PUBH 5409 - Lung Cancer Screening

Andrea Borondy Kitts@findlungcancer

April 30, 2015

Agenda• What is Lung Cancer • Natural History and Treatment • Lung Cancer Statistics • Lung Cancer Risk Factors • National Lung Screening Trial (NLST) Design and Results• NLST Follow-on Analysis• Lung Cancer Screening Class Evaluation

– Good Disease for Screening?– Good Screening Test?

• USPSTF and CMS Recommendations• Challenges• Summary04/15/2023 2

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Lung Cancer is a Non-Infectious Chronic Disease

http://www.nccn.org/patients/guidelines/nscl/index.html#8

Most are carcinomas and initiate in the lining of the airways

• Bronchi• Bronchiole• Alveoli

Today’s smokers are more likely to develop lung cancer than smokers 50 years ago.

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87% Non-Small Cell Lung Cancer (NSCLC); 13% Small Cell Lung Cancer (SCLC) Histology

Molecular Challenges in Lung CancerBen Leach Published Online: December 17, 2012http://www.targetedonc.com/publications/targeted-therapy-news/2012/November-2012/Molecular-Challenges-in-Lung-Cancer

NSCLC further characterized histologically into:

• Adenocarcinoma• Squamous Cell• Large Cell

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Natural History of Lung Cancer

DNA damage to cells

Abnormal cell

growth

Lesion

Pathologica

l Evidence

Metastasi

s

Diagnosis

Treatment

Death

Damage accumulates with age and exposure to agents e.g. tobacco. Average age of diagnosis is 70

Few symptoms in early stages

Screening test (LDCT) not generally available until 2015

Approximately 80% of diagnoses at a late stage

Early stage – Surgery and possible adjuvant chemo/radiation

Late stage – palliative and life extension

CTPET/CTBiopsyMRIStaging

5 year survival 16.8%Localized – 54%Distant – 4%

http://seer.cancer.gov/statfacts/html/lungb.html

http://www.nccn.org/patients/guidelines/nscl/index.html

Surgical Treatment in Early Stages; Systematic Treatment in Late Stages

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Surgical Options include wedge resection, lobectomy, bilobectomy, and pneumonectomy via traditional, minimally invasive (VATS) or robotic surgery • sometimes preceded by, or followed

with, adjuvant chemotherapy and/or radiation

Systematic treatments include chemotherapy, radiation, targeted molecular treatments, and immunotherapy

• Approximately 67% of NSCLC have an identified genetic mutation

http://www.onclive.com/publications/Oncology-live/2013/January-2013/Targeting-Tumors-Early-Trials-Push-Novel-Agents-to-Forefront/2

Lung Cancer is the 2nd Leading Cause of Death in the US

• Lung cancer is the leading cause of cancer deaths in both men and women in the US– 160,000 die each year, more than

breast, colon, prostate and pancreatic cancer combined

– 5 year survival at 16.8% essentially unchanged since 1975

• Most common cancer worldwide – 1.6 million deaths in 2012

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Lung Cancer Incidence and Mortality Rates Decreasing in the US

04/15/2023 10http://seer.cancer.gov/statfacts/html/lungb.html

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Overall Lung Cancer Incidence in US is 60.1 cases per 100,000; Highest in African American Men at 93.0 per 100,000

http://seer.cancer.gov/statfacts/html/lungb.html

Average age at diagnosis 70

Annual Productivity Loss due to Cancer Lung Cancer Leads with $36 Billion

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Over 80% of Lung Cancers are caused by Tobacco

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U.S. Department of Health and Human Services. (2014). The Health Consequences of Smoking – 50 Years of Progress A Report of the Surgeon General. Retrieved from http://www.surgeongeneral.gov/library/reports/50-years-of-progress/50-years-of-progress-by-section.html

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Risk of Lung Cancer Increases with Age and Dose Tobacco Use

© 2014 Free to Breathe

Other than smoking, what else can cause lung cancer?- Secondhand exposure to smoke- Radon- Having had smoking related cancer - Family History- Environmental pollutants (pollution, dust,

asbestos)- COPD or Pulmonary Fibrosis

Lung Cancer Risk

© 2014 Free to Breathe

• Lung Cancer Risk

94 Million Current and Former Smokers in the US

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Stigma due to Strong Link with SmokingAdverse Impacts on Depressive Symptoms, Quality of Life and Physical

Symptoms

People with lung cancer blamed and/or blame themselves for their diseasehttp://cancergeek.wordpress.com/2013/11/16/cancer-the-harsh-story-of-lung-cancer-vs-breast-cancer/

Stage IV NSCLC

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<1% = 5 year OS

80% of Lung Cancers Diagnosed after the Cancer has Spread When Chance of Cure Small

Annual Low Dose CT Scan Screening Finds Lung Cancer Early When Chance for Cure High

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92% 5-year Overall Survival

Stage T1AN0

Goldstraw P, Crowley J, Chansky K, et al. (2007) The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706–714.

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Smoking Dose and Time Since Quit Key Considerations for Screening Program Design

Tammemagi MC, Katkiha HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med. 2013;368(8):728-236 DOI: 10.1056/NEJMoa1211776

Tammemagi MC, Church TR, Hocking WG, et al. Evaluation of the lung cancer risks at which to screen ever-and never-smokers: Screening rules applied to the PLCO and NLST cohorts. PLoS Medicine 2014;11(12):e1001764. doi:10.1371/journalpmed1001764.

National Lung Screening Trial Design Overview

• 53,456 participants– LDCT scan

or– CXR

• Enrolled 2002 – 2004• 3 Annual Screenings

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National Lung Screening Trial Research Team (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365(5):395–409.

National Screening Trial Results

The National Lung Screening Trial Research Team . N Engl J Med 2011;365:395-409.

More Lung Cancers found in LDCT Arm• Total Cases

• LDCT 1060 • CXR 941

• Cases per 100k person years• LDCT 645 • CXR 572

Difference primarily early stage disease More Lung Cancer Deaths in CXR Arm• Total Deaths

• LDCT 356 • CXR 443

• Deaths per 100k person years• LDCT 247• CXR 309

20% Reduction in lung cancermortality with LDCT 6.7% Reduction in all cause mortality

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NLST Low Dose CT (LDCT) Lung Cancer Screening Efficacy

Prevalence = 1 percent (Initial Screen)Incidence = 0.8 (Following Annual Screens)

For initial screen Sensitivity =93.5 (90.7-96.3)* Specificity = 73.4 (72.9-73.9)False Positives = 26.60 (26.10-27.10)PPV = 3.80 (3.30 – 4.20)NPV = 99.90 (99.86-99.94)NNS = 320

Incidental Findings not suspicious for lung cancer – 7.5%*Numbers in parentheses 95% Confidence Intervals

NLST False Positive Invasive Procedure Tracking

• False positives (Lung Cancer Not Confirmed) (17053)• Number with:

• No invasive procedure (16596) (97.3%)• Thoracotomy, thoraoscopy, or mediastinoscopy (164) (0.96%)• Bronchoscopy (227) (1.33%)• Needle Biopsy (66) (0.39%)• Total invasive – (457) (2.68%)

• Positives with lung cancer confirmed (649) • No invasive procedure (31) (4.77%)• Thoracotomy, thoraoscopy, or mediastinoscopy (509) (78.43%)• Bronchoscopy (76) (11.71%)• Needle Biopsy (33) (5.08%)• Total invasive – (649) (95.22%)

• Also track complications by procedure and classify as: • Minor• Intermediate• Major

Complications after the Most Invasive Screening-Related Diagnostic Evaluation Procedure, According to Lung-Cancer Status.

The National Lung Screening Trial Research Team . N Engl J Med 2011;365:395-409.

Complications Resulting From False Positives in NLST

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Reverted to cancers being diagnosed at late stage once screening stopped

The National Lung Screening Trial Research Team . N Engl J Med 2011;365:395-409.

Radiation Exposure LDCT <1 mSv Years of annual lung

screening

Mammogram .7 mSv

Lumbar Spine Films 2 mSv 2

Diagnostic Chest CT 10 mSv 10

Triphasic CT AB/P 25 mSv 25

Background Exposure Colorado

3 mSv/year4.5 mSv/year

34.5

Occupational Exposure 50 mSv/year 50

Transatlantic Flight .1 mSv 7 flights = 1 LDCT

10 -30 year latency period to develop secondary malignancies from exposure

Average age of patients in screening trials is 62

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An Actuarial Analysis Shows That Offering Lung Cancer Screening As An Insurance Benefit Would Save Lives At

Relatively Low Cost

• Cost per life-year saved would be below $19,000 (ages 50-64)

Pyenson et al, Health Affairs 31, No.4 770-779: April 2012

Adding Smoking Cessation Estimated to Increase QALY and Lower Cost of Screening by 20 to 45%

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NLST Lung Cancer Screening Cost Effectiveness Analysis $81,000 per QALY

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Black WC et al. N Engl J Med 2014;371:1793-1802

Lung Cancer Screening Cost Effectiveness in Medicare Population

$18,452 per QALY

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Lifetime Overdiagnosis for NSCLC (excluding BAC) with LDCT screening estimated at approximately 3%

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Patz EF, Jr, Pinsky P, Gatsonis C, et al. Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer. JAMA Intern Med. 2014;174(2):269-274. doi:10.1001/jamainternmed.2013.12738.

Is Lung Cancer a “Good” Disease for a Screening Test?

• Is Disease important to Public Health?– Leading cause of cancer deaths – 450 a day– High Mortality; 5 year survival 16.7%– 93 million current and former smokers in US;

about 10 million in high risk group – Estimate potential to save 20,000 lives per year – $36 billion annual lost productivity

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Is Lung Cancer a “Good” Disease for a Screening Test?

• Is there a Long Asymptomatic Period– Annual screening shown to be effective for NSCLC

• Is There an Effective Intervention?– If Caught Early Surgery, SBRT and adjuvant

chemotherapy and radiation results in 92% 5 year survival

– Cost per QALY comparable to other screening tests• 18,000 – 81,000 (threshold $100,000 per QALY)

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Is LDCT a Good Screening Test for Lung Cancer? • Is test effective in correctly identifying those with and without disease? • Find cases (rule in) or find healthy people (rule out)

– Rule in – SPIN – High Specificity – Sensitivity 93.5%– Specificity 73.4% - high false positive rate – Follow-up over 95% not invasive – mainly imaging– Screening high risk population

• Is Test Low Cost?– CT scan fully clothed, No IV, 10 sec breath hold, 15 minutes total– Annual screen frequency– Current Medicare reimbursement to provider approx. $250 per scan– No-copay for participant– Anxiety due to false positive– Radiation exposure– Overdiagnosis estimated at 3% for lifetime

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Is LDCT a Good Screening Test for Lung Cancer? • Reliably reproduce results in many locations?

– NLST 33 screening locations, most major academic or medical centers

– Lahey Hospital & Medical Center matched NLST results in clinical application

– American College of Radiology (ACR) accreditation program, MeVis radiologist training, LungRADS structured reporting criteria

– Multidisciplinary follow-up may be challenging for some locations

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Annual Lung Cancer Screening Recommended For the High Risk Population

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Covered by Insurance and Medicare without a Co-Pay Age 55 to 80 (age 77 for Medicare)

Smoking History 30 pack years or more• 1 pack a day for 30 years/2 packs per day for 15 years etc.

Current or Former Smoker Quit within the last 15 years

Asymptomatic

Low Dose CT scan15 minutes, 10 second breath holdNo IVDon’t need to change

Additional CMS Requirements for Lung Cancer Screening

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• Lung cancer screening counseling and shared decision making dedicated visit prior to initial screen with physician or qualified non-physician practitioner • Use of one or more decision aids

• Benefits and harms of screening• Follow-up diagnostic testing • Over-diagnosis• False positive rate• Total radiation exposure

• Counseling on• Importance of adherence to annual lung cancer LDCT screening • Impact of comorbidities• Ability or willingness to undergo diagnosis and treatment• Importance of maintaining cigarette smoking abstinence if former

smoker• Importance of smoking cessation if current smoker • Furnishing of information about tobacco cessation interventions

Elements of shared decision making• Understands the risk or seriousness of the

disease or condition• Understands the preventive service, including

the risks, benefits, alternatives and uncertainties• Have weighed his/her values regarding the

potential harms and benefits associated with the service

• Have engaged in decision-making at a level he or she desires and feels comfortable

Sheridan SL, Harris RP, Woolf SH. Shared Decision making about screening and chemoprevention, a suggested approach from the U.S. Preventive Services Task Force. American journal of preventive medicine. 2004;26(1):55-56

Additional CMS Requirements for Lung Cancer Screening

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• Radiology imaging facility eligibility criteria:

• Performs LDCT with volumetric CT dose index (CTDIvol) of ≤ 3.0 mGy (milligray) for standard size patients (defined to be 5’ 7” and approximately 155 pounds) with appropriate reductions in CTDIvol for smaller patients and appropriate increases in CTDIvol for larger patients

• Utilizes a standardized lung nodule identification, classification and reporting system

• Makes available smoking cessation interventions for current smokers

• Collects and submits data to a CMS-approved registry for each LDCT lung cancer screening performed.

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LUNG RADS – Lung Cancer Screening Reporting and Classification System

Lung Number Category• Category 1: Negative• Category 2: Negative with

benign pulmonary findings • Category 3: Positive/likely

benign • Category 4: Positive/suspicious

for malignancy• Category 5: Known cancer

“S” Category

• Positive for extra-pulmonary finding not suspicious for lung cancer but requiring clinical follow-up– Thyroid mass– Aneurysm– Kidney Mass

Additional CMS Requirements for Lung Cancer Screening

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• Reading radiologist eligibility criteria:

• Board certification or board eligibility with the American Board of Radiology or equivalent organization

• Documented training in diagnostic radiology and radiation safety

• Involvement in the supervision and interpretation of at least 300 chest computed tomography acquisitions in the past 3 years

• Documented participation in continuing medical education in accordance with current American College of Radiology standards

• Furnish lung cancer screening with LDCT in a radiology imaging

facility that meets the radiology imaging facility eligibility criteria below.

On the Horizon

2.Pinsky PF, Gierada DS, Black W, et al. Performance of Lung-RADS in the National Lung Screening Trial A retrospective assessment. Ann Intern Med Published on-line 10 Feb 2015

1. Brady J. McKee, Shawn M. Regis, Andrea B. McKee, Sebastian Flacke, Christoph Wald, Performance of ACR Lung-RADS in a Clinical CT Lung Screening

Program, Journal of the American College of Radiology, Volume 12, Issue 3, March 2015, Pages 273-276, ISSN 1546-1440, http://dx.doi.org/10.1016/j.jacr.2014.08.004.

(http://www.sciencedirect.com/science/article/pii/S1546144014004736)44

• Change in Criteria for Positive Findings predicted to reduce false positives to approximately 10% • Lahey retrospective analysis of 2180 LDCT scans using “ACR

LungRADS” showed 2.5X increase in PPV with no change in sensitivity (single screening site - re-analysis done by same team as original analysis) (1)

• Retrospective analysis of NLST data showed reduction of false positives with ACR LungRADS from 26.6% to 12.8%, however sensitivity decreased from 93.5% to 84.9% (33 screening sites, no standard protocol- re-analysis by NLST team not site radiologists) (2)

• Studies on effective smoking interventions for lung cancer screening population

• Georgetown/Lahey/Hartford Hospital et al. PCORI proposal RCT telephone counseling

• Studies to date show 2 to 3X population smoking cessation rates in lung cancer screening programs

Challenges

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• Participation – getting the word out to physicians and the population at risk

• Multidisciplinary follow-up positive findings including incidental findings

• Separate Shared Decision Making (SDM) Visit• Effective Aids to help Physicians with Discussion and

Counseling Session• Access for all to Physicians for SDM visit

• Radiololgist Training • MeVis Education Tool has 125 scan module with test

• Site Suitability • ACR Accreditation program• Lung Cancer Alliance (LCA) Centers of Excellence

• Screening high risk folks not meeting screening criteria

Recent Study Shows Only 1/3 of 1855 Operable Lung Cancer Patients Met Screening Criteria

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AATS Abstract presented 4/29/2015 Proportion of Newly Diagnosed Non-Small Cell Lung Cancer Patients That Would Have Been Eligible for Lung Cancer ScreeningGeena Wu1, Leanne Goldstein2, Jae Y. Kim1, Dan J. Raz1 1City of Hope National Medical Center, Duarte, CA;2City of Hope National Medical Center, Duarte, CA

• More than 10 million Americans in the recommended population to

screen• Estimated to save more than 20,000 lives a year• Additional benefit for smoking cessation

– Published smoking cessation rates in lung cancer screening trials and studies show 2 to 3 times the cessation rate as compared to the general population (11 to 22% vs 5 to 7%)

"This has the biggest impact on lung cancer that we have ever seen in our lifetime," he said. "This will do more to save lives than anything else we have done to date in lung cancer, from a clinical perspective.”

Reginald Munden, MDMD Anderson Cancer Center in Houston Principal site investigator in the NLST

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Lung Cancer Incidence/Mortality: US

Kills 450 PeopleEvery Day

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Summary

• Lung Cancer is a Non-Infectious Chronic Disease – More than 80% of cases caused by tobacco use– 90% of regular tobacco use starts by age 18– Smoking harder to quit than heroin – Cigarettes more addictive now than in 1960’s

• Lung cancer is the most common cancer worldwide and the leading cause of cancer deaths in men and women in the US – Mortality rate high due late stage at diagnosis

• USPSTF and CMS now recommend LDCT screening annually for the high risk population– 10 million Americans eligible– Estimate more than 20,000 lives saved per year– Need to raise awareness with primary care physician community and the population

at risk • Tobacco control efforts, although resulting in some success, have failed to

eliminate smoking– E-cigarettes threaten to erode smoking incidence reduction achieved to date

• Increased research funding needed for improved screening and treatment modalities