To our knowledge, this is the first comprehensive effort to pool and compare data on lung cancer incidence and death rates in lifelong nonsmokers from multiple sources. The combination of data from cohort studies and population registries provides a more coherent picture of how background lung cancer risk varies by age, sex, geographic location, race/ethnicity, and time period than can be obtained from any single study. All of the available data have limitations and unknowns regarding the accuracy of the diagnostic information, the validity and comparability of the exposure information on active smoking or its absence, and the lack of measurements of other exposures that affect lung cancer risk. In the interest of clarity, however, we first discuss the series of questions raised in the introduction and later consider how these data limitations could affect our conclusions.
How Common Is Lung Cancer in People Who Have Never Smoked Actively?
The incidence of lung cancer among lifelong nonsmokers falls within the National Cancer Institute's (NCI) definition of a “rare” cancer (fewer than 40,000 cases per year, age-standardized incidence rate <15 per 100,000). The incidence rate approximates that of brain cancer (plus other nervous system cancers) in the SEER registries for individuals of European descent under age 70 y. At older ages, the incidence rates increase more rapidly than the incidence of brain cancer and become comparable to the SEER incidence rates for liver and kidney cancer.
The lung cancer incidence and death rates among never-smokers are predictably much lower than those of smokers. Men who report never smoking have a 1.1% cumulative risk of dying from lung cancer before age 85 y in the pooled analysis of individuals of European descent; the corresponding estimate for women is 0.8%. This compares to cumulative risk estimates of 22.1% and 11.9% for male and female current cigarette smokers, respectively, during the first 6 y of follow-up of CPS-II. Nevertheless, the disease burden from lung cancer would be comparable to that of many other cancers, even if the entire population experienced the death rates of lifelong nonsmokers. While we lack information on the lung cancer death rates among Hispanic, Native American, and Asian never-smokers who live in North America, we can make such estimates for individuals of European descent and African Americans. Our estimate that approximately 16,000 lung cancer deaths would have occurred among individuals of European descent and African Americans, ages 40–79 y in 2004, had the never-smoker rates applied, is larger than the number reported for five of the 12 most common fatal cancers in the US in that year. Lung cancer is obviously a significant public health and medical problem, even beyond the overwhelming disease burden caused by tobacco smoking.
Do Women Have Higher Risk Than Men?
The question of whether women are more susceptible to develop lung cancer than men has been debated since the early 1990s, when reports from case-control studies showed higher odds ratios in women than in men associated with putatively comparable levels of cigarette smoking [38
]. These reports were not replicated by large prospective studies in the US [41
] or Europe [42
] that measured lung cancer mortality rates. The prospective cohort studies have consistently found higher lung cancer death rates in men than women, both in the presence [41
] and absence [4
] of active smoking. The literature is less consistent with respect to incidence, however [44
]. The debate has been further complicated by publications from national and international Early Lung Cancer screening studies [9
], suggesting that the gender relationship may be different for incidence than for mortality. Screening studies have found that women are more likely to be diagnosed with lung cancer than men when high risk smokers are tested with low-dose spiral computerized tomography. Although screening studies measure disease prevalence rather than incidence, Henschke and others hypothesize that lung cancer incidence may be higher in women than in men who smoke, even though the opposite is true for mortality [9
]. Wakelee et al. provided limited support for this hypothesis by documenting that lung cancer incidence rates were higher in women than men among never-smokers, age 40–79 y in six cohort studies [11
Our findings are much clearer for lung cancer mortality than for incidence. The lung cancer death rates are higher in men than women who have never smoked, and the gender difference in mortality increases with age. This has been previously reported for individuals of European descent and African Americans [4
]; the addition of new data from Korea [27
] and Japan [25
], extends this finding to Asians. The gender difference in mortality may be narrowing over time, as suggested by the decrease in the HR comparing the male to female rate in CPS-I (HR = 1.52, 95% CI = 1.28–1.79) to that in CPS-II (HR = 1.21, 95% CI = 1.09–1.36). Whether this trend will continue into the future is unknown.
In contrast to the mortality findings, the gender relationship observed for lung cancer incidence is more complex and less convincing. We had no a priori hypothesis that age would modify the relationship between gender and lung cancer incidence rates; the rate was higher in women than men before age 70 y, but lower in women than men at age 80 y and above. Chance may explain this unexpected finding. The incidence rate was significantly higher in women than men in only two age groups (50–54 y and 55–59 y). Age was marginally significant (p
= 0.06) as an effect modifier when all cohorts are included in the pooled analysis; the association is much weaker when analyses consider only those cohorts or pairs of cohorts that provide incidence data on both sexes (p
= 0.21). Biases may affect some ages more than others. The gender-specific rates vary across cohorts, and different studies contributed differentially to different age groups. In any case, our analyses do not provide independent replication of the Wakelee et al. results [11
], since three cohorts (NHS, HPFS, MEC) were included in both studies.
It is nevertheless provocative that younger women have higher lung cancer incidence rates than men among never-smokers of European descent, and that African American and Asian women have higher age-standardized lung cancer incidence rates than men, even though the differences are not statistically significant. Relative survival is somewhat better in women than men among all patients with lung cancer, especially at younger ages [32
]. However, unless the gender difference in survival is considerably larger in never-smokers than smokers with lung cancer, one would not expect a 1-y relative survival of 41.3% in women and 38.3% in men to account for the gender pattern in lung cancer incidence that we observed.
Do African Americans Have Higher Risk Than Individuals of European Descent?
The pooled cohort data strengthen the evidence that lung cancer risk is higher in African Americans than individuals of European descent who have never smoked. The death rate from lung cancer was previously reported to be higher in African American women than in women of European descent in CPS-II [4
], but with limited data for African American men, and no information by which to compare incidence rates in individuals of European descent and African Americans. The pooled data in these analyses add new information on mortality rates among African American from BWHS, MEC, and additional follow-up of CPS-II, and new data on lung cancer incidence from BWHS, MEC, and the CPS-II Nutrition cohort. The lung cancer mortality rate among African Americans who report no active smoking, compared to that of individuals of European descent, is higher for both women (RR = 1.34, 95% CI = 1.1–1.7) and men (RR = 1.33, 95% CI = 0.9–2.1) in the age range 40–84 y. Similarly, the incidence of lung cancer is higher in African American women than in women of European descent who have never smoked (RR = 1.56, 95% CI = 1.1–2.1); there are too few cases among African American men to make meaningful comparisons. These data support the hypothesis that lung cancer incidence and death rates are higher among African Americans than individuals of European descent, even in the absence of active tobacco smoking, and that this difference in baseline risk may explain part but not all of the disparity in risk observed between African American and smokers of European descent.
Do Asians Have Higher Lung Cancer Risk Than Individuals of European Descent?
Lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low prevalence of female smoking. The very high incidence rates observed among women in the Tianjin registry in northeastern China and the Chiang Mai registry in northern Thailand are consistent with the large regional variations that have been reported previously among women in Asia, and especially in China [46
]. Li et al. reported a 20-fold difference between the lung cancer death rate between Chinese women living in counties at the tenth and 90th percentiles, based on a retrospective mortality survey conducted from 1973 to 1975 [46
]. Some of this variation undoubtedly reflects variation in active smoking. The prevalence of active smoking among women in China in 2003 ranged from about 4% in the southern provinces of Hainan and Guangxi to approximately 13% in the northern provinces of Heilongjiang and Inner Mongolia [50
]. Other factors likely to contribute to lung cancer risk among Chinese women include indoor air pollution from coal smoke from unventilated coal-fueled stoves [51
], volatilization of oils from cooking at high temperatures in open woks [53
], and secondhand smoke [53
]. Older women in northeastern China (Tianjin and Harbin) and northern Thailand (Chiang Mai and Lampang) have traditionally smoked more than women in other parts of China and southern Thailand. Pipe smoking was once common among older women in northeastern China. A local tobacco product called keeyo was smoked historically by women in northern Thailand. It remains unclear to what extent active smoking versus indoor air pollution from cooking and secondhand smoke contribute to the high rates of lung cancer and chronic obstructive lung disease among women in northeastern China and northern Thailand.
We did not expect that lung cancer incidence rates would be two to three times higher among Asian women, age 40–69 y, living in the Philippines, Hong Kong, Japan, and the Chinese population of Singapore than among Western women of the same age in populations with low female smoking prevalence. Other studies have reported that lung cancer rates have decreased over successive birth cohorts among women in Hong Kong [60
] and Singapore [61
]. In these countries, the lung cancer incidence rate peaked among women born around 1908 and decreased in later birth cohorts. Further population-based research is needed to characterize lung cancer incidence and death rates among women in Pacific Rim countries by birth cohort, smoking status, and exposure to other factors that may affect risk. The data needed must come from cohort studies and not hospital-based case series that measure proportions rather than rates. Several studies from Korea and other Pacific Rim countries have observed a smaller proportion of active smokers among female lung cancer patients in Asia than in the West [62
], yet these are difficult to interpret because they measure only the proportion of people who are exposed to the risk factor of interest, not the actual risk (incidence or death rates) among smokers or never-smokers. Active smoking has been considered uncommon among women in most Asian countries, but the relatively high lung cancer rates raise the possibility of incomplete reporting of active smoking.
Has Lung Cancer Risk among Lifelong Nonsmokers Changed over Time?
A challenge in interpreting temporal trends in cancer incidence and death rates is to distinguish actual changes in disease occurrence from artifacts due to changes in disease detection or classification. Technological advances such as bronchoscopy, percutaneous thin needle biopsy, and imaging technologies make it possible to biopsy pulmonary masses without open chest surgery [64
]. These technologies particularly affect the rates in older patients, increasing the likelihood that primary lung cancers will be detected, and decreasing the chances that pulmonary metastases will be misdiagnosed as lung cancer. Thus, temporal comparisons are most informative when restricted to the age range 40–69 y, where the diagnostic information was more reliable, even before the advent of these technologies. We find no indication that lung cancer rates have changed among lifelong nonsmokers within this age range in the US since the 1930s. The historical incidence rates among Connecticut women aged 40–69 y in 1935–1940 are similar to the incidence rates in the mid-1980s in other Western countries where female smoking is still uncommon. Likewise, the death rates among US women of this age in the 1930s are similar to the contemporary death rates among never-smokers in the pooled cohort studies. Nor have the lung cancer death rates changed appreciably among never-smokers from CPS-I (1959–1972) to CPS-II (1982–2004). The death rate was slightly lower in CPS-II than in CPS-I for men of European descent ages 40 y and above (RR = 0.83, 95% CI = 0.66–1.05) but slightly higher for women of European-descent (RR = 1.11, 95% CI = 0.98–1.25) and African American women (RR = 1.15, 95% CI = 0.62–2.13). Even among never-smokers age 80 y and above, the lung cancer death rates in the two studies appear to be converging with longer follow-up of CPS-II.
Our findings do not support assertions by Enstrom, Axelson, and others [12
] that lung cancer risk has increased substantially in the United States in lifelong nonsmokers. Most of the increase reported by Enstrom was based on a comparison of national lung cancer mortality rates in 1935 with the much lower death rates recorded in 1914 in a survey of deaths in 24 states conducted by the US Census [67
]. However, the 1914 survey was conducted before the International Classification of Diseases (ICD) was modified to include respiratory cancer (1929) or cancers of the lung and pleura (1938) [68
]. Furthermore, some of the deaths attributed to tuberculosis in the early 20th century may have involved misdiagnosis of lung cancer. The death rate from tuberculosis decreased by two-thirds between 1915 and 1935 [69
], a period when lung cancer mortality was rising, especially in men [70
]. Several other studies that reportedly found an increase in lung cancer risk among never-smokers [13
] relied on statistical modeling rather than direct measurement, and failed to consider the progressive increase in the risks associated with active smoking as the average duration of smoking has lengthened in the population.
Strengths and Limitations of the Analyses
A singular strength of our analysis is its ability to compare incidence and death rates from multiple sources in well-defined populations from different countries, time periods, and demographic subgroups. The general population or ecological data on women cover a 70-y time span and represent the total population—not a selected subgroup—of a diverse range of countries or regions. The pooled cohort data, which provide individual level information on smoking behavior and disease endpoints, yield more stable and statistically precise estimates of age-, sex-, and race-specific incidence and death rates than have been available from individual studies. The use of a common set of weights to standardize for age allows valid comparisons of age-standardized as well as age-specific rates across all groups.
It is reassuring that the pooled incidence and death rates for women age 40–69 y in the cohort studies are similar to those in the general population of countries with a similar level of economic development. It is also noteworthy that the lung cancer incidence rates among male never-smokers in the more affluent cohorts (CPS-II and HPFS) are similar to those in SCW. This argues against the assertion by some [13
] that the CPS-II rates underestimate the occurrence of lung cancer among men in the general population who have never smoked because the participants are less exposed to occupational and environmental pollutants. The incidence and death rates in the different cohort studies are far more remarkable for their similarities than their differences, despite the statistical evidence of some heterogeneity.
Our analyses are limited by uncertainties about the accuracy and completeness of the diagnostic information, by potential errors in the classification of exposure, and by the paucity of data available to examine risk in relation to race/ethnicity (especially in African American men and Hispanics). Diagnostic errors are especially problematic when comparing lung cancer rates across different time periods or countries at different stages of economic development. Missed diagnoses almost certainly contribute to the low recorded rates of lung cancer in Africa and parts of India during the 1980s, and to the lower incidence and death rates recorded in the oldest age groups. It is not clear how to quantify or minimize this uncertainty, except by restricting comparisons to the age range 40–69 y. Diagnostic errors are less of a concern in the cohort studies than in the ecological data, since most of the follow-up of these cohorts was conducted since 1980 in industrialized countries.
Uncertainties about errors or incompleteness in the exposure information complicate the interpretation of regional variations in lung cancer risk among women in China and other countries in East Asia. Even a small amount of misclassification of smokers among the never-smokers could have a substantial impact on the rates. It is difficult to find historical information on regional variations in active smoking by women or other exposures that may affect lung cancer risk. It is possible that smoking histories may be reported differently in Asia than in the West, and that former smokers or others who consumed relatively few cigarettes over a lifetime were more likely to be classified as never-smokers in the Korean and Japanese cohorts than studies based in Europe or North America.
Our analyses had limited ability to examine risk in subgroups of the population that have been historically underrepresented in cohort studies. Both the incidence and mortality data were especially sparse for African American men and Hispanics. The incidence data were also limited for Asian men and women and African American women. Even in individuals of European descent, the incidence data were not sufficiently robust to resolve whether women under age 60 y have higher lung cancer incidence rates than men, or whether age modifies the gender relationship.
Finally, we did not attempt to identify specific exposures that may contribute to lung cancer risk in various settings. Known risk factors include secondhand smoke, active smoking of other tobacco products, and exposure to other carcinogens such as asbestos, radon, radiation therapy, combustion products, and various other exposures in occupational, environmental, and/or medical settings [4