Extended follow-up of participants in the National Lung Screening Trial (NLST) continued to show a lung cancer-related mortality benefit for low-dose computed tomography (LDCT) screening.
The NLST, which randomized more than 53,000 high-risk current and former smokers to annual screening with either LDCT or chest x-ray for 3 years, showed a significant reduction in lung cancer mortality for the LDCT group after a median of 6.5 years of follow-up.
The newly published analysis, which includes an additional median 6 years of follow-up mortality data, reaffirmed the previous findings, which suggested that screening patients at high-risk for lung cancer saves lives, said investigator Paul Pinsky, PhD, of the National Cancer Institute in Bethesda, Maryland.
Based on the , the researchers estimated that 320 high-risk patients would need to be screened to prevent one lung cancer death.
In the extended follow-up, published online in the , the estimated number needed to screen to prevent a single lung cancer death shifted down to 303.
"The stability of this difference over time indicates that LDCT screening did not just delay lung cancer death by a few years, but prevented it, or at least delayed it for more than a decade," Pinsky and colleagues wrote.
"Lung cancer is the leading cause of cancer death worldwide and early detection and treatment through screening with low-dose computed tomography has been investigated as a potential means of reducing lung cancer deaths for more than two decades," Pinsky noted in a written press statement.
He added that the NLST extended follow-up "adds further weight to the notion that CT screening is effective."
The original NLST trial included 26,732 participants randomized to receive LDCT and 26,730 participants randomized to receive chest x-rays annually for 3 years at 33 medical centers across the U.S.
Median follow-up for lung cancer incidence in the extended analysis was 11.3 years in both groups: range of 9.0-11.8 and 8.9-11.8 years, respectively, in the two groups. Median follow-up for lung cancer death was 12.3 years (11.9-12.8) in both groups.
A total of 1,701 lung cancer cases were identified over the extended follow-up in the LDCT arm and 1,681 in the chest x-ray arm, for a rate ratio of 1.01 (95% CI 0.95-1.09).
The excess cumulative number of LDCT cases (vs chest x-ray) was shown in the analysis to peak at the end of the screening phase of the study -- around year 3.
The overdiagnosis rate was 3.1% (20 of 649) overall and 79% (75 of 95) for bronchioloalveolar carcinomas (BAC). "Almost all cases classified as bronchioloalveolar carcinoma were overdiagnosed, and BAC represented the majority of all overdiagnosed cases," the researchers wrote.
They noted that in 2011 an expert panel recommended abandoning the term BAC, and instead reclassifying patients previously given the diagnosis into new categories:
- Adenocarcinoma in situ
- Minimally invasive adenocarcinoma
- Invasive lepidic adenocarcinoma
- Invasive mucinous adenocarcinoma
Mathematical modeling performed by Pinsky and colleagues, , predicted that excluding BAC cases, 94% of lung cancers would be clinically apparent within 10 years of LDCT screening diagnosis.
"Since the average follow-up of LDCT screen-diagnosed cases is now about 10 years, the 94% estimate is generally consistent with the current observation of no increase in (non-BAC) lung cancer in the LDCT arm," the researchers wrote, noting that a "large excess" of BAC cases continued in the LDCT arm (n=121) versus the chest x-ray arm (n=46).
In contrast to earlier findings from the NLST cohort, the extended follow-up showed no statistically significant reduction in all-cause mortality in the LDCT versus chest x-ray groups, but the researchers pointed out that the P-value was much higher (from 0.02 to a non-significant 0.18) in the extended follow-up "due to the extra noise associated with the dilution effect."
In the original analysis, the difference in all-cause mortality between the two arms was 4.6 per 1,000. In the updated analysis this difference was 4.2 per 1,000, "indicating that the all-cause mortality difference was essentially sustained," they wrote.
"The current lack of a statistically significant effect for all-cause mortality should not be taken to negate the original significant finding," they wrote, "It is more likely related to using the 'incorrect window' for follow-up (i.e., too long a period post-screening)."
The researchers also wrote that "the magnitude of overdiagnosis as estimated from LDCT screening trials depends critically on the length of follow-up following the final screen."
"For NLST, the overdiagnosis rate decreased from 18% in the original analysis (median 4.5 years follow-up after the last screen) to 3% with extended follow-up," the team said. "However, even controlling for follow-up time, there is great variability in overdiagnosis rates across trials."
The lack of information on post-study LDCT screening was cited by the researchers as a study limitation. LDCT screening was not covered by Medicare until 2015, and private insurance reimbursement was also not common prior to this.
Disclosures
The National Lung Screening Trial was funded by the National Cancer Institute.
Primary Source
Journal of Thoracic Oncology
Black WC, et al "Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial" J Thoracic Oncol 2019; DOI: 10.1016/j.jtho.2019.05.044.