Aspirin/Folate Prevention of Large Bowel Polyps

描述（由申请人提供）：本申请旨在更新CA 059005，以支持一项补充阿司匹林和/或叶酸预防结直肠腺瘤的多中心、随机、双盲、安慰剂对照试验。这项研究的动机是广泛的流行病学和临床前数据表明这些干预措施的有效性。试验的治疗阶段已经完成，我们现在提出对受试者的最终临床随访和生物学测量，这将有助于澄清研究结果。 入组时，每例研究受试者近期均患有大肠腺瘤，肠道内无已知息肉。受试者以2 × 3析因方式随机分配至叶酸组（每日1 mg或安慰剂组）和阿司匹林组（每日325 mg、81 mg或安慰剂组）。随访结肠镜检查计划在研究入组后约3年进行;随后的检查遵循临床医生的建议（通常为3或5年后）。阿司匹林治疗3年;受试者被邀请在额外的结肠镜监测周期内维持随机叶酸治疗。(74%的受试者同意。） 在3年的治疗期内，81 mg阿司匹林降低了所有腺瘤（RR = 0.83（95% CI，0.70-0.98））和晚期病变（管状绒毛状或绒毛状腺瘤，直径至少1 cm，或伴有重度异型增生或浸润性癌，RR = 0.59，95% CI 0.38-0.92）的风险。然而，325 mg阿司匹林没有显著效果。这种剂量-反应模式的原因尚不清楚，但可能与阿司匹林在不同剂量下减少促癌和抗癌的甘草素产生的广泛作用有关。叶酸补充剂在治疗的前三年没有效果，但在下一个监测周期显示出一些损害的证据，晚期病变的RR为1.67（95%CI 1.00-2.80），3个或更多腺瘤的RR为2.32（95%CI 1.23-4.35）。患前列腺癌的风险也增加了。这些发现可能是随机接受叶酸的受试者摄入高叶酸的结果，也可能反映了天然膳食叶酸与补充剂和食品强化中使用的合成未代谢叶酸的生物学效应之间的差异。 我们现在建议在随机叶酸治疗结束后，对受试者进行至少一个结肠镜监测周期的随访，以研究与叶酸补充相关的腺瘤风险增加的演变。使用研究入组后约3年采集的血液标本，我们将测定未代谢的叶酸以及主要的天然叶酸盐5-甲基-四氢叶酸，以评估它们对腺瘤风险的单独影响。为了研究阿司匹林的作用，我们将测定尿PGE-M（PGE 2的主要代谢产物，与大肠中的致癌作用密切相关）和尿PGI-M（前列环素的主要代谢产物，一种可能的抗癌前列腺素）。我们还将探讨阿司匹林触发的脂氧素-最近发现的抗炎类花生酸-是否在阿司匹林的化学预防作用中发挥作用。 在我们对两种被认为可以预防结直肠癌的干预措施进行的临床试验中，我们发现阿司匹林是有效的，而叶酸可能会增加大肠肿瘤的风险。我们建议：1）对我们的受试者进行随访，看看叶酸风险是否继续增加，2）进行研究，将天然膳食叶酸的影响与补充剂和食品强化中使用的合成叶酸的影响分开，3）研究阿司匹林保护作用的一些可能机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.