Int. J . Cancer: 45, 852-854 (1990) Publication of the International Union Against Cancer Publication de I‘Union lnternationale Contre le Cancer 0 1990 Wiley-Liss, Inc.

THE CONSUMPTION OF TOBACCO, ALCOHOL AND THE RISK OF ADENOCARCINOMA IN BARRETT’S OESOPHAGUS Fabio LEVI’,~, Jean-Baptiste OLLYO~, Carlo LA VECCHIA334, Peter BOYLE~, Philippe MONNIER~ and Marcel SAVARY’ ‘Registre Vaudois des Tumeurs, Institut Universitaire de Me‘decine Sociale et Pre‘ventive, C H W BH-06, 101 I Lausanne; 2Clinique O.R.L., Centre hospitalier universitaire vaudois, 101 1 Lausanne; 31nstitut Universitaire de Me‘decine Sociale et Pre‘ventive, Bugnon 17, 1005 Lausanne, Switzerland; 41stituto di Ricerche Farmucologiche “Mario Negri”, Via Eritrea 62, 20157 Milano, Italy; and Sunit of Analytical Epidemiology, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon, France.

The relationship between tobacco, alcohol and the risk of oesophageal adenocarcinoma in Barrett’s oesophagus was evaluated in an endoscopy-clinic-based case-control study of 30 histologically confirmed cases of adenocarcinoma and 140 controls with Barrett’s oesophagus but no evidence of malig- nant lesions. Among the cases, 18 (60%) were non-smokers and 14 (47%) non-drinkers, the corresponding proportions in the controls being 52% and 44%. Thus, there was no apparent relation between tobacco, alcohol and the risk of adenocarci- noma of the oesophagus, the age- and sex-adjusted point es- timates being I .O for moderate and 0.9 for heavy smokers, 0.7 and I .5 respectively for moderate and heavy drinkers. Upper 95% confidence limits were I .6 for ever-use of tobacco and I .9 for ever alcohol drinking. The findings of this study, although based on a limited number of cases, indicate that alcohol and tobacco are unlikely to play a major role in the aetiology of adenocarcinoma in Barrett’s oesophagus.

In populations of developed countries of Europe and North America, alcohol and tobacco are the major risk factors for oesophageal neoplasms. Most published studies, however, do not distinguish between various histological types of oesoph- ageal cancer. Consequently, their results are chiefly applicable to squamous-cell carcinomas, which represent over 90% of oesophageal cancers (at least in European series), whereas little is known on the aetiology of adenocarcinoma of the oesopha- gus.

Columnar-lined (Barrett’s) oesophagus is probably an ac- quired disorder. It was originally described as heterotopic gas- trointestinal columnar epithelium lining the distal oesophagus (Barrett, 1950; Spechler and Goyal, 1986; Heading, 1987). Long-standing oesophagitis has been suspected of leading to the transformation of the oesophageal epithelium into Barrett’s oesophagus, i .e . , with columnar epithelium of gastric, cardiac or specialized type replacing the ordinary squamous epithe- lium. Moreover, it is well established that Barrett’s epithelium is associated with an increased risk of oesophageal carcinoma, particularly adenocarcinoma (Naef et al., 1975; Witt et al., 1983). Sarr et al. (1985) reported that 15% of symptomatic patients with Barrett’s oesophagus (13 of 84 patients) had a co-existent adenocarcinoma arising from their Barrett’s mu- cosa. This estimate was comparable to the prevalence rate derived for the Mayo Clinic dataset (Cameron et al . , 1985) and for the same Swiss series as considered for the present analysis (Ollyo et al., 1985).

Most of past work on the determinants of adenocarcinoma in Barrett’s oesophagus was purely descriptive and uncontrolled (Spechler and Goyal, 1986; Heading, 1987; Kalish et a l . , 1984; Sanfey et al., 1985). We used, therefore, a nested case- control approach to investigate the role of alcohol and tobacco on the risk of adenocarcinoma in Barrett’s oesophagus, using data from an endoscopy-clinic study conducted in Lausanne, Switzerland.

SUBJECTS AND METHODS

The data were derived from the records of the endoscopy

clinics of 2 teaching and general hospitals of the Swiss canton of Vaud (Ollyo el a l . , 1985).

Between 1963 and 1985, there were 30 patients (aged 37 to 86) with histologically confirmed diagnosis of adenocarcinoma in Barrett’s oesophagus (cases).

The control subjects (n = 140) were chosen, in the lists of the same clinics, among patients who had endoscopy of the upper digestive tract over the same calendar period, and whose histological diagnosis was of Barrett’s oesophagus in the ab- sence of malignant pathological features. The definition given for Barrett’s oesophagus in this series included diffuse circular forms measuring at least 3 cm of columnar epithelium.

The distribution of cases and controls according to sex and age groups is given in Table I.

Information was collected from the patients or, for deceased subjects (4 cases and 15 controls), from the next of kin or attending physician, on socio-demographic factors, smoking habits, alcohol consumption and related medical history ( i . e . , duration of gastro-oesophageal reflux and symptoms, previous malignant diseases). These data were cross-checked against clinical records and the files of the Vaud Cancer Registry (Levi, 1982, 1987).

Relative risks of oesophageal adenocarcinoma, together with their 95% approximate confidence intervals, were computed from data stratified for sex and age by means of the Mantel- Haenszel procedure (Mantel and Haenszel, 1959; Miettinen, 1976).

RESULTS

Among the 30 cases of adenocarcinoma of the oesophagus, 18 (60%) were non-smokers, compared with 73 out of 140 (52%) controls. Thus, there was no significant association be- tween tobacco and oesophageal adenocarcinoma and, indeed, the point estimates were below unity in heavy smokers (Table 11).

The relation between alcohol drinking and adenocarcinoma of the oesophagus is considered in Table 111. Almost 50% of the cases (14/30) did not drink alcohol, and the proportions of non-drinkers, moderate and heavy drinkers were similar in cases and controls. Consequently, the estimated relative risks were close to unity (0.7 for moderate and 1.5 for heavy drink- ers).

The interaction between alcohol and tobacco on adenocar- cinoma risk is considered in Table IV. There was no suggestion that the risk increased with exposure to both factors consid- ered, and in fact the lowest point estimate was observed among

6To whom reprint requests should be sent.

Received: December 19, 1989 and in revised form February 3, 1990.

TOBACCO, ALCOHOL AND ADENOCARCINOMA IN BARUETT’S OESOPHAGUS 853

TABLE I11 - DISTRIBIJTION OF 30 CASES OF ADENOCARCINOMA IN

Oesophageal adenocarcinoma Controls

Sex Males 21 (70) 85 (61) Females 9 (30) 55 (39)

Age (years) <50 2 (7) 24 (17)

30 7

subjects who both drank and smoked, although, on account of small absolute numbers of cases, none of the risk estimates presented in Table IV is statistically significant.

DISCUSSION

The findings of this study, albeit based on a small number of cases, indicate that alcohol and tobacco consumption are not important determinants of the risk of adenocarcinoma in Bar- rett’s oesophagus in this Swiss population. Risks as large as those commonly reported for all oesophageal cancers can be excluded, however.

Among 3 1 oesophageal adenocarcinomas included in the cancer Registry of the canton of Vaud over the period 1975-82 (Levi, 1982, 1987), 22 (71%) were in the lower oesophagus and 13 showed evidence of Barrett’s oesophagus.

These results are consistent with the SEER population-based cancer registration system (Yang and Davis, 1988), where 79% of 608 adenocarcinomas occurred in the lower third of the oesophagus, and with a pathologic series from Beth Israel Hos- pital in Boston (Wang et al., 1986), where 12 out of 12 ade- nocarcinomas were in the lower third of the oesophagus and 11 showed evidence of Barrett’s epithelium. In that study, the relative risks for smoking, using gastric adenocarcinomas as the reference category, was 1.4 for oesophageallcardiac ade- nocarcinomas and 7.3 for oesophageal squamous-cell carcino- mas. Likewise, in a previous comparison between 49 cases of gastric cardiac adenocarcinomas versus 22 adenocarcinomas arising in Barrett’s oesophagus, the prevalence of smoking and drinking was lower in the latter subgroup (Kalish et al., 1984).

Nonetheless, limitations and potential sources of bias should be considered before drawing definite conclusions from our data. First, the number of cases was low, on account of the rarity of the subsite and the histological type considered. Con- sequently, the power of this study was limited as well: for ever tobacco consumption the 95% upper confidence limit was 1.6

Oesophageal Relative risks1 adenocarcinoma estimates (95% C.I.)

~~

Non-smoker 18 73 12

Smoker <15 glday 3 13 1.0

( 0 . 3 4 1)

(0.2-1.9) 15-24 glday 5 33 0.6

>25 glday 4 21 ‘ 0.9 ’

(0.3-2.9)

~ _..._ ~ ~~ ~. ~~~~~~ ~~ ~ ...... BARRETT‘s OESOPHAGUS AND 140 CONTROLS WITH BARRETT’S

OESOPHAGUS BUT NO MALIGNANT LESION. ACCORDING TO ALCOHOL CONSUMWION

Oesophageal Relative risks] adenocarcinoma estimates (95% C.I.)

~~ ~~ ~~~ ~~

Non-drinker 14 61 1 2

Drinker <60 ml/day 9 54 0.7

>60 ml/dav 7 25 1.5 (0.3-2.0)

(0 5 - 4 4 )

‘Mantel-Haenszel estimates adjusted for age and sex.-2Reference category.

TABLE I V - INTERACTION BETWEEN AI.COHOI. AND TOBACCO ON THE RISK OF ADENOCARCINOMA 1s BAKRElT’S OESOPHAGUS

Relative risk1 estimated for: Alcohol

Nan-drinkers Drinkers ~ ~~~ ~~~~

Tobacco Non-smoker 12 1.8

Smoker 2.4 0.8 ( 1 2 ~ 5 7 ) ~ (6: 16)

(2:4) (10:63) lMantel-Haenszel estimates adjusted far age and sex.-2Reference category.

-3Number of cases: number of controls are given in parentheses.

and for alcohol consumption 1.9, Thus, this study could not exclude moderate increases in risk.

Second, the source of information from dead patients (next of kin or attending physicians) may have introduced some in- formation bias. Further, Barrett’s oesophagus per se may be positively related to alcohol and tobacco. The data, therefore, indicate that occurrence of adenocarcinomas in Barrett’s oe- sophagus is unlikely to be strongly related to alcohol and to- bacco, but cannot exclude the possibility that both conditions are related to these risk factors.

It is however unlikely that the extent of these potential biases is totally responsible for the negative results of this study, chiefly in consideration of the large proportions of non- smokers (60%) and non-drinkers (47%) in the cases, and since smoking and drinking habits were determined at the time the Barrett’s oesophagus was first diagnosed. These proportions are substantially different from those observed in overall series of oesophageal cancer cases of unspecified histology from Southern Europe. In a study conducted in Calvados, France (Tuyns et al., 1977), for instance, among 743 oesophageal cancer cases, only 19 (3%) had never consumed alcohol and 74 (10%) had never smoked, and in a study of 250 cases from Northern Italy (La Vecchia and Negri, 1989), only 30 (12%) had never drunk and 38 (15%) never smoked.

Thus, although the limitations of the present study are con- siderable, they do not entirely obscure its major finding, i .e . , that alcohol and tobacco are unlikely to play a major role in the development of oesophageal adenocarcinoma in existing Bar- rett’s oesophagus, at least as compared with their overwhelm- ing importance in squamous-cell cancer of the oesophagus in European populations (Tuyns et al., 1977; La Vecchia and Negri, 1989).

Adenocarcinomas arising in Barrett’s oesophagus, to which the inferences from this study directly apply, represent only a proportion, however large, of all gland-cell neoplasms of the oesophagus. It is thus possible that oesophageal adenocarcino- mas can be further subdivided in different aetio-pathological entities.

In conclusion, the determinants of various histological types of oesophageal neoplasms appear to be heterogeneous: if an ’Mantel-Haenszel estimates adjusted for age and sex.-2Reference category

854 LEV1 ET AL.

appreciable proportion of adenocarcinomas which tend to arise in the lower third of the oesophagus is indeed unrelated or not strongly related with alcohol and tobacco, the associations of these risk factors with squamous-cell carcinoma may have been diluted and hence underestimated in studies which did not dis- tinguish between various histological types or subsites of oe- sophageal cancer. Moreover, in a prevention perspective this report shows that among patients with Barrett’s oesophagus

who are regularly followed with endoscopy, those most liable to develop a cancer cannot be selected on the basis of their smoking or drinking habits.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the contribution made by the Swiss League against Cancer. We thank Ms. M. Me- nond and Ms. F. Golay for editorial assistance.

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