The results of this pooled analysis demonstrate a consistent association between cigarette smoking and risk of esophageal adenocarcinoma, esophagogastric junctional adenocarcinoma, and all adenocarcinoma. In addition, our results demonstrate that risk increases monotonically with increasing total dose (pack-years). Last, they show a risk reduction after smoking cessation, compared with current smokers.
In total, these results provide strong support for an association between cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction. Tobacco smoke is known to contain several carcinogens (29
), which provides mechanistic support to our conclusions. In addition, the temporal relationships of these exposures and outcomes also provide supporting evidence; cigarette smoking is typically initiated many years before tumor diagnosis in smokers. Plausible biological mechanisms that may explain the association between cigarette smoking and adenocarcinoma, either singly or in combination, include the genotoxicity of tobacco smoke to esophageal cells (30
), increased gastroesophageal reflux via induced transient lower esophageal sphincter relaxations from biologically active constituents of tobacco smoke (31
), and changing constituents of cigarettes over time with increasing amounts of nitrosamines (33
Summary odds ratios for analyses of cigarette smoking, shown herein, were similar for esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma, although these cancers have other features in common, too. They are both more common among white men (21
) and share several risk factors including obesity (34
) and gastroesophageal reflux (36
). Similarity of risk factors could, in part, be due to the fact that these two tumor types cannot always be accurately distinguished from one another. Occasionally, tumors may traverse the esophagogastric junction, which can make the site of origin diagnostically contentious. Although traversing cancers may lead to misclassification, the above similarities between esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma, and the fact that all studies included in analyses of this pooling project present fairly homogeneous estimates of risk, should assuage concerns that these results are significantly altered via misclassification bias. Given the similarities between esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma, we decided to combine these cancers into one analytic category—that of all adenocarcinoma.
Prospective studies (37
) have shown that smoking also increases the risk of gastric noncardia adenocarcinoma by approximately twofold (hazard ratio = 2.04, 95% CI = 1.32 to 3.16) (19
). Therefore, one may conclude that cigarette smoking increases the risk of all adenocarcinomas of the esophagus and stomach by an average of twofold, and that risk increases further with increasing total dose (pack-years of cigarette smoking). In comparison, smoking is a stronger risk factor for squamous cell carcinoma of the esophagus (10
), the other major histological type of esophageal cancer.
Our pooled analysis, to our knowledge, provides the first precise sex-specific risk estimates of the associations between cigarette smoking and esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma. Summary odds ratios of these associations were similar for men and women. These results are consistent with previous studies of lung cancer showing that the association with cigarette smoking is similar in both sexes (39
). Estimating the proportions of esophageal adenocarcinoma or esophagogastric junctional adenocarcinoma that are associated with cigarette smoking is difficult because cigarette smoking prevalence varies by population and has changed over time, and the exact time period between exposures and outcome, which is etiologically relevant, is unclear. Because men have traditionally smoked more than women (41
), cigarette smoking has likely caused many more adenocarcinomas of the esophagus and esophagogastric junction in men than in women, which may account for part of the sex differences in the incidence of these cancers. However, because the prevalence of smoking in the United States has been declining and converging between the sexes since 1965 (41
), it is unlikely that smoking could explain the recent and continuing rise of esophageal adenocarcinoma (42
) and the eightfold difference in sex disparity (23
Cigarette smoking is one of the most extensively investigated exposures in epidemiological studies, and several models have been used for analysis of smoking in relation to health outcomes (43
). In lung cancer studies, it has been argued that the contribution of smoking intensity and duration to risk of disease may not be equal, and therefore, using cumulative total exposure in terms of pack-years may not be an optimal strategy to deduce risk associations (43
). Other authors have suggested using duration and intensity as separate variables in analytic models, but for a constant duration, increasing intensity means increased total exposure, so attributing the effect to intensity could be misleading (45
). Therefore, as Samet et al. (41
) noted, there is perhaps no single model that is entirely satisfactory. We chose categories of pack-years of cigarette smoking as the main exposure because of the following reasons: most studies have shown a dose–response association of this variable with lung and other cancers (47
); interpretation of the results is relatively easy; results are meaningful for causal inferences and public health purposes; and no assumptions are made about linearity of the associations.
Because of the fact that total exposure is affected by smoking intensity, smoking duration, age of smoking initiation, and years of smoking cessation, we adjusted for total exposure (pack-years) when analyzing these associations. After adjustment, we did not observe any association between smoking intensity, age of smoking initiation, and cigarette type, with risk of esophageal adenocarcinoma or esophagogastric junctional adenocarcinoma. Because total exposure is the product of intensity and duration, no effect of intensity after adjustment for total exposure suggests that for a constant total exposure, lower intensity and longer duration have approximately the same effect as higher intensity and shorter duration. More in-depth analyses, including wasted dose, which is defined as reduced carcinogenic potency of higher smoking intensities relative to lower intensities given equal total exposure (45
), may reveal more details.
We noted that cigarette type was not statistically significantly associated with risk of esophageal adenocarcinoma or esophagogastric junctional adenocarcinoma after taking into consideration total exposure. Data on the effect of cigarette type on these cancers are sparse. However, for lung cancer, the body of evidence accumulated so far suggests that both filtered and nonfiltered cigarettes substantially increase the risk of cancer (50
). Also, studies show that there is little difference, if any, between cigarette types in their carcinogenic potential or in the amount of tar or nicotine that smokers receive from them (50
Because there was a dose–response relationship with pack-years in our analyses, we speculated that smoking cessation might truncate further increase in risk. Our analyses showed that even after adjusting for total pack-years, smoking cessation was associated with risk reduction. In other words, if one quits smoking today, one's risk would not only stop increasing but may also decrease over time. However, the summary odds ratios for greater than or equal to 10 years of smoking cessation suggested that risk does not decrease to the level of never–cigarette smokers. Indeed, the risk of all adenocarcinoma in those with greater than or equal to 10 years of smoking cessation was 1.7-fold of that of never–cigarette smokers (data not shown). Still, little is known about the long-term effects of smoking cessation on risk of all adenocarcinoma after adjusting for pack-years, and even this analysis had only adequate statistical power to stratify the sample into three groups of exposure. Using lung cancer as a model, most long-term studies with follow-up of up to 40 years have shown that although further increased risk of lung cancer is avoided by quitting, the risk will always remain higher in cigarette smokers than in never–cigarette smokers (50
Although our results demonstrate clear relationships of cigarette smoking with esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma, it is unlikely that smoking is solely responsible for the recent increase in cancer incidence. The prevalence of cigarette smoking started rising from 1881 (51
) when James Bonsack invented the first cigarette-rolling machine; yet, incidence of esophageal adenocarcinoma was still very low 95 years later, in the mid-1970s (42
). Prevalence of smoking among the United States male population started declining from 1965 (52
) after publication of the first report of the United States Surgeon General on smoking and health (53
); yet, esophageal adenocarcinoma rates, especially among white men, are still increasing (42
). During the same period that esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma rates have increased, incidence rates of esophageal squamous cell carcinoma, a cancer closely related to smoking, have decreased (42
). Although a longer latency period for esophageal adenocarcinoma may account for part of the difference between esophageal adenocarcinoma and esophageal squamous cell carcinoma, it is unlikely to explain it all. Furthermore, because cigarette smoking on average increases esophageal adenocarcinoma risk by twofold and only a fraction of the population smoke, cigarette smoking can at most contribute only part of the recent four- or fivefold increased incidence observed in some populations (42
This combined analysis has several notable strengths, including its large sample size, inclusion of population-based case–control and cohort studies, and availability of data on major confounders. The use of individual-level data permitted combined analyses with comparable variables, a feature not available in meta-analyses that use only published odds or risk ratios. There was no evidence of substantial heterogeneity between the study populations; results were robust to the choice of analytic methods (adjustment for confounders and random- vs fixed-effect models), analytic subgroups (men vs women and tumor location), and study design (case–control vs cohort).
This analysis may have several limitations. Because it is difficult to differentiate esophageal adenocarcinoma from esophagogastric junctional adenocarcinoma and adenocarcinomas of the lower stomach, there may have been misclassification. However, this misclassification may be less of a problem in this analysis, given the consistency of association across sites, and therefore, we decided to produce a combined analytic group pertaining to these sites—all adenocarcinoma. Also, case–control studies may be affected by recall bias and interviewer bias, although the intensity and duration of smoking are usually recalled relatively reliably (54
), but the two cohort studies (which obtained exposure information before the outcome) included in our pooled analysis showed results similar to those of the case–control studies. Therefore, we believe these biases are unlikely to have had a major impact on the results.
In summary, we found a statistically significant dose–response association between cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction that was seen in both men and women. Smoking cessation reduced the risk with decreasing risk associated with longer duration since quitting. These results strongly suggest that cigarette smoking is causally related to these two cancers.