National Lung Screening Trial (NLST)

Lung cancer is the leading cause of cancer death in the United States, where an estimated 135,720 people died of it in 2020, largely because most cases are diagnosed at an advanced stage when surgery is no longer an option. The case for screening was intuitive: if tumors could be detected while still small and localized, survival should improve. The problem was that intuition had failed before. The Mayo Lung Project and other chest radiograph screening studies in the 1970s and 1980s showed no mortality benefit, leaving screening as a practice with no randomized foundation.

Low-dose computed tomography offered better resolution than plain radiographs and could detect nodules too small for conventional x-ray. Observational data from the Early Lung Cancer Action Project in New York suggested that CT-detected stage I lesions had high surgical cure rates. Whether this translated to mortality reduction was a different question, one that required a randomized trial large enough and long enough to measure deaths, not detection rates.

The National Lung Screening Trial, funded by the National Cancer Institute, enrolled 53,454 current or former heavy smokers aged 55 to 74 at 33 centers across the United States between August 2002 and April 2004. Participants were randomly assigned to three annual rounds of low-dose CT or standard chest x-ray. After a median follow-up of 6.5 years, lung cancer mortality was 20% lower in the CT arm, translating to 247 versus 309 deaths per 100,000 person-years. All-cause mortality was 6.7% lower. The trial was stopped when interim analysis crossed the prespecified efficacy boundary.

The false-positive rate was a prominent finding alongside the mortality benefit. Approximately 24% of CT rounds produced a positive result, and about 96% of those positives were ultimately not cancer, leading to a chain of follow-up imaging, bronchoscopy, and in some cases surgical biopsy. The number needed to screen to prevent one lung cancer death was estimated at around 320. These figures shaped how guidelines framed shared decision-making: patients were to be told how likely follow-up procedures were before they entered a screening program.

The USPSTF first recommended screening in 2013 and updated the recommendation in 2021 to cover adults aged 50 to 80 with at least a 20 pack-year smoking history who currently smoke or quit within the past 15 years. Denise Aberle was first author of the main NLST report. CMS coverage followed, though uptake in eligible populations remained well below the rates seen in breast and colorectal cancer screening programs.