Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection.

PURPOSE: Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. PATIENTS AND METHODS: In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. RESULTS: Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. CONCLUSION: Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.

Association of Helicobacter pylori infection and diet on the risk of gastric cancer: a case-control study in Hawaii.

OBJECTIVE: The risk factors most strongly associated with gastric cancer are the gastric bacteria Helicobacter pylori and diet. Utilizing data from a case-control study among residents in Hawaii, we examined the association of diet, presence of H. pylori, and non-cardia gastric cancer risk. METHODS: Serum taken at diagnosis for cases (n = 212) and at interview for controls (n = 336) was assayed for IgG antibodies to H. pylori group antigens and to a recombinant fragment of the cytotoxin-associated antigen A (CagA) protein, and subjects completed food frequency questionnaires. Risk measures were calculated using logistic regression. The likelihood ratio test was used to assess interactions. RESULTS: Inverse associations were found between gastric cancer risk and increasing intake of several micronutrients and vegetables among all individuals. For H. pylori/CagA-positive subjects, significant trends were present for total, green, and yellow vegetables, while a significant trend was present only for yellow vegetables among H. pylori/CagA-negative individuals. For intestinal gastric cancer, there was a suggestion that intake of vegetables, especially cruciferous vegetables, had a stronger protective effect for the H. pylori/CagA-positive group. CONCLUSIONS: Diet may play a greater role in the etiology of non-cardia gastric cancer among individuals with evidence of H. pylori infection than among those without.

Helicobacter pylori, pepsinogen, and gastric adenocarcinoma in Hawaii.

BACKGROUND: The objective was to investigate the association of Helicobacter pylori and serum pepsinogen (PG) levels with gastric adenocarcinoma. METHODS: Serum obtained from 299 patients at the time of cancer diagnosis and from 336 population-based control subjects was tested for PG I, PG II, and antibodies to H. pylori and to CagA. RESULTS: Subjects with low PG I levels or low PG I/II ratios were at increased risk for cardia and noncardia gastric cancer, whereas those with H. pylori or CagA seropositivity had an elevated risk for noncardia cancer only. Subjects seropositive for either H. pylori or CagA who had low PG I levels had the highest odds ratio (OR) (9.21 [95% confidence interval {CI}, 4.95-17.13]) for noncardia cancer, compared with subjects with neither factor. Elevated risks were also found among subjects with only 1 factor (OR, 5.40 [95% CI, 2.61-11.20] for low PG I level only; OR, 4.86 [95% CI, 5.90-8.13] for H. pylori or CagA seropositivity only). This pattern persisted when PG I/II ratio replaced PG I level and when CagA seropositivity alone replaced H. pylori immunoglobulin G or CagA seropositivity. CONCLUSIONS: The results suggest that persons with both H. pylori or CagA seropositivity and a low PG I level or PG I/II ratio are highly susceptible to development of noncardia gastric cancer.

Prospective study of the association of serum triglyceride and glucose with colorectal cancer.

To determine if serum triglyceride and glucose levels are associated with colorectal cancer, a prospective study among 7619 Japanese-American men was conducted. From 1968 to 1998, 376 colon and 124 rectal cancer incident cases were diagnosed. A strong positive association of alcohol intake and pack-years of cigarette smoking with colorectal cancer was observed. Body mass index and heart rate were also positively related to colon, but not to rectal cancer. In contrast, serum triglyceride did not predict the development of either colon or rectal cancer. There was a modest association of serum glucose in the highest quartile group with rectal cancer (relative risk = 1.33; 95% confidence interval, 0.79-2.26), but it was not statistically significant. This study did not find a strong positive association of serum triglyceride or glucose with colorectal cancer, but additional studies including other metabolic consequences associated with increased serum triglyceride and glucose may clarify the relationship.

Case-control study of diet and other risk factors for gastric cancer in Hawaii (United States).

OBJECTIVE: To investigate the association of diet and other factors with gastric adenocarcinoma of the distal stomach. METHODS: Three hundred cases and 446 population-based controls were interviewed with a quantitative, food frequency questionnaire, which listed over 250 foods. The questionnaire also included information on smoking history, alcohol intake, education, medical history, medication use, and a family history of cancer. RESULTS: Cigarette smoking, family history of gastric cancer and personal history of gastric ulcer were positively associated with gastric cancer, while education and past use of non-steroidal anti-inflammatory drugs were inversely related to risk. The consumption of all vegetables, mainly dark green, light green, and yellow vegetables, reduced risk. Many of these vegetables contain beta-carotene, vitamin C, vitamin E or folate, which were also inversely related to gastric cancer risk. When these nutrients were analyzed simultaneously, the inverse association was mainly with beta-carotene. The intake of processed meats and bacon was positively associated with gastric cancer risk, but primarily in men. When we simultaneously adjusted these meats for the intake of the different vegetables, the association was no longer significant. CONCLUSIONS: These findings provide additional support that the consumption of dark green and yellow vegetables are protective against adenocarcinoma of the distal stomach.

Serum vitamins and the subsequent risk of bladder cancer.

PURPOSE: We determined whether serum vitamins are inversely related to bladder cancer risk. MATERIALS AND METHODS: A cohort of 9,345 Japanese-American men was examined from 1971 to 1977. At examination a blood specimen was obtained and the serum was frozen. After a surveillance period of more than 20 years 111 tissue confirmed incident cases of bladder cancer were identified. Stored serum and that of 111 age matched controls were tested by high pressure liquid chromatography for certain micronutrients, including lutein, zeaxanthin, anhydrolutein, alpha-cryptoxanthin, beta-cryptoxanthin, lycopene, dihydrolycopene, alpha-carotene, beta-carotene, total carotenoids, retinol, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol and total tocopherols. RESULTS: Based on quartiles of serum micronutrient levels the ORs for bladder cancer were determined using the general estimating equations approach. There were statistically significant inverse linear trends in risk for alpha-carotene (p <0.01), beta-carotene (p = 0.03), lutein plus zeaxanthin (p = 0.03), beta-cryptoxanthin (p = 0.04) and total carotenoids (p = 0.02). However, after adjustment for pack-years of cigarette smoking none of the inverse trends remained significant. CONCLUSIONS: These results suggest that cigarette smoking, which is a strong risk factor for bladder cancer, may explain the apparent protective effect of individual and total carotenoids against this common cancer.

Serum insulin-like growth factor I and subsequent risk of colorectal cancer among Japanese-American men.

Recent reports suggest that colorectal cancer is positively related to insulin-like growth factor I (IGF-I) and inversely related to insulin-like growth factor binding protein 3 (IGFBP-3). To evaluate these associations further and separately for colon and rectal cancer, the authors conducted a nested case-control study in a cohort of 9,345 Japanese-American men examined in Hawaii in 1971-1977. A total of 177 incident colon cancer cases and 105 incident rectal cancer cases were identified from 1972 to 1996. These patients' stored sera and those of 282 age-matched controls were measured for IGF-I and IGFBP-3. The adjusted mean level of IGF-I was higher in colon cancer cases than in controls (154.7 ng/ml vs. 144.4 ng/ml; p = 0.01). However, the multivariate odds ratio for the highest quartile compared with the lowest was just 1.8 (95% confidence interval: 0.8, 4.3). Adjusted mean IGF-I levels were similar between rectal cancer cases and their controls. For IGFBP-3, adjusted mean levels were lower for both colon and rectal cancer cases than for their matched controls, but the differences were not significant. The IGF-I results weakly support findings from other studies and suggest that there are differences in IGF-I findings between colon and rectal cancer cases. It is possible that IGF-related risk is confounded by other factors that may vary among different cohorts. Further research is needed to clarify these relations.

Helicobacter pylori CagA seropositivity and gastric carcinoma risk in a Japanese American population.

Helicobacter pylori colonization is associated with gastric cancer, but whether and to what extent the risk is greater for strains with the cagA gene than for those without needs to be determined. Between 1967 and 1977, 9963 Japanese American men were recruited and examined. By 1996, incident cases of gastric carcinoma of the distal stomach had been diagnosed in 261 men. Stored serum samples from these case patients and 261 age-matched control subjects were tested for immunoglobulin G antibodies to H. pylori and to the CagA product of H. pylori, using antibody-specific enzyme-linked immunosorbent assays. Compared with H. pylori-negative, CagA-negative men, H. pylori-positive, CagA-negative men had an odds ratio (OR) of 2.7 (95% confidence interval [CI], 1.3-5.6) for intestinal gastric carcinoma. Men seropositive for both H. pylori and CagA had an OR of 4.1 (95% CI, 2.2-7.7). This suggests that colonization by an H. pylori strain with the cagA gene is associated with a greater risk of intestinal gastric carcinoma.

Gastric carcinoma: pathology findings in a multiethnic population.

OBJECTIVES: To assess the pathology of gastric carcinoma and to determine whether carcinoma of the cardia occurs more often among whites than among other ethnic groups in Hawaii. This study focuses on demographic differences in subsite locations and histologic types of gastric carcinoma. METHODS: We reviewed 532 sequential gastric carcinomas accessioned between 1993 and 1999 in the Hawaii Tumor Registry. Pathology reports and slides were reviewed by the study pathologist. RESULTS: Carcinoma of the cardia occurred in 51 (15.8%) of 323 males compared with 18 (8.6%) of 209 females (P = 0.02, after age adjustment). The age-adjusted percent of cardia cases was 41.8% for Hawaiian white males compared with 13.4% for men of all other ethnic groups (P = 0.0002). The age-adjusted percent of cardia cases was 22.4% for Hawaiian white females compared with 7.3% for females of other groups. (P = 0.08). At all age levels, females had more frequent diffuse carcinomas and less frequent intestinal type gastric carcinomas than men. The age-adjusted percent with diffuse carcinoma was 35.3% for females and 13.7% for males (P < 0.0001). Also, the sex-adjusted percent with diffuse carcinoma was 26.0% for patients younger than 75 years of age compared with 17.0% for patients 75 years or older (P = 0.01). Conversely, the sex-adjusted percent with intestinal carcinoma was 67.9% for patients younger than 75 years of age compared with 77.1% for patients 75 years or older (P = 0.02). The proportion of cases showing precursor lesions (intestinal metaplasia or superficial gastritis) increased progressively with the distance of the carcinoma from the cardia. CONCLUSIONS: Carcinoma of the cardia is predominantly a tumor of white males and is not associated with the multifocal gastritis characteristically found with carcinoma distal to the cardia. Diffuse gastric carcinoma shows no ethnic predilection, but expression of this phenotype is clearly related to the age and gender of the patient.

Gastric carcinoma distal to the cardia: a review of the epidemiological pathology of the precusors to a preventable cancer.

A distinctive gastritis precedes the development of cancer distal to the cardia. Helicobacter pylori infection and the use of pickled foods as substitutes for fresh fruits and vegetables constitute the most important environmental factors that generate this gastritis. This review describes the anatomical changes that characterise the step-by-step evolution of a process that begins in childhood and culminates in invasive cancer in middle and old age. Progression of the gastritis can be followed by measuring the host antibody response to the H. pylori infection and by serum assays that indicate loss of parietal cell mass. Cancer of the distal stomach will disappear if adequate, sanitary housing and year-round fresh vegetables are made available to all economic levels of society. Programmes that offer these reforms must be sustained over several generations, since the anatomical changes that precede gastric cancer are probably not reversible and begin early in life. In the absence of these reforms, death from gastric cancer may be prevented if patients with asymptomatic, early cancers are identified. High H. pylori antibody levels and serum pepsinogen assays may be used to identify persons with the extensive gastritis that favours the presence of such early cancers.