mm 3 (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 2 nd round New nodule: same as baseline Positive: >500 mm 3 (>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 1 st 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% 2 nd 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 1 st year = 1 in 1000 o 2 nd 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 2003 Lindell et al. Radiology 2007

2007 2010 Lindell et al. Radiology 2007 Hasegawa et al, Br J Radiology 2000 Adenocarcinoma Mean VDT =533-746 days

Small cell lung cancer Mean VDT 49-97 days Jan 2010 Apr 2011 Lindell et al. Radiology 2007 Hasegawa 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 -ve n 44 No n 367 Total n 1060 +ve n 279 -ve n 137 No n 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 No absolute stage shift Saghir et al. Thorax2012

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 941 Negative 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 2004 by Radiological Society of North America Brenner DJ. Radiology 2004

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 Earlier detection of slow-growing tumors Earlier Diagnosis Apparent survival advantage No effect on the disease-specific mortality

Lead Time Bias A B C D Preclinical Screening +ve Lead Time Clinical Onset of disease Screening Develop S&S Death Screening Survival No screening Survival

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

Screening: Length-Time Bias 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 +ve n 649 -ve n 44 N0 n 367 Total n1060 +ve n 279 -ve n 137 N0 n 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 2003 Lindell 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 DANTE: (age > 60, exclusively men) 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) The mortality benefit from lung cancer screening far smaller than anticipated Infante et al, AJRCCM 2009

Workload Screened group: 3-folds diagnosis of lung cancer 10 folds thoracic resection Smoking ส ำน กงำนสถ ต แห งชำต พ.ศ. 2550 9,486,311 Cigarette smokers Male 9,068,002, Female 418,309 55.9% บ หร มวนเอง, บ หร ข โย 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 ล ำนบำท Follow-up CT (13.2%) 356,400 x 5000 = 1,782 ล ำนบำท Lung Biopsy: Lung resection: Pathology : 3000+ Baht 30000+ Baht 500+ Baht