Earlier this year, a group of US researchers reported that the incidence of non-small cell lung cancer (NSCLC) among never-smokers had apparently doubled over the last two decades, but a new report from Australia finds that the incidence has remained stable in recent years. An expert not connected with either study says that more research is needed, and at the moment there is not enough data to give a "firm message."

The new report, based on an analysis of almost 4000 lung cancer cases in Australia, found that the incidence among never-smokers has remained unchanged since 2000, with the rate fluctuating around 5% to 7%, as in previous studies.

This new report, published as a research letter on October 16 in the Journal of the National Cancer Institute (JNCI), is a follow-up to a study published earlier this year in the same journal, which came to a completely different conclusion.

That earlier report, published in the JNCI in January 2017, had suggested that the prevalence of never-smokers among patients with NSCLC had almost doubled since the 1990s, while that in patients with small cell lung cancer (SCLC) had barely increased.

Doubling of Incidence in United States

That set of authors, led by Lorraine Pelosof, MD, PhD, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, conducted a retrospective analysis of cancer registry data from three institutions. Focusing on the period 1990 to 2013, they gathered demographic data, including self-reported smoking history, on 10,593 NSCLC and 1510 SCLC cases.

Among NSCLC cases, the proportion of never-smokers increased significantly, from 8.0% in 1990-1995 to 14.9% in 2011-2013 (P < .001), a finding that remained even after multivariable logistic regression taking into account sex, stage at diagnosis, and race/ethnicity.

In contrast, the proportion of never-smokers did not significantly increase among patients diagnosed with SCLC, at 1.5% in 1990-1995 and 2.5% in 2011-2013 (P = .36).

The proportion of never-smokers among patients with NSCLC was significantly higher in women than men, at 17.5% vs 6.9% (P < .001).

Never-smokers with NSCLC also were younger than those with the disease who smoked, at an average of 60.6 years vs 63.4 years (P < .001).

Dr Pelosof and colleagues wrote: "We demonstrated that the proportion of lung cancer patients who reported themselves as 'never smokers' is increasing at three diverse institutions."

"Given that this increase is not related to sex, stage, or race/ethnicity and was not seen in small cell lung cancer, these results suggest that the incidence of lung cancer arising in the never-smoking population is likely increasing."

These results suggest that the incidence of lung cancer arising in the never-smoking population is likely increasing. Pelosof et al

They added that if that findings are verified in other databases, they would signal "an urgent need to perform combined and integrated epidemiology and tumor molecular analyses to identify potential environmental lung cancer–causing carcinogens that will clearly impact prevention and treatment."

If this incidence rate is indeed rising, that would have "important implications and possibly signal a shift in underlying etiological factors," commented Jonathan Samet MD, from the Department of Preventive Medicine at the Keck School of Medicine, University of Southern California, Los Angeles, writing in an accompanying editorial.

The findings also underline that lung cancer "is not static; in fact, there have been major shifts in the epidemiological characteristics of lung cancer over the last half-century," he noted.

However, at the same time, Dr Samet pointed out that established risk factors for lung cancer in never-smokers, such as exposure to secondhand smoke and air pollution, have declined in recent years, while radon exposure has been relatively constant.

He also observed that there are many limitations to the study and suggested that the change in the proportion of never-smokers observed in the study could "reflect temporal changes in the populations…a declining incidence of cancer among ever smokers because of cessation, and changing patterns of misclassification of smoking."

Dr Samet therefore called for further research to estimate the incidence of lung cancer among smokers and nonsmokers separately. He said the data reported by Dr Pelesof and colleagues are "provocative findings" that are "incomplete until complemented by the proper denominators."

Incidence Stable in Australia

Now, in a research letter to the JNCI, researchers from Australia, led by Barbara J. Page, MPhil, from the University of Queensland, Chermside, Queensland, report an analysis of data from their institution.

They included 3992 patients with primary lung cancer with a mean age of 68 years treated between 2000 and 2016, of whom 329 (8.2%) had SCLC.

Overall, 1500 (37.6%) of the patients were women and 252 (6.3%) were never-smokers. Among the female patients, 169 (67.1%) were never-smokers.

They write that, on a two-sided Pearson chi-square test, the proportion of never-smokers did not change significantly over time: It was 5.5% in 2000 and 7.2% in 2014-2016 (P = .30).

There was "thus no evidence of a temporal change in the proportions of lung cancer cases in never-smokers at our institution," despite acknowledging that their research "also lacks the critical person-time denominator" specified by Dr Samet.

In a response to the Australian study, Dr Pelosof and colleagues point to differences in sample sizes between the studies and that they separated out SCLC cases from those from NSCLC, which "is particularly important in light of our conclusion that the proportion of never-smokers among NSCLC patients is increasing at our institutions."

They also note that some of the limitations of their study remain an issue in the research letter, and thus they "hope that groups will continue to examine the question as more registry data are collected and analyzed."

Approached for comment, Dr Samet told Medscape Medical News that the latest research by Page et al "is useful for showing that the earlier findings were not replicated at another institution, albeit in Australia."

He emphasized, however, that "the question of trends in lung cancer rates will not be answered without measuring the actual incidence rates in smokers and in never-smokers," adding: "Since that is not done routinely, establishing trends will be particularly difficult."

As such, he feels it is "hard to give a firm message to the public," although the latest results "confirm that about 5% to 7% of lung cancers are in never-smokers, translating in the US to around 15,000 (or more) cases."

Dr Samet concluded: "Certainly, we cannot say that there is an absolute increase in incidence."

The original study was supported in part by the Simmons Comprehensive Cancer Center, Lung Cancer SPORE, and the Margot Johnson Foundation. The authors have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online October 16, 2017. Page et al letter, Pelosof et al response

Follow Medscape Oncology on Twitter: @MedscapeOnc