Cigarette smoking and other possible risk factors for lung cancer

INTRODUCTION — Lung cancer is among the most common cancers worldwide. In the United States and other industrialized countries, it is the major cause of cancer mortality, primarily because of exposure to cigarette smoke.

The epidemiology and risk factors associated with the development of lung cancer are reviewed in this topic.

EPIDEMIOLOGY — The majority of data examining the epidemiology of lung cancer come from the developed world, where cigarette smoking is the predominant risk factor. In resource-limited areas, additional risk factors, such as smoke and air pollution, may be particularly important.

Lung cancer is the leading cause of cancer deaths worldwide in men, and the second leading cause in women. Worldwide, lung cancer occurred in approximately 2.1 million patients in 2018 and caused an estimated 1.8 million deaths [1]. In the United States, lung cancer occurs in approximately 235,000 patients and causes approximately 130,000 to 160,000 deaths annually [2,3]. However, tobacco control efforts are likely to reduce lung cancer incidence. In a modeling study using United States data on smoking and lung cancer mortality from the 1960s to the early 2010s, the annual smoking, age-adjusted lung cancer mortality rate was projected to decrease by 79 percent between 2015 and 2065 [2]. Nevertheless, 4.4 million lung cancer deaths are still expected to occur during this period.

There are substantial variations in lung cancer incidence between different countries and between men and women. These differences are a reflection in large part of differences in the prevalence of tobacco smoking. Changes in the incidence of lung cancer over time have been closely correlated with increases and decreases in the smoking of cigarettes.

SMOKING — Smoking tobacco products (primarily cigarettes) is the most important risk factor for the development of lung cancer. Secondhand smoke is also a significant cause of lung cancer.

Cigarettes — The primary risk factor for the development of lung cancer is cigarette smoking, which is estimated to account for approximately 90 percent of all lung cancers [4]. The possibility that inhalation of cigarette smoke might be a cause of lung cancer was first suggested in 1912 [5]. Since then, a large volume of epidemiologic evidence has confirmed the relationship between smoking and lung cancer and led to efforts to decrease smoking in the population [6-10].

Differences in smoking habits between men and women have reflected the epidemiologic changes in the incidence of lung cancer [11]. With the increase in smoking in women to levels very similar to those in men, there was an increase in lung cancer incidence. However, subsequently, with the contemporary decrease in cigarette smoking, the incidence of lung cancer reached a plateau and has decreased slightly in men.

Estimates of the relative risk of lung cancer in the long-term smoker compared with the lifetime nonsmoker vary from 10- to 30-fold. The cumulative lung cancer risk among heavy smokers may be as high as 30 percent, compared with a lifetime risk of lung cancer of 1 percent or less in never smokers [12,13].

The risk of lung cancer increases with both the number of cigarettes smoked per day as well as the lifetime duration of smoking [14]. Other factors that may influence the likelihood of developing lung cancer in smokers include the age at onset of smoking, the degree of inhalation, the tar and nicotine content of the cigarettes, and the use of unfiltered cigarettes [15].

Smoking cessation — Smoking cessation decreases the risk of lung cancer [12,16,17]. (See "Overview of smoking cessation management in adults".)

Estimates of risk reduction vary from 20 to 90 percent. The reduction in risk becomes evident within five years with a progressive decline associated with an increasing duration of abstinence. Case-control studies show that former smokers who had been abstinent for more than 15 years had an 80 to 90 percent reduction in risk of lung cancer compared with current smokers [16,18]. However, lung cancer risk remains higher than in the never smoker, even after prolonged periods of complete abstinence [16,19]. In fact, for the individual, the risk of lung cancer continues to rise with age, even after smoking cessation, but it rises at a much lower rate than it would have had smoking continued [18].

The mortality benefit from smoking cessation was illustrated in a survey of smoking history in approximately 200,000 men and women [20]. Adults who quit smoking gained 6 to 10 years of life expectancy, depending upon the age at which they quit smoking.

Smoking cessation may be beneficial even among patients who have been treated for lung cancer. In a systematic review with meta-analysis, ongoing smoking by patients with early- or limited-stage lung cancer was associated with increased likelihood of all-cause mortality, tumor recurrence, and development of a second primary tumor [21]. (See "Overview of approach to lung cancer survivors".)

Smoking reduction — Even if smokers are unable to quit, encouraging them to decrease smoking may result in harm reduction, including a decreased risk of lung cancer. An observational study that included 19,714 adults found that smokers who used ≥15 cigarettes or an equivalent amount of tobacco in another form per day and who continued to smoke but cut back by at least 50 percent reduced their risk of lung cancer by 27 percent (95% CI 2 to 46 percent) after a mean follow-up of 18 years [22].

Secondhand smoke — The intensity of exposure to environmental tobacco smoke (ie, passive or "secondhand" exposure) is far less than that which occurs with active smoking. On the other hand, exposure to environmental tobacco smoke can begin earlier in life than it does with active smoking, and the exposure to carcinogens occurs over a longer period of time. There is a dose-response relationship between intensity of exposure and relative risk of lung cancer.

The data supporting the relationship between secondhand smoke and lung cancer and the possible role of genetic factors are discussed separately. (See "Secondhand smoke exposure: Effects in adults".)

Cigar and pipe smoking — Smoking cigars or a pipe is also associated with an increased risk of lung cancer, although the risk may be lower than with cigarettes [23-25].

●In a cohort study, 1546 cigar-only smokers and 16,228 nonsmokers were followed for 24 years [23]. Cigar smoking was associated with a higher risk of lung cancer (relative risk 2.1, 95% CI 1.1-4.1). There was a dose-response effect, with men who smoked five or more cigars per day having the greatest risk.

●In a prospective study, 137,243 men were followed for 12 years [26]. Men who smoked cigars only had an increased risk of death from lung cancer (relative risk 5.1, 95% CI 4.0-6.6) compared with nonsmokers. In a cohort study that followed 15,263 pipe-only smokers and 123,044 nonsmokers for 18 years, current pipe smoking was associated with an increased risk of death from lung cancer (relative risk 5.0, 95% CI 4.2-6.0) [25]. The risk of lung cancer correlated with the intensity and duration of pipe smoking.

Marijuana and cocaine — The risk of lung cancer due to smoking marijuana or cocaine is less clear than with tobacco [27-30]. An association between lung cancer and smoking these agents has been difficult to prove because studies were limited by selection bias, small sample size, and failure to adjust for tobacco smoking. In addition, the duration from the onset of drug use to outcome (ie, lung cancer) may have been too short for lung cancer to develop because young participants were enrolled in most studies. (See "Pulmonary complications of cocaine use".)

Several reports have documented histologic and molecular changes in the bronchial epithelium of marijuana smokers that are similar to the metaplastic premalignant alterations that are seen among tobacco smokers [27,31,32]. Users of these drugs are probably at increased risk for lung cancer, although the magnitude of risk has not been well quantified [33,34].

Electronic cigarettes — Electronic cigarettes (e-cigarettes) are battery-operated devices that heat liquid usually containing nicotine, producing a vapor that the user inhales. The effect of e-cigarettes on the incidence of lung cancer is not well established due to confounding effects of cigarette smoking among many patients who smoke e-cigarettes. E-cigarettes are discussed in detail in another topic. (See "Vaping and e-cigarettes" and "Vaping and e-cigarettes", section on 'Smoking reduction'.)

OCCUPATIONAL AND ENVIRONMENTAL CARCINOGENS — Numerous occupational and environmental carcinogens increase the risk of lung cancer. The best known factors are asbestos and radon. Other exposures that have been associated with lung cancer include arsenic, bis(chloromethyl) ether, chromium, formaldehyde, ionizing radiation, nickel, polycyclic aromatic hydrocarbons, hard metal dust, and vinyl chloride [35-44]. Many of these factors act synergistically with tobacco smoke to produce lung cancer, and are also independent risk factors in nonsmokers.

Asbestos — Asbestos exposure is an established risk factor for lung cancer. Patients with asbestos exposure complicated by interstitial fibrosis (ie, asbestosis) are much more likely to develop lung cancer than patients with asbestos exposure alone. (See "Asbestos-related pleuropulmonary disease".)

Occupational exposure — There is a clear association of occupational exposure with asbestos and the subsequent development of lung cancer (table 1). The risk of lung cancer is dose-dependent but varies according to the type of asbestos fiber. For a given level of exposure, the risk appears to be considerably higher for workers exposed to amphibole fibers than for those exposed to chrysotile fibers [45].

Tobacco smokers exposed to asbestos have a greatly increased risk of lung cancer, in addition to mesothelioma. (See "Asbestos-related pleuropulmonary disease", section on 'Malignancy'.)

Nonoccupational exposure — The degree to which low-level, nonoccupational asbestos exposure increases the risk of lung cancer is less well defined. However, the potential risk is of great public health concern because of the large number of individuals who work or attend school in buildings that contain asbestos, and the cost and potential hazards of asbestos removal. The United States Environmental Protection Agency (EPA) standards for low-level asbestos exposure are based upon linear extrapolation of data from occupational settings to nonoccupational airborne concentrations that are approximately 100,000-fold less [46]. The health risk to occupants of a building in which asbestos is in good repair and undisturbed (ie, not respirable) is not considered significant [47]. (See "Asbestos-related pleuropulmonary disease".)

One population study of women who resided in chrysotile mining towns in Quebec found that differences in estimated cumulative lifetime environmental asbestos exposure did not produce significant differences in the incidence of lung cancer [46]. The authors speculated that the EPA model may overestimate the dose-response relationship between low-level environmental asbestos exposure and lung cancer, although the study's negative findings might also relate to its potential overestimation of asbestos exposure, the fact that the mined asbestos was predominantly chrysotile, or because mined asbestos particles are larger and less respirable than refined asbestos [48]. However, an Italian study also failed to detect an increased risk of lung cancer among persons who resided near an asbestos cement factory in which refined asbestos was used [49].

Radon — Increased concentrations of radon gas in the home are associated with a small, but statistically significant, increase in the risk of lung cancer.

Radon, a gaseous decay product of uranium-238 and radium-226, is capable of damaging respiratory epithelium via the emission of alpha particles. Underground uranium miners who were occupationally exposed to radon and its decay products have an increased risk of lung cancer [50], and there is an interactive effect between radon exposure and cigarette smoking [51,52].

Radon is present in soil, rock, and groundwater, and it can accumulate in homes. However, the risk associated with exposure to radon in the home remains uncertain in the face of conflicting data. A 2005 meta-analysis of 13 European case-control studies reported a linear relationship between the amount of radon detected in the home and the risk of developing lung cancer [53]. Based upon that meta-analysis, the authors estimated that radon exposure could be responsible for up to 2 percent of lung cancer deaths in Europe [53].

Smoke from cooking and heating — The indoor burning of unprocessed biomass fuels (wood, coal) is widely used for cooking and heating in many areas of the world and is associated with significant pollution. Such pollution has been associated with multiple respiratory problems, including an increase in the incidence of lung cancer.

The importance of such indoor pollution as a cause of lung cancer is illustrated by a retrospective cohort study of over 27,000 individuals from China [54]. The lifelong burning of bituminous coal, which is associated with smoke, was associated with a significant increase in the incidence of lung cancer compared with those individuals who used anthracite (smokeless) coal (hazard ratio 36 for men, 99 for women). The lifetime risk of developing lung cancer was approximately 20 percent for both men and women who used bituminous coal compared with 0.5 percent for those who used anthracite coal.

Other studies have similarly implicated smoke from wood burning as a significant risk factor for the development of lung cancer [55-59].

Air pollution and diesel exhaust — An analysis of a cohort of over 300,000 persons and 4,000,000 person-years in nine European countries found a significant association between particulate matter air pollution and the incidence of lung cancer [60].

Multiple studies have demonstrated that exposure to diesel exhaust is associated with an increased risk of lung cancer [61,62]. This risk is proportional to the extent of exposure, and exists even after adjusting for any confounding effects due to smoking.

Although these factors are significantly related to the risk of lung cancer, it should be remembered that their contribution to lung cancer causality is relatively small quantitatively compared with the effects of cigarette smoking.

OTHER ESTABLISHED AND POSSIBLE FACTORS — A variety of other factors may have an impact on the risk of lung cancer but are relatively less important in contributing to the overall global lung cancer burden.

Radiation therapy — Radiation therapy (RT) can increase the risk of a second primary lung cancer in patients who have been treated for other malignancies. This increase in risk appears to be most pronounced in smokers.

●RT for Hodgkin lymphoma has been associated with an increased risk of secondary lung cancer. A systematic review of the literature suggested that the relative risk of developing lung cancer was approximately 2.6 to 7.0, and that the increased risk may last for 20 to 25 years [63].

●In an observational cohort study, among 7408 patients with breast cancer, including approximately 5700 patients who underwent RT and 1700 who did not, those undergoing RT experienced a higher rate of lung cancer than those who did not (2.3 versus 0.2 percent, respectively), a difference that was statistically significant with an adjusted hazard ratio of 10 [64].

Improved RT techniques limit the dose of radiation to nonmalignant tissue, and contemporary equipment and dose planning is thought to significantly reduce the risk for secondary lung cancer.

Inflammation and benign lung disease — Various benign lung diseases have been associated with an increased risk of lung cancer, which appears to be mediated through chronic inflammation.

The most extensive data come from a pooled analysis from the International Lung Cancer Consortium, which analyzed 24,607 cases of lung cancer and 81,829 controls in 17 studies [65]. The risk of lung cancer was elevated in patients with a history of emphysema (odds ratio [OR] 2.44, 95% CI 1.64-3.62), chronic bronchitis (OR 1.47, 95% CI 1.29-1.68), pneumonia (OR 1.57, 95% CI 1.22-2.01), and tuberculosis (OR 1.48, 95% CI 1.17-1.87). The increased risk involved all histologic types of lung cancer (adenocarcinoma, squamous cell, small cell), and was similar in never, former, and current smokers (except for chronic bronchitis in nonsmokers).

These findings are consistent with other studies that have looked specifically at the risk of lung cancer in individuals with tuberculosis [66-71] or obstructive lung disease [72-75].

Other less common benign lung diseases may also be associated with an increased risk of lung cancer:

●Individuals with diffuse pulmonary fibrosis have an 8- to 14-fold increased risk for lung cancer, even when age, gender, and smoking history are taken into consideration [76,77].

●Carriers of an allele for alpha-1 antitrypsin deficiency (usually the S or Z allele) have an approximately twofold increased risk of lung cancer [73]. Because of the prevalence of these alleles in this population, an alpha-1 antitrypsin deficiency carrier state may contribute to as much as 12 percent of lung cancer cases. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

●Although nontuberculous mycobacterial lung disease may also be a risk factor for lung cancer, data are very limited [78,79].

Chronic obstructive pulmonary disease — Chronic obstructive pulmonary disease (COPD) is primarily due to smoking. However, COPD is independently associated with an increased risk of developing lung cancer, probably related to the inflammation and scarring that is part of the development of COPD [80-82]. It is the most common independent risk factor, other than smoking, for lung cancer, increasing the risk of lung cancer by 2- to 5-fold [83].

Genetic factors — The role of genetic factors as a cause of lung cancer is poorly understood, but evidence suggests that such factors play a role. First-degree relatives of individuals with lung cancer have an increased risk of developing lung cancer. In most studies, this excess risk of lung cancer in close relatives persists after adjustment for age, gender, and smoking habits.

A meta-analysis of 28 case-control studies and 17 observational cohort studies revealed an increased lung cancer risk associated with having an affected relative (relative risk 1.8, 95% CI 1.6-2.0) [84]. The risk was greatest in relatives of patients diagnosed with lung cancer at a young age and in those with multiple affected family members. The increased risk in relatives of patients with early-onset lung cancer appears to extend to nonlung malignancies [85]. Additional research is required to identify the genes involved in an increased risk.

Race/ethnicity — Although the incidence of lung cancer varies by race, with Hispanic individuals having lower odds of lung cancer compared with non-Hispanic White individuals, these differences are attenuated in adjusted multivariate analyses, suggesting that other factors (smoking characteristics, diet, physical activity, etc.) likely contribute [86].

Dietary factors — Differences in diet are considered as one of the reasons explaining heterogeneity in the occurrence of lung cancer among people with similar risk factors (ie, smoking and other exposures) for this disease. The findings in observational cohort studies that suggest that diets higher in fruits and vegetables decrease the risk of lung cancer have not been replicated in clinical trials that examine supplementation.

Body mass index — Multiple observational studies have suggested an inverse relationship between body mass index (BMI) and lung cancer [87-92]; however, this may reflect confounding due to cigarette smoking, comorbidity, or other factors.

In a large prospective study, there was an inverse association between BMI and lung cancer incidence, with a mean BMI of 27.3 among those without cancer and 26.4 kg/m² among those diagnosed with lung cancer [93].

Separately, in a report of 29,000 cases of lung cancer and over 56,000 controls, a positive association between small cell lung cancer and BMI was observed; however, there was an inverse relationship between BMI and lung adenocarcinoma, after adjustment for smoking behaviors [94]. These findings highlight the need for additional prospective studies to clarify the effect of BMI on lung cancer development, particularly among histologic subtypes of lung cancer.

B-vitamins — Observational data have suggested that B6 and B12 supplements may be associated with an increased risk of lung cancer among men but not women [95]. More data are required to evaluate this risk.

In the VITAL cohort study, including over 77,000 participants aged 50 to 76 years in whom 808 invasive lung cancers were identified over a mean follow-up of six years, use of vitamin B6 and B12 from individual supplement sources was associated with a 30 to 40 percent increase in lung cancer risk in men [95]. Use of multivitamins that contained vitamin B6 or B12 was not associated with an increased risk. No association was observed with vitamin B supplementation and lung cancer in women.

Beta-carotene supplementation — Beta-carotene has been studied as a chemopreventive agent, based upon preclinical and epidemiologic data. However, multiple chemoprevention trials have failed to demonstrate any benefit from beta-carotene supplements and have suggested that this approach may be associated with an increased incidence of lung cancer. (See "Chemoprevention of lung cancer", section on 'Investigative strategies'.)

A meta-analysis of chemoprevention trials found that high-dose beta-carotene supplementation significantly increased the incidence of lung cancer in smokers (OR 1.24, 95% CI 1.10-1.39) [96]. Among former smokers, the difference was not statistically significant (OR 1.10, 95% CI 0.84-1.85). The high doses of beta-carotene used in these trials may be also be found in multivitamin formulations used to promote visual health.

Endocrine factors — The impact of estrogen and progesterone on the risk and natural history of lung cancer is discussed separately. Early studies yielded conflicting data regarding the effect of hormonal factors on the risk of lung cancer in women [5,23,24,97-100], although large randomized studies suggest that estrogen plus progestin therapy is associated with an increased risk of lung cancer [25,26,101]. (See "Menopausal hormone therapy: Benefits and risks".)

Opium — Opium is an illicit substance derived from the poppy plant, specifically from the juice of the unripe seedpod, and contains multiple alkaloids. Per the International Agency for Research on Cancer, opium is considered to be carcinogenic to humans when smoked or ingested in various forms (eg, raw, dross, or sap opium) [102]. As an example, in the Galeston Cohort Study of 50,045 patients in Iran, opium use was associated with an increased, dose-dependent risk of developing lung cancer (hazard ratio 2.2) [103]. Of note, these data do not include other opiates such as heroin, morphine, codeine, or fentanyl.

Oncogenic viruses — Oncogenic viruses do not have an established role as etiologic agents in the development of lung cancer.

A potential causal role for human papillomavirus (HPV) in squamous cell carcinoma of the lung has been hypothesized because of the presence of HPV DNA within squamous cell carcinomas of the cervix, anorectum, skin, esophagus, and upper airways [104]. Studies analyzing specimens from patients with non-small cell lung cancer have yielded mixed results [105-108].

Patients with HIV have an elevated risk of lung cancer than patients without HIV. However, lung cancer is considered a non-AIDS-defining cancer. The relationship between lung cancer and HIV is discussed in detail elsewhere. (See "HIV infection and malignancy: Management considerations", section on 'Lung cancer' and "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Non-AIDS-defining cancers'.)

LUNG CANCER RISK ESTIMATION — It is possible to estimate the risk for lung cancer for an individual based on various factors including age, family history, and smoking status and duration, among others [93,109,110]. Screening for lung cancer among patients thought to be at risk is discussed elsewhere. (See "Screening for lung cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Quitting smoking (Beyond the Basics)" and "Patient education: Lung cancer risks, symptoms, and diagnosis (Beyond the Basics)")

SUMMARY

●Smoking – Cigarette smoking is the primary cause of lung cancer in North America and Europe. This causal link is well established, and changes in smoking patterns (increased prevalence of smoking in women, decreased in men) have been correlated with changes in the epidemiology of lung cancer. Smoking cessation gradually reduces the risk of lung cancer, although not to baseline levels. Other forms of tobacco smoke, including secondhand smoke, are also associated with significant increases in the risk of lung cancer. (See 'Smoking' above.)

●Occupational and environmental carcinogens – A number of occupational and environmental factors are also associated with an increased incidence of lung cancer. Well-identified factors include exposure to asbestos, radon, and smoke from wood burning. (See 'Occupational and environmental carcinogens' above.)

●Inflammation – Other pulmonary diseases that are associated with inflammation (pulmonary fibrosis, chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, tuberculosis) have been associated with a statistically significant increase in the incidence of lung cancer. (See 'Inflammation and benign lung disease' above.)