This application is for the renewal of CA059005, supporting a multicenter, randomized, double blind, placebo controlled trial of aspirin and/or folate supplementation for the prevention of colorectal adenomas. The study was motivated by extensive epidemiological and preclinical data suggesting the efficacy of these interventions. The treatment phase of the trial has been completed, and we now propose final clinical follow- up of subjects and biological measurements that will help clarify the study findings. At enrollment, each study subject had a recent large bowel adenoma, with no known polyps remaining in the bowel. Subjects were randomized in a 2 x 3 factorial manner to folic acid (1 mg or placebo daily) and to aspirin (325 mg, 81 mg or placebo daily). Follow-up colonoscopies were scheduled for approximately 3 years after study entry;subsequent examinations followed clinician recommendations (typically 3 or 5-years later). Aspirin treatment was for three years;subjects were invited to maintain randomized folic acid treatment for an additional colonoscopic surveillance cycle. (74% of subjects agreed.) Over the 3-year treatment period, 81 mg aspirin reduced the risk of all adenomas (RR = 0.83 (95% CI, 0.70-0.98) and of advanced lesions (tubulovillous or villous adenomas, those at least 1 cm in diameter, or with severe dysplasia or invasive cancer, RR = 0.59, 95% CI 0.38-0.92). However, 325 mg aspirin did not have significant effects. The reasons for this dose-response pattern are not clear, but may relate to the broad effect of aspirin in reducing production of both pro-carcinogenic and anti-carcinogenic prostaglandins at various doses. Folic acid supplementation had no effect during the first three years of treatment, but showed some evidence of harm during the next surveillance cycle, when the RR for advanced lesions was 1.67 (95% CI 1.00-2.80) and the RR for 3 or more adenomas was 2.32 (95% CI 1.23-4.35). Risk of prostate cancer was also increased. These findings could be a consequence of the high folate intake in subjects randomized to folic acid or could reflect differences between the biological effects of the natural, dietary folates and those of the synthetic, unmetabolized folic acid used in supplements and food fortification. We now propose to investigate the evolution of the increased adenoma risks associated with folic acid supplementation by following subjects for at least one colonoscopic surveillance cycle after randomized folic acid treatment ended. Using blood specimens drawn about 3 years after study entry, we will assay unmetabolized folic acid as well as the main natural folate, 5-methyl-tetrahydrofolate, to assess their separate effects on adenoma risk. To study the aspirin effects, we will assay urinary PGE-M (the main metabolite of PGE2, strongly associated with carcinogenesis in the large bowel) and urinary PGI-M (the main metabolite of prostacyclin, a likely anti-carcinogenic prostaglandin). We will also explore whether aspirin-triggered lipoxins - recently identified anti-inflammatory eicosanoids - played a role in the chemopreventive effects of aspirin.
In our clinical trial of two interventions thought to prevent colorectal cancer, we found aspirin to be effective, while folic acid may have increased risk of large bowel tumors. We propose to: 1) conduct a follow-up of our subjects to see if the increased folic acid risk continued, 2) conduct studies that will separate the effects of natural, dietary folates from those of the synthetic folic acid used in supplements and food fortification, and 3) study some possible mechanisms for the protective effects of aspirin.
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