Cigarette Smoking and Esophageal and Gastric Cardia Adenocarcinoma

Adenocarcinomas of the esophagus and gastric cardia have increased in incidence over the past few decades in the United States, while the incidence of squamous esophageal carcinoma has changed little and that of distal gastric adenocarcinoma has decreased (1,2). Similar trends have been seen in Denmark, the U.K., Switzerland, and Sweden. Unexplained increases in adenocarcinomas of the lung and cervix have also occurred (in contrast to squamous carcinomas at these sites) both in the United States and elsewhere and are believed to be real. The causes of the increased incidence of adenocarcinomas of the esophagus and gastric cardia are still unknown. In 1993, the National Cancer Institute launched a 3-year multicenter population-based, case‐control study to identify the potential causes of the increase in the incidence of this disease. The results of this large, carefully designed and executed study have been eagerly awaited. In this issue of the Journal, Gammon et al. (3) present the first findings. They observe a strong association between tobacco smoking and increased risk of adenocarcinomas of the esophagus and gastric cardia. Risk of adenocarcinomas of the esophagus and gastric cardia appears to be more than doubled, with a dose‐response pattern, among smokers. Little reduction in risk was observed until smoking cessation for more than 30 years. This study, which employed a well-developed and standardized questionnaire, was conducted in centers in New Jersey, Connecticut, and Washington State. Five separate groups were sampled: case patients with esophageal adenocarcinoma, case patients with adenocarcinoma of the gastric cardia, case patients with other gastric adenocarcinoma, case patients with squamous cell carcinoma of the esophagus, and control subjects. This is the largest population-based, case‐control study of these adenocarcinomas conducted to date. The data resulting from this study will afford examination of a rich set of etiologic hypotheses. The response rates are reported by the authors as approximately 80% among case patients with adenocarcinomas of the esophagus and gastric cardia, 74% among those with the other cancers (comparison subjects), and 70% among control subjects. Unfortunately, the rapid course of these diseases means that substantial proportions of all case patients were not available for interview by the time the investigators identified them. Thus, for approximately one third of the targeted case patients and comparison subjects, a proxy respondent provided exposure data. The authors express some comfort with the data extracted from these proxy respondents, and they indicate that the exclusion of subjects with proxy data made little difference in the results. It is important that in one of the studies (4) cited by the investigators on the quality of smoking data extracted from proxy respondents, 35% of proxy respondents were not able to estimate the age at which the subject began smoking. Among those who were able to make an estimate, there was clear evidence of underestimation of the years of smoking (4). Thus, Gammon et al.’s estimates of the effects of smoking on risk may be conservative. Gammon et al.’s estimates of the effects of education, income, smoking, and alcohol consumption on risk are adjusted for body mass. Considering that smoking may affect body weight and that esophageal cancer itself may induce weight loss prior to the diagnosis of the disease, controlling for body mass may induce bias. Whether body mass was assessed prior to or at diagnosis or whether it was assessed at interview would seem to be an important consideration. It is difficult to predict the direction of the bias that might result from confounding by body mass. Estimates of the association between smoking and adenocarcinomas of the esophagus and gastric cardia have varied in several earlier case‐control studies (5‐15). This larger scale case‐ control study adds definitive evidence on the effect of smoking on risk. The finding is consistent with six other case‐control studies (5‐10).In four case‐control studies (5‐8)of a combination of adenocarcinomas of the esophagus and gastric cardia, all identified a statistically significant association between cigarette smoking and disease. Among five studies (9‐13)looking at only adenocarcinomas of the gastric cardia, two (9,10) demonstrated an association. In two studies (14,15) with only adenocarcinomas of the esophagus and relatively small sample sizes, no association with smoking was found. This variable outcome may simply be explained by the sample sizes or the power of the studies, since among six studies (5‐10)finding a positive association with tobacco, five (5‐8,10)had relatively larger sample sizes. These findings may also indicate that the influence of tobacco on adenocarcinoma of the esophagus might be different from that on adenocarcinoma of the gastric cardia. Although the incidence rate of adenocarcinoma of the esophagus was still rising from 1988 through 1990, no further increase in the incidence of gastric cardia adenocarcinoma was observed (2). Whether adenocarcinomas of the esophagus and gastric cardia are a single neoplastic entity or two different diseases still needs more study. In view of the large sample size, the moderate effect of smoking, and the demonstrated dose‐response relationship,