In an analysis of updated evidence on low-dose computed tomography (CT) screening for lung cancer reported in JAMA, Jonas et al found that screening can reduce lung cancer mortality but may be associated with a range of potential harms. The analysis was performed to inform the new U.S. Preventive Services Task Force recommendation statement on low-dose CT screening.

Study Details

After review of the literature through November 2020, a total of 223 articles were included in the systematic review. Of these, seven randomized trials that assessed the effect of low-dose CT screening mortality were included in the analysis of lung cancer mortality:

• National Lung Screening Trial (NLST)
• Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays (DANTE) trial
• Danish Lung Cancer Screening Trial (DLCST)
• Italian Lung Cancer Screening (ITALUNG) trial
• Lung Screening Study (LSS)
• German Lung Cancer Screening Intervention (LUSI) trial
• Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial.

The total number of patients included in all the selected trials was 86,486.

Lung Cancer Mortality

Data from the seven trials were not pooled due to the heterogeneity of study populations and screening protocols.

The cumulative incidence of lung cancer was higher in low-dose CT groups than in control groups for all studies, except ITALUNG.

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Only the two largest trials—NLST (n = 53,454) and NELSON (n = 15,792)—were adequately powered to assess the benefit of screening in regard to lung cancer mortality. Over 6.5 years of follow-up and more than 140,000 person-years of follow-up in each group, NLST showed a significant reduction in lung cancer mortality with three rounds of annual low-dose CT screening vs chest radiography in high-risk current and former smokers aged 55 to 74 (calculated incidence rate ratio [IRR] = 0.85, 95% confidence interval [CI] = 0.75–0.96).

Based on these findings, the number needed to screen to prevent one lung cancer death was 323 over 6.5 years of follow-up. Extended follow-up in NLST at 12.3 years after random assignment showed a risk ratio of death from lung cancer of 0.92 (95% CI = 0.85–1.00).

The NELSON trial reported a reduction in lung cancer mortality for four rounds of screening with increasing intervals between screens vs no screening for high-risk current and former smokers aged 50 to 74 (calculated IRR = 0.75, 95% CI = 0.61–0.90). Based on these findings, the number needed to screen to prevent one lung cancer death was 130 over 10 years of follow-up.

As stated by the investigators, “Results of the other trials were very imprecise and did not show statistically significant differences between groups.”

Potential Harms

Potential harms associated with screening included radiation-induced cancer, false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, and increases in distress. Among nine studies assessing radiation exposure with LDCT, one estimated that the lifetime risk of cancer from radiation of 10 annual low-dose CTs was 0.26 to 0.81 major cancers for every 1,000 individuals screened.

Among 27 publications with information on false-positive results, the range of false-positive rates was 7.9% to 49.3% for baseline screening and 0.6% to 28.6% for individual incidence screening rounds. Among trials that found lung cancer screening mortality benefit and U.S.-based cohort studies, false-positive rates were 9.6% to 28.9% for baseline and 5.0% to 28.6% for incidence rounds. The NLST reported false-positive rates for baseline, year 1, and year 2 of 26.3%, 27.2%, and 15.9%, respectively. The NELSON trial reported false-positive rates of 19.8% at baseline, 7.1% at year 1, 9.0% for male patients at year 3, and 3.9% for male patients at year 5.5 of screening.

Among 14 studies reporting on evaluation of false-positive results, interventions for false-positive results included needle biopsy in 0.09% to 0.56%, surgical procedures in 0.5% to 1.3%, and surgical resection in 0.1% to 0.5% among all screened participants. For every 1,000 persons screened in the NLST, false-positive results led to 17 invasive procedures (number needed to harm = 59).

In five studies specifically examining overdiagnosis and seven additional trials assessed for differences in cancer diagnosis between low-dose CT and comparison groups, estimates of overdiagnosis of lung cancer with screening ranged from 0% to 67.2%. In eight studies, the estimated proportion of individuals with screening-related incidental findings that were considered significant or requiring further evaluation ranged from 4.4% to 40.7%. 

The investigators concluded, “Screening high-risk persons with low-dose CT can reduce lung cancer mortality but also causes false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, increases in distress, and, rarely, radiation-induced cancers. Most studies reviewed did not use current nodule evaluation protocols, which might reduce false-positive results and invasive procedures for false-positive results.”

Daniel E. Jonas, MD, MPH, of the Department of Internal Medicine, The Ohio State University, Columbus, is the corresponding author for the JAMA article.

Disclosure: The research was funded under contract from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, under a contract to support the U.S. Preventive Services Task Force. For full disclosures of the study authors, visit jamanetwork.com.