Gastric cancer and esophageal cancer are the second and sixth most common causes of cancer death worldwide. Both of these upper gastrointestinal tract (UGI) cancers have a very poor prognosis, largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of new modifiable risk factors and development of new methods to diagnose and treat more cases at earlier, more curable stages of disease. PURPOSE:
The aims of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal cancers, and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. METHODS: Both etiologic and early detection studies are most efficiently done in high-risk populations, so many of the studies in this project are performed in such populations. (1) Etiologic studies: (a) China: Between 1985 and 1991, we conducted two randomized nutrition intervention trials (NIT), in Linxian, China, a county where cumulative death rates due to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) exceed 20%. These trials, with a combined enrollment of nearly 33,000 people, evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E. Since 1991, we have followed the NIT participants as a cohort, and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. In addition, we have performed other etiologic studies specifically designed to evaluate individual exposures such as polycyclic aromatic hydrocarbons (PAHs), acetaldehyde, and human papillomavirus (HPV). (b) Iran: We are currently conducting two etiologic studies in Golestan Province, Iran, another population with very high rates of ESCC. The Gastric and Esophageal Malignancies in Northern Iran (GEMINI) Case-Control Study is enrolling 300 ESCC cases and 900 controls, and The Golestan Cohort Study is enrolling 50,000 participants. Comparing results from high-risk populations in Iran and China, which are quite distinct geographically, ethnically and culturally, should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Other UGI cancer studies: We have begun preliminary studies evaluating PAH exposure in high ESCC risk populations in southern Brazil and in western Kenya. (2) Early Detection of Esophageal Cancer: This part of the project includes four studies: (a) the Cytology Sampling Study (CSS), to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) the Mucosal Staining Study (MSS), to develop methods for endoscopic localization of squamous and glandular dysplasia of the esophagus and stomach; (c) the Endoscopic Therapy Pilot Study (ETPS), to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC; and (d) the Chemoregression Study (CRS), to test chemoprevention strategies to reduce progression and increase regression of low-grade esophageal squamous dysplasia. PROGRESS: (1) Etiologic studies: (a) China: Recent results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16, HPV 18, or HPV 73 and ESCC, gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer; and (x) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer. Tumor and non-tumor tissue collection for a separate study of the presence and functionality of HPV in ESCC and GCA has also been completed. (b) Iran: The patient accrual for the GEMINI Case-Control Study (300 cases, 900 controls) has now been completed, and analysis of questionnaire data and biological samples is now underway. The accrual for the Golestan Cohort Study has now reached 41,000 participants. (c) Other UGI cancer studies: Recent results from southern Brazil show a association between urinary 1-hydroxypyrene glucuronide (a PAH metabolite) and consumption of mate, a local tea which has been associated with ESCC risk. (2) Early Detection of Esophageal Cancer: (a) CSS: We recently analyzed a CSS study in which 720 asymptomatic Linxian adults were examined by one of two esophageal balloon samplers, followed by blood collection and endoscopy. The sensitivity/specificity of the two samplers for identifying biopsy-proven esophageal squamous dysplasia or cancer were 39%/85% and 46%/84%, insufficient for general use as a primary screening test for these lesions. (b) CRS: We recently completed the analysis of our first chemoregression study. This study randomized 267 Linxian patients with biopsy-proven mild or moderate squamous dysplasia to one of four treatment groups: selenomethionine 200ug once/day, celecoxib 200mg twice/day, both agents, or neither. Endoscopy was performed at baseline (T0) and after 10 months of intervention (T10). The primary endpoint was change in each patients worst dysplasia grade between T0 and T10 (regression/stable disease/progression). 238 patients (89%) completed the trial. Analysis showed that celecoxib treatment did not influence dysplasia grade (p=0.78). Selenomethionine had no effect in patients who began the trial with moderate dysplasia (p=1.00), but showed a significant improvement in dysplasia grade in patients who began with mild dysplasia (p=0.02)
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