Smokers with a negative baseline low-dose CT (LDCT) scan do not have a significantly increased risk for lung cancer until 3 years later, according to a recent study conducted in China.

These findings support the evaluation of extended screening intervals for high-risk individuals, reported lead author Yin Liu, PhD, of the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China, and colleagues. But other experts were not convinced that recommended lung cancer screening intervals are too short.

“Although the National Lung Screening Trial reported lower lung cancer incidence among heavy smokers with a negative baseline screen result, it failed to quantify how smoking shapes the lung cancer risk over time,” the investigators wrote in their new paper published in JAMA Network Open. “This gap hinders evidence-based tailoring of surveillance intervals.”

To learn more, the investigators analyzed data from the Cancer Screening Program in Urban China. The final dataset comprised 30,565 participants aged 40-74 years who had a negative baseline LDCT scan between October 2013 and December 2021, including 14,761 never-smokers and 15,804 smokers.

Participants were followed until December 2023 to monitor lung cancer incidence, with investigators evaluating associations with self-reported smoking status, pack-years, and cessation duration. Unlike US practice, participants were not routinely rescreened annually. Instead, they were followed through registry linkage and active follow-up after a single baseline scan. That follow-up “was based on the outcomes of a single baseline LDCT.” Those with a positive lung cancer screening “were placed into active surveillance,” while those with a negative screen “received a combination of passive surveillance (linking study data to the Henan Provincial Cancer Registry) and active follow-up (telephone or home visits to verify cancer outcomes).”

Over a median follow-up of 4.35 years, 76 incident lung cancer cases were identified (crude incidence rate, 54.7 per 100,000 person-years). Smokers had a significantly higher risk than never-smokers, driven primarily by those with a history of 20 pack-years or more. However, time-stratified analyses revealed no significant risk increase among smokers at 1 year (adjusted hazard ratio [AHR], 1.81; 95% CI, 0.54-6.08) or 2 years after a negative scan (AHR, 2.07; 95% CI, 0.91-4.69). The risk for smokers only became significantly elevated at year 3 (AHR, 2.54; 95% CI, 1.19-5.41) and onward.

“These findings suggest that annual screening within the first 2 years offers limited benefit and supports the evaluation of extended screening intervals,” Liu and colleagues wrote, suggesting that “a biennial screening interval appears more acceptable.”

The study also reported sex-based risk disparities. At comparable exposure levels of 30 or more pack-years, women faced a nearly sixfold higher risk (AHR, 5.78; 95% CI, 1.87-17.83) than men (AHR, 1.36; 95% CI, 0.18-10.39).

In addition, 95% of the lung cancers detected in never-smokers occurred in women (19 of 20 cases), all of whom reported substantial exposure to cooking oil fumes.

“This finding aligns with evidence that non-risk-based screening detects cancers in ineligible individuals and that smoker-focused criteria may underdiagnose many at risk, particularly Chinese women,” the investigators wrote. “Thus, adopting risk model-based eligibility that incorporates nonsmoking risk factors, rather than relying solely on smoking history, is crucial.”

Outside Perspectives on Screening Intervals

“It’s important to monitor the real-world impact of screening programs since we know that results from randomized controlled trials often do not apply directly to the real world,” Rebecca Landy, PhD, a principal scientist for the Cancer Risk Factors and Screening Research team at the American Cancer Society, told Medscape Medical News.

Landy said the large proportion of never-smokers in the present dataset adds “important information on this population.”

She also noted that the findings align with previous studies showing low risk for lung cancer 1 year after negative LDCT.

Even so, a longer screening interval may not be appropriate for everyone, Landy said. To back this up, she cited a 2017 analysis of the NELSON trial, published in Thorax, which evaluated different screening intervals and found that a longer screening interval was associated with more interval cancers and more advanced-stage, screen-detected cancers.

“Screening guidelines must be appropriate for the setting they are designed to be implemented in,” Landy said. “The exposures in China differ to the exposures in the US, and therefore guidelines appropriate for one country may not be appropriate for the other.”

Ashley Elizabeth Prosper, MD, and Yannan Lin, MD, MPH, PhD, both of the University of California, Los Angeles, shared a similar perspective in an editorial published alongside the new JAMA Network Open study.

They noted that the Chinese study protocol relied on a single baseline screen followed by passive and active follow-up, which contrasts with the continuous annual screening practiced in the US.

“Absent annual screening, there is potential for these de novo lung cancers to grow undetected and unchecked,” Prosper and Lin wrote. Such de novo cancers have been associated with worse outcomes in prior analyses of the National Lung Screening Trial, they added.

Expanding Screening Eligibility

Experts not involved with the new study also responded to Liu and colleagues’ suggestion that lung cancer screening protocols should be personalized based on sex and nonsmoking risk factors.

The editorialists suggested this was “worthy of consideration” but called for randomized data from a more heterogenous population to increase generalizability of the findings.

Landy noted that 95% of the never-smokers in the study were women, “many of whom were eligible [for the trial] due to their high exposure to cooking fumes; therefore, the finding that 95% of the lung cancers detected in never smokers occurred in women has limited value.”

Still, the concept of personalized screening “remains valid,” Landy said, as “the majority of people diagnosed with lung cancer [in the US] are not eligible for screening.”

Expanding screening to include these individuals, however, may be easier said than done.

“In the US, it has proven extremely difficult to identify lung cancer risk factors for individuals who never smoked, which makes identifying high risk individuals who never-smoked challenging,” Landy said.

The study was supported by the Henan Province Medical Science and Technology Public Relations Plan Province Department and the Henan Province Science and Technology Research Project. Prosper disclosed having relationships with MedQIA, Bayer Medical, Canon Medical, and others. Lin and Landy reported having no conflicts of interest.