A Dose of Reality in Low-Dose CT Lung Cancer Screening

Aaron B. Holley, MD


April 07, 2016

The Brief History of Lung Cancer Screening

The landmark National Lung Screening Trial (NLST), published in 2011, randomly assigned patients to screening with low-dose computed tomography (LDCT) versus chest x-ray and found a 20% reduction in lung cancer mortality in the LDCT arm.[1] Consequently, several organizations endorsed screening with LDCT after the NLST was published, and the Center for Medicare & Medicaid Services (CMS) now provides reimbursement.[2] A screening test must meet rigorous criteria prior to implementation, and potential harms must be carefully evaluated.[3,4] The population at risk for lung cancer is typically older with multiple comorbidities,[5] and the procedures involved in nodule biopsy and removal are associated with harm. This article analyzes existing data and reviews the challenges in interpretation and clinical application.

On April 30, 2014, a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting was held to review lung cancer screening. At that time, the US Preventive Services Task Force (USPSTF), the American College of Chest Physicians (CHEST), and the American Society of Clinical Oncology (ASCO) had already endorsed screening with LDCT.[6,7,8] Citing relatively low confidence in the benefits of screening and high confidence that significant evidence gaps remained, the Committee recommended against providing Medicare reimbursement for lung cancer screening.[9] The decision was nonbinding and CMS ultimately approved reimbursement, but why did MEDCAC express such uncertainty?

First, the NLST is the only randomized controlled trial (RCT) to show benefit from screening. The study enrolled 53,000 patients between the ages of 55 and 74 years with at least 30 pack-years of tobacco exposure (one pack-year is equal to smoking 20 cigarettes per day). All were either active smokers or had recently quit, defined as quitting within the past 15 years. LDCT was considered positive for all nodules ≥ 4 mm and screening was conducted annually for 3 years. The absolute risk for death from lung cancer was reduced by 0.3%, meaning that three lung cancer deaths were prevented for every 1000 patients screened annually for 3 years. The number needed to screen (NNS) to prevent one lung cancer death was 320.[1,10]

There are two other published RCTs of LDCT for lung cancer screening: the Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays Trial (DANTE) and the Danish Lung Cancer Screening Trial (DLCST).[11,12] DANTE and DLCST enrolled 2811 and 4104, respectively, and were probably underpowered to detect statistical differences in outcomes. When both were analyzed together with the results of the NLST in a systematic review, LDCT still showed a significant reduction in lung cancer mortality.[8] Inclusion criteria for the DLCST were more liberal than for the NLST—for example, 20 instead of 30 pack-years of tobacco use and an age range spanning 50-70 instead of 55-74. Inclusion criteria for DANTE included participants aged 60-74 and with 20 or more pack-years of tobacco use. Follow-up data from the DLCST identified a high-risk subgroup with chronic obstructive pulmonary disease (COPD), more than 35 pack-years of tobacco exposure, and older age. Lung cancer mortality was significantly reduced in this subgroup, and only 13% of lung cancer deaths occurred in patients without COPD and who had smoked less than 35 pack-years.[13] In summary, DANTE and DLCST had small sample sizes and screened lower-risk patients, so the evidence for benefit from LDCT screening comes primarily from the NLST.[7,8]


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