Lung Cancer on the Rise in Nonsmokers - But Why?

The proportion of lung cancer patients who never smoked more than doubled from 2008 to 2014, a British investigator reported here.

Never-smokers accounted for 13% of non-small cell lung cancer (NSCLC) cases at the beginning of the study period and rose steadily to 28% by November 2014. Women accounted for two-thirds of the nonsmokers who developed NSCLC, which was associated with nonspecific symptoms or no symptoms in a majority of cases.

Both the percentage and absolute number of NSCLC cases involving nonsmokers increased during the study period, supporting the view that the increase is real and not an artifact created by reductions in smoking prevalence, Eric Lim, MD, of the Royal Brompton Hospital in London, reported at the World Conference on Lung Cancer.

“As this group of patients do not have established risk factors, research into early detection - ideally, by noninvasive or molecular screening - is urgently required to identify early lung cancer in nonsmokers,” Lim said.

We found that the absolute numbers are increasing in real time,” he added. “But I say that with a caveat: We are starting from a position where we know the diagnosis. We really don’t know the true incidence in the undiagnosed population.”

Lung Cancer Risks for Non-smokers

Secondhand smoke
. Each year, an estimated 3,400 non-smoking adults die of lung cancer as a result of breathing secondhand smoke. Laws that ban smoking in public places have helped to reduce this danger. The American Cancer Society Cancer Action Network (ACS CAN), the nonprofit, nonpartisan advocacy affiliate of the American Cancer Society, is working to expand and strengthen these laws to further protect both smokers and non-smokers from the dangers of secondhand smoke.

Cancer-causing agents at work. For some people, the workplace is a source of exposure to carcinogens like asbestos and diesel exhaust. Work-related exposure to such cancer-causing materials has decreased in recent years, as the government and industry have taken steps to help protect workers. But the dangers are still present, and if you work around these agents, you should be careful to limit your exposure whenever possible.

A study conducted at three U.S. medical centers also showed a rising incidence of NSCLC in nonsmokers since 1990, including a two-fold increase at one of the centers. The proportion of nonsmokers among patients with small cell lung cancer (SCLC) did not change from 1990 through 2013, said Lorraine Pelosof, MD, PhD, of the University of Texas Southwestern Medical Center in Dallas.

The reasons for the increase in nonsmokers among patients with NSCLC remain unclear. Mutation analysis of tumors could help inform the issue, but detailed studies have yet to be done in nonsmokers, said Everett Vokes, MD, of the University of Chicago.

Passive smoking, or the inhalation of tobacco smoke from other smokers sharing living or working quarters, is an established risk factor for the development of lung cancer. Non-smokers who reside with a smoker have a 24% increase in risk for developing lung cancer when compared with other non-smokers. Each year, up to 3,000 lung cancer deaths are estimated to occur in the U.S. that are attributable to passive smoking.

Radon gas
, a naturally-occurring gas that forms when uranium decays, is another known cause of lung cancer. An estimated 12% of total lung cancer deaths in both smokers and non-smokers, or 15,000 to 22,000 lung cancer-related deaths annually in the U.S, are believed to be at least partially related to radon gas exposure. Those who do smoke and are exposed to radon have an even greater risk of developing lung cancer than non-smokers who are exposed to radon gas. Radon gas can travel up through soil and enter homes through gaps in the foundation, pipes, drains, or other openings. The U.S. Environmental Protection Agency estimates that one out of every 15 homes in the U.S. contains dangerous levels of radon gas. Radon gas is invisible and odorless but can be detected with simple test kits.

I think it is clear that there is concern that the rate of nonsmoking tumors is increasing,” Vokes said during a press briefing. “What is causing that is very, very speculative at this point. Second-hand smoke is still there. Radon is still around, but that wouldn’t necessarily explain an increase because it is remaining constant or decreasing. Then there are factors related to small particles and carcinogens in the air.”

Lung Cancer on the Rise in Nonsmokers - But Why? About 15% of men with lung cancer and half of women have no history of smoking. As smoking prevention and cessation efforts reduce smoking prevalence, the proportion of lung cancer cases not associated with smoking is expected to increase. Whether the increase is real or merely a change in proportion has not been studied carefully.

U.K. Study

To evaluate the current status of lung cancer and smoking status, Lim and colleagues retrospectively reviewed records of patients who underwent surgery for lung cancer at the Royal Brompton Hospital, a large tertiary care center. Investigators defined “incidence” as the number of patients with newly diagnosed lung cancer who had never smoked versus current and ex-smokers.

The analysis showed that 2,170 patients had surgery for lung tumors from March 2008 through November 2014, including 436 (20%) patients who had never smoked. Lung cancer incidence in nonsmokers increased steadily over the 8 years, making the biggest jump from 2013 (20%) to 2014 (28%). In absolute terms, total cases of lung cancer in nonsmokers increased from about 60 in 2010 to almost 100 in 2014.

Women accounted for 295 (67%) of the never-smokers, who had a mean age of 60, mean forced expiratory volume in 1 second (FEV1) of 90%, and mean forced vital capacity (FVC) of 97%. Pathology reports showed that 151 (54%) of tumors in never-smokers were adenocarcinoma, followed by carcinoid histology in 76 (27%).

Lim said 52% of the patients with a negative smoking history had nonspecific symptoms at diagnosis (cough in 34% and chest infections in 18%), and 36% had no symptoms. The single most common symptom at diagnosis was hemoptysis (11%).

About half of the lung cancers not associated with smoking were identified by incidental imaging, including chest x-ray in 14% of cases, CT in 30%, PET/CT in 7%, and MRI in 1%. A majority of cases were stage I at diagnosis, including 33% stage IA and 21% stage IB. Lim said 17% of patients had advanced disease (stages III and IV) at diagnosis.

U.S. Study

Pelosof reported findings from a review of NSCLC identified in cancer registries at UT Southwestern, Parkland Hospital in Dallas, and Vanderbilt University in Nashville, Tenn. Investigators queried the databases for the years 1990 to 2013 and noted patient sex, age at diagnosis, NSCLC or SCLC, stage at diagnosis, race/ethnicity, and self-reported smoking history.

Heredity, since all smokers do not eventually develop lung cancer, it is likely that other factors, such as individual genetic susceptibility, may play a role in the causation of lung cancer. Numerous studies have shown that lung cancer is more likely to occur in both smoking and non-smoking relatives of those who have had lung cancer than in the general population.

Air pollution from vehicles, industry, and power plants, can raise the likelihood of developing lung cancer in exposed individuals. It has been estimated that up to 2,000 lung cancer deaths per year may be attributable to breathing polluted air, and many experts believe that prolonged exposure to highly polluted air can carry a risk for the development of lung cancer similar to that of passive smoking.

Data analysis comprised 10,593 patients with NSCLC and 1,510 with SCLC. The proportion of nonsmokers with NSCLC increased in all three registries, the largest increase occurring at UT Southwestern, where the incidence rose from 8.9% during 1990 to 1995 to 19.5% during 2011 to 2013 (P<0.0001) At Vanderbilt, the proportion of nonsmokers with NSCLC increased from: 9.8% to 12.9% (P=0.02). Parkland started with a higher incidence (12.9% during 1990 to 1995) then declined to 8.2% (1996 and 2000) and 7.6% (2001 to 2005) and then almost doubled to 14.2% during 2011 to 2013 (P=0.0002). The overall change in nonsmokers with NSCLC was statistically significant (P<0.0001), but not SCLC, which ranged from 2% to 3% across the study period at Parkland and Vanderbilt. The proportion varied more at UT Southwestern (1.4% to 7.0%, ending at 4.5%), but the overall trend was not significant. The UT Southwestern data showed no differences in the frequency of stage I, II, or III at diagnosis of NSCLC among nonsmokers. At Parkland, the frequency of stage IV disease at diagnosis increased significantly as the frequency of earlier-stage disease decreased significantly (P=0.0071). The findings dispelled any notion that the increased incidence of NSCLC in never-smokers resulted from increased incidental diagnosis of early-stage disease, Pelosof said. The study had some limitations: Smoking history was self-reported but race-ethnicity was not.
Lim disclosed relevant relationships with Strategen, Abbott Molecular, GlaxoSmithKline, Pfizer, Novartis, Covidien, Ethicon, Roche, Imidex, Eli Lilly, Medella, Boehringer Ingelheim, ScreenCell, Informative Genomics, and the BUPA Cromwell Lung Cancer Screening Programme. Pelosof disclosed no relevant relationships with industry.
### Source Reference: Cufari ME, et al “Increasing incidence of nonsmoking lung cancer: Presentation of patients with early disease to a tertiary institution in the UK” WCLC 2015; ORAL24.03.

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