DIETARY ANTIOXIDANT INTAKE AND THE RISK OF CARDIA CANCER AND NONCARDIA CANCER OF THE INTESTINAL AND DIFFUSE TYPES: A POPULATION-BASED CASE-CONTROL STUDY IN SWEDEN Anna Mia EKSTR ¨ OM 1 * , Mauro SERAFINI 2 , Olof NYR´ EN 2 , Lars-Erik HANSSON 3 , Weimin YE 1 and Alicja WOLK 1 1 Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden 2 Unit of Human Nutrition, Istituto Nazionale della Nutrizione, Rome, Italy 3 Department of Surgery, Mora Hospital, Mora, Sweden In spite of diverging incidence trends, subsite, and subtype- specific gastric cancer data on the association with dietary antioxidants are sparse. We aimed to test whether the ap- parent protective effect of antioxidants is mainly confined to noncardia (distal) cancer of the intestinal subtype, to which most of the incidence decline in gastric cancer has been ascribed. In a Swedish study base (total population 1.3 mil- lion), we interviewed 567 cases uniformly classified to subsite (cardia vs. noncardia) and subtype (intestinal vs. diffuse), and 1165 population-based controls, frequency matched for age and sex. Serologic data on H. pylori status was available for a subset of 542 individuals. Ascorbic acid (vitamin C) was in- versely associated with all subsites and subtypes of gastric cancer in a significant dose–response manner (all p<0.05), with risk reductions between 40% and 60%. -carotene was also strongly and negatively associated with risk, particularly with the intestinal type. The associations with -tocopherol (vitamin E) were less clear. The highest parallel intake of all three antioxidants (quartiles 4), compared to those with the lowest parallel intakes (quartiles 1), was associated with a 70% lower risk of developing noncardia cancer (OR 0.3, 95% CI 0.1– 0.9). Our results suggest that antioxidants might be especially beneficial among subjects at increased risk for gastric cancer such as smokers and those infected by H. pylori. We conclude that a high intake of antioxidants, as a consequence of high consumption of fruit and vegetables, may lower the risk not only for gastric cancer of the intestinal type, but also for diffuse type adenocarcinoma and cardia cancer. Int. J. Cancer 87:133–140, 2000. © 2000 Wiley-Liss, Inc. Antioxidants have the potential to neutralise DNA-damaging free radicals (Shklar, 1998) generated by smoking (Endoh and Leung, 1994) and by chronic Helicobacter pylori infection (Correa et al., 1998) and might therefore lower the risk of gastric cancer. The protective effect of fruit and vegetables in relation to gastric cancer shown by several investigators (Steinmetz and Potter, 1996) is presumably attributable to a high content of antioxidants. As the immediate target of ingested carcinogens and pro-mutagenic com- pounds, the gastric mucosa is likely dependent on these counter- acting factors for its maintenance and protection. Trends of gastric cancer differ markedly depending on tumour location (subsite). The spontaneous decline in the incidence of distal (noncardia) stomach cancer observed in many populations does not pertain to tumours originating in the gastric cardia region (Blot et al., 1991), strongly indicating different aetiologies. Fur- thermore, discrepancies in incidence trends between the two major histologic subtypes (Laure ´n, 1965), intestinal and diffuse, have prompted the hypothesis that the former is more linked to envi- ronmental factors than the latter (Laure ´n and Nevalainen, 1993). Subtype-specific data on the association with dietary antioxidants are sparse (Buiatti et al., 1991; Harrison et al., 1997), and to our knowledge, no study on antioxidants has ever distinguished be- tween both subsite (cardia vs. noncardia) and histologic subtype of distal gastric cancer. Our aim was to test the hypothesis that the apparent protective effect of antioxidants is confined mainly to noncardia cancer of the intestinal histologic subtype to which most of the decline has been attributed. Acknowledging that gastric cancer results from a mul- tifactorial process, we collected detailed data on potential risk modifiers to investigate the interplay between known risk factors (such as smoking and H. pylori infection) and antioxidants, in relation to risk of gastric cancer stratified for both anatomic subsite and histologic subtype. MATERIAL AND METHODS Our study was conducted in five counties with a total population of 1.3 million. Three counties situated in central Sweden have an incidence close to the national average, whereas the two northern counties have the nation’s highest incidence of gastric cancer. The study base consisted of all individuals aged 40 –79, born in Swe- den, and living in one of the above-mentioned counties during the study period; from February 1989 through January 1995. Cases We identified all patients with newly diagnosed gastric adeno- carcinoma during the study period via clinicians enrolled as con- tact persons at all hospitals in the study area and through contin- uous surveillance of gastric cancer specimens at the Hospital Pathology Departments. Moreover, we performed monthly double checks with regional cancer registries to which all new cancers must be reported according to Swedish law. These double-checks included up-date reports several years following the end of study to identify cases reported with long delays. Of the 908 patients who met the study base eligibility criteria, 567 [mean (SD) age 67.9 (9.1) years, 33.3% women] agreed to participate in an interview (participation rate 62.4%). The reasons for nonparticipation were early death or very advanced disease in 270 (29.7%), mental or physical illness other than gastric cancer in 40 (4.4%), patient refusal in 28 (3.1%), whereas 3 (0.3%) could not be located. Our very thorough case-ascertainment resulted in com- pleteness exceeding that of the nationwide Swedish Cancer Reg- ister (100% vs. 98%) (Ekstro ¨m et al., 1999). To uniformly classify tumour subsite and histological type (Lau- re ´n, 1965), the clinicians prospectively completed standardised reports on the tumour location, patient records were scrutinised, and all histological slides were re-evaluated by one pathologist (A. Lindgren). Cancer of the gastric cardia (n = 90) was defined as an adenocarcinomatous lesion with its centre located within 1 cm proximal and 2 cm distal to the gastro-oesophageal junction (Ek- stro ¨m et al., 1999). For a small fraction (0.9% of the cases, n = 5) the exact site of origin could not be determined. Intestinal differ- entiation was characterised by malignant cells forming definite glandular patterns (n = 337, 59.4%). Poorly differentiated cells, Grant sponsor: National Cancer Institute; Grant number: R01 CA 50959; Grant sponsor: Swedish Cancer Society. *Correspondence to: Department of Medical Epidemiology, Karolinska Institutet, Box 281, S-171 77 Stockholm, Sweden. Fax: 46-8-314975. E-mail: Annamia.Ekstrom@mep.ki.se Received 26 August 1999; Revised 13 January 2000 Int. J. Cancer: 87, 133–140 (2000) © 2000 Wiley-Liss, Inc. Publication of the International Union Against Cancer