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Goals of Presentation Review context of lung cancer screening why is it important? Review data from NLST supporting screening with lowdose CT (LDCT) scanning Discuss the pros and cons of LDCT screening and current guidelines Review the components of a lung cancer screening program

Cancer Screening Fundamental principle: detection of cancer at an early, asymptomatic stage will result in more effective treatment and reduced cancer-specific mortality Ideal screening program Target high risk individuals Use a cost-effective test Exclude individuals without clinically significant abnormalities

Lung Cancer Epidemiology 14% of all US cancers Leading cause of cancer-related mortality 1.4 million annual deaths worldwide 160,000 annual deaths in U.S. 27% of all cancer deaths Exceeds deaths due to colorectal, breast, prostate and pancreatic cancers combined Lung cancer among never-smokers would be the 6 th -8 th most common cause of cancer mortality Seigel R, CA J Clinicians 2014; 64: 9

Lung Cancer in Wisconsin 4020 estimated cases 2014 3000 estimated deaths 2014 192-257 cases annually seen at Marshfield Clinic

Lung Cancer Risk Factors Environmental factors Tobacco smoking 85-90% of lung cancers occur in smokers Relative risk 20-30x Radon 222 exposure Indoor cook stoves Other exposures (e.g. asbestos, silica, arsenic) Diet? Host factors Family history Specific genetic polymorphisms or mutations Chronic lung disease

Effect of Smoking Cessation on Lung Cancer Incidence Smoking Status Risk Ratio Men Women Current Smoker 1.00 1.00 Quit < 10 years 0.66 0.69 Quit 10-19 years 0.44 0.21 Quit 20-29 years 0.20 0.05 1 > 30 years 0.10 Never-smoker 0.03 0.05 1 For women > 20 years Peto R, et al BMJ 2000; 321: 323-9

NSCLC Prognosis Stage Frequency 5 Year Survival (%) 0 NA 100 IA 75 10 IB 55 IIA 50 20 IIB 40 IIIA 15-35 30 IIIB 5-10 IV 40 5-10

Lung Cancer Screening Until 2010, no evidence existed for a mortality benefit from screening with chest x-ray, lung CT scanning or sputum cytology October 2010 results of the National Lung Screening Trial (NLST) initially announced followed by a full report published online June 29, 2011 and in print August 2011

National Lung Screening Trial (NLST) Randomized, controlled trial comparing low dose CT scans (LDCT) to chest radiograph (CXR) annually for 3 years in high risk population Powered to detect 20% reduction in lung cancer- specific mortality 55,434 randomized (2520 @ Marshfield Clinic) Screening conducted at 33 sites in US 2002-2007 NLST Research Team, NEJM 2011; 365: 395

National Lung Screening Trial (NLST) Eligibility and Exclusions Eligibility Age 55-74 years 30 pack-years smoking history Former smokers quit 15 years Exclusions Previous lung cancer diagnosis Chest CT within 18 months Hemoptysis Unexplained weight loss >15 lbs. NLST Research Team, NEJM 2011; 365: 395

Positive LDCT Screen in NLST Non-calcified nodule > 4 mm (97.6% of positives) Adenopathy Pleural effusion Consolidation, atelectasis

NLST Results Screen positivity T0 27.3% T1 27.9% T2 16.8% False positivity 96.4% of positive screens are false + Of all LDCTs, 23.3% false +

NLST Results With median follow-up 6.5 years, cancer deaths LDCT 247 CXR 309 20% mortality reduction 13% excess of lung cancers in LDCT arm possible overdiagnosis 63% of cancers in LDCT arm stage IA-IB Number needed to screen to prevent 1 death=320 NLST Research Team, NEJM 2011; 365: 395

NLST Lung Cancer Mortality?Overdiagnosis NLST Research Team, NEJM 2011; 365: 395

Complications in NLST Complications a LDCT (%) CXR (%) Total 1.4 1.6 Patients without lung ca 0.06 0.02 Patient with lung ca 11.2 8.2 Death within 60 days of procedure 1.5 3.9 a Major: respiratory failure, anaphylaxis, cardiac arrest, BP fistula, MI, CVA, hemothorax, empyema, thromboembolism, brachial plexopathy Intermediate: blood loss, fever, infection, pain, arrhythmia, vocal cord injury or paralysis, pneumothorax Minor: allergic reaction, bronchospasm, vasovagal reaction, subcutaneous emphysema, ileus

Lung Cancer Screening NLST cited as 1 of 10 most important advances in 2011 Estimated potential to save 30,000 lives annually in US

LDCT Lung Cancer Screening Pros and Cons PROS Reduced lung cancer mortality Teachable moment for smoking cessation CONS False + LDCT, resulting in: Anxiety, stress Unnecessary testing Overdiagnosis Morbidity and mortality from diagnostic evaluations Radiation exposure and risk of 2 nd malignancy False examinations Cost to healthcare system

Overdiagnosis Detection of cancer (usually through screening) that would not otherwise have become apparent during the individual s lifetime Results in unnecessary treatment, morbidity, cost, anxiety and labeling of patient with diagnosis Occurs in all forms of cancer screening

Overdiagnosis in LDCT Screening Estimates of overdiagnosis rate NLST 18-22% (comparison of screened to control arm) COSMOS 25% (based on volume doubling time) Implications These are probably maximum estimates based on 3-7 years follow-up Overdiagnosed cancers predominantly indolent A high proportion of overdiagnosed lung cancers are broncho-alveolar (lepidic growth) carcinomas

LDCT Screening Radiation Risk Radiation exposure LDCT Screening exam (non-contrast) 1.5 msv (comparable to 6 months normal background radiation) Diagnostic chest CT 7 msv (2 years background radiation) Radiation-induced lung cancer risk Individual 0.2-1.0% estimated risk Population estimates 1.8% increase in lung cancers, if 50% of eligible patients are screened over 25 years (Brenner DJ) 3-6 cases/100,000 screened patients over 15-20 years (International Commission on Radiologic Protection) 11.7-20.5 fatal lung cancers/100,000 screened (Italung-CT Trial) Conclusion: there is some increased individual risk and greater population risk, but benefits of screening outweigh this risk

LDCT Screening Recommendations 2014 Organization 1 0 Population Other Considerations USPSTF (2013) AATS (2012) ASCO-ACCP (2012) ACS (2013) NCCN (2011) Age 55-80 a + >30 packyears; quit <15 years Age 55-79 + >30 packyears Age 55-74 + >30 packyears; quit <15 years c Age 55-74 + >30 packyears; quit <15 years c Age 55-74 + >30 packyears; quit <15 years c NA Age>50+ 20 pack-years + additional risk factor b ; or lung ca survivor >5 years NA NA Age >50 + 20 pack years + additional risk factor d a Based on modeling predictions b COPD, environmental or occupation exposure, prior cancer, thoracic RT, genetic or family history c NLST eligibility criteria d cancer history, lung disease, family history of lung ca, radon or occupational exposure

USPSTF Recommendations

Lung Cancer Screening Coverage ACA requires private insurance coverage without costsharing for USPSTF A or B recommendations CMS coverage decisions are independent of ACA requirement

LDCT Lung Cancer Screening CMS (Medicare) Coverage Medicare Evidence Development and Advisory Committee (MEDCAC) recommended against approval 4-30-14, based on Complications of screening Radiation exposure Uncertainty about benefit of screening in Medicare-aged population

NLST Results by Age Parameter 65+ <65 PPV 4.9% 3.0% Screen-detected cancer 394/10 4 188/10 4 Lung cancer resection Overall 73.2% 75.6 Stage I 93.0% 96.9% Surgical mortality 1.0% 1.8% False + 27.7% 22.0% Invasive procedures after false+ 3.3% 2.7% 5-year all cause survival 55.1% 64.1% NNTS to prevent 1 death 245 364 Pinsky PF, et al Ann Int Med 2014; 161: 627-33

NLST Results by Age LDCT screening is more efficient in the 65+ age group (but no data on patients >76 years old at time of screening) Higher false + rate in 65+ group Higher rate of invasive diagnostic procedures in 65+ group, but equivalent ratio of invasive procedures to lung cancer deaths averted (5.9) in both age groups Both age groups had comparably high rates of surgical resection and low surgical mortality; this may in part reflect a healthy volunteer effect Pinsky PF, et al Ann Int Med 2014; 161: 627-33

NLST and Age Take Home Message... LDCT screening seems to involve similar tradeoffs for persons who meet NLST eligibility criteria in both the older and younger age groups. Until there is new and direct evidence to the contrary, it does not seem reasonable to exclude persons aged 65 to 74 years from access to screening. Gould MK, Ann Int Med 2014; 161: 672-3

LDCT Lung Cancer Screening CMS (Medicare) Coverage CMS approval 2-5-15... evidence is sufficient to add a lung cancer screening counseling and shared decision making visit, and for appropriate beneficiaries, annual screening for lung cancer with low dose computed tomography (LDCT), as an additional preventive service benefit under the Medicare program...

LDCT Screening Cost-Effectiveness Incremental cost-effectiveness ratios $52,000/life-year gained $81,000/quality life-year gained Higher cost-effectiveness Women Higher risk individuals Current vs former smokers Older age Estimates vary with assumptions Adding smoking cessation program improves costeffectiveness estimates Black WC, et al NEJM 2014; 371: 1793-802

Standard fee $250 LDCT Screening Cost Marshfield Clinic Covered by WI Medicare and Medicaid Commercial coverage variable Much of the total screening-related cost results from diagnostic evaluation of positive LDCTs

How Can We Improve Efficiency and Effectiveness of LDCT Screening? Improve selection criteria by refined risk prediction models PLCO M2012 (Tammemagi MC, et al NEJM 2013) Liverpool Lung Project Risk Model (Raji OY, et al Ann Int Med 2012) Use of modified criteria for positive scans e.g. Lung- RADS (Pinsky PF, Ann Int Med 2015)

Targeting LDCT Screening by Risk of Lung Cancer Death 5 year lung cancer death risk quintiles Q5 > 2.00% Q4 1.24-2.00% Q3 0.85-1.23% Q2 0.56-0.84% Q1 0.15-0.55% Kovalchik SA, et al NEJM 2013; 369: 245-54

PLCO M2012 Modified logistic regression prediction model for lung cancer risk Model variables: age, race, education, BMI, COPD, history of cancer, family history of lung cancer, smoking status, smoking intensity, duration of smoking, smoking quit time

Selection Criteria NLST vs PLCO M2012 Tammemagi MC, et al NEJM 2013; 368: 728-36

How Can We Improve Efficiency and Effectiveness of LDCT Screening? Improve selection criteria by refined risk prediction models PLCO M2012 (Tammemagi MC, et al NEJM 2013) Liverpool Lung Project Risk Model (Raji OY, et al Ann Int Med 2012) Use of modified criteria for scan assessment e.g. Lung- RADS (Pinsky PF, Ann Int Med 2015)

Lung-RADS Nodule Surveillance http://www.acr.org/~/media/acr/documents/pdf/qualitysafety/resources/lungrads/assessmentcategories.pdf

Application of Lung-RADS to NLST Parameter Baseline (%) After Baseline (%) Lung- Rads NLST Lung-Rads NLST Sensitivity 84.9 93.5 78.6 93.8 False + 12.8 26.6 5.3 21.8 PPV 6.9 3.8 11.0 3.5 NPV 99.81 99.90 99.81 99.93 Retrospective application of Lung- RADS criteria to NLST 75% reduction in false + Uncertain impact of sensitivity on lung cancer mortality Pinsky PF, et al Ann Int Med 2015

Goals of Presentation Review context of lung cancer screening why is it important? Review data from NLST supporting screening with lowdose CT (LDCT) scanning Discuss the pros and cons of LDCT screening Review the components of a lung cancer screening program

Implementation of LDCT Screening Program American College of Chest Physicians and American Thoracic Society issued policy statement October 2014 Nine essential components of LDCT screening program Mazzone PJ, et al Chest 2014

ACCP/ATS Principles for High-Quality Lung Cancer Screening Programs Use of existing guidelines such as USPSTF to determine who to screen, how frequently and how long Use of ACR-STR specifications for performance of LDCT Use of consistent definition of positive LDCT exam Use of structured reporting system, such as Lung-RADS Availability of multi-disciplinary clinical team for management of lung nodules and lung cancers Use of evidence-based nodule management algorithms Mazzone PJ, et al Chest 2014

ACCP/ATS Principles for High-Quality Lung Cancer Screening Programs-2 Inclusion of smoking cessation program with screening Standardized communication to referring provider and patient Patient and provider education programs are part of screening program Data collection (nodules, cancers, complications) Support for research into all aspects of lung cancer screening Development of multi-society/multi-disciplinary oversight and credentialing body Mazzone PJ, et al Chest 2014

LDCT Screening Many Questions Remain Who should be screened (what are optimal selection criteria)? How frequently should screening occur? When should screening begin, and how long should screening continue? What are the health risks of LDCT screening, including radiation exposure? Can LDCT be combined with biomarker studies to improve effectiveness?

Future Role of Biomarkers Currently no established role in screening In the future will likely be helpful Risk models Screening

Summary Lung cancer is the #1 cause of cancer mortality Data from NLST demonstrate a 20% mortality reduction from LDCT screening of high-risk population In appropriate populations, the benefits of screening outweigh the harms LDCT screening now covered by CMS and most insurers Implementation of an effective screening program is complex and requires multi-disciplinary collaboration, organization, data collection, quality improvement There remain many unanswered questions that can be addressed by continued data collection and research WCC should support and monitor development of high-quality lung cancer screening programs in Wisconsin

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