Colorectal Cancer _ ___________________________________________________________________________
Vitamin Supplementation Vitamin E
calcium) or placebo. At four-year follow-up, those receiving calcium (compared with placebo) showed a 19% reduction in developing one or more recurrent adenoma and the average number of adenomas was 24% lower. This reduced risk was likely to extend up to five years following cessation of calcium supplementation [80; 81]. Calcium has not shown benefit in patients with FAP. In the general population, there was no significant effect of calcium on risk of colorectal cancer, although studies were of relatively short duration [57]. There is fair evidence that 1,000–1,200 mg/day oral calcium without vitamin D supplementation increases the risk of myocardial infarction. Calcium supplementation with vitamin D at doses less than 1,000 mg/ day has few harmful effects [82; 83]. NONMODIFIABLE RISK FACTORS While most cases of colorectal cancer result from complex interactions between inherited susceptibility and environmental or lifestyle factors, certain heritability factors place the individual at very high risk of colorectal cancer, while other patterns of familial colorectal cancer elevate individual risk. Furthermore, specific medical conditions are associated with colorectal cancer risk. The presence or absence of these nonmodifiable risk factors influences the probability that colorectal cancer will develop. Assessment and identification of these risk factors determines the timing, frequency, and modality of colorectal cancer screening and intervention [84; 85]. Assessment of Nonmodifiable Colorectal Cancer Risk Factors Clinicians should perform an individualized assessment of colorectal cancer risk in all adults in order to understand patient risk level for colorectal cancer. Patient risk is assessed by a thorough personal and family history to identify factors associated with increased vulnerability to colorectal cancer. The colorectal cancer risk factors of smoking, obesity, coronary artery disease, diabetes, acromegaly, renal transplantation, and cholecystectomy have no bearing on the timing, frequency, and modality of colorectal cancer screening or intervention (in the absence of adenomatous polyps or colorectal cancer) [86]. Familial Colorectal Cancer Risk Factors A targeted colorectal cancer family history should include a detailed family history of cancer and polyps, especially in first-degree (e.g., parent, sibling, child) and second-degree (e.g., grandparent, uncle/aunt, half sibling) relatives on both sides of the family [87; 88]. Clinicians should ask about polyps in relatives, including [89]: • Age at first colon exam • How diagnosed (e.g., colonoscopy, flexible sigmoidoscopy, barium enema) • How many (during each colonoscopy or lifetime total) • Type (adenomas, hyperplastic, juvenile, serrated, hamartomas)
A prospective cohort study of 35,215 women found an inverse association between the risk of colon cancer and vitamin E intake [70]. However, a later cohort study found no relationship between every-other-day use of vitamin E 600 IU and colorectal cancer, and a meta-analysis of 14 randomized trials of supplemental antioxidant vitamins involving 170,025 individuals found no evidence for prevention of colorectal adenoma or colorectal cancer [71; 72]. Vitamin D A systematic review of published cohort studies found that daily intake of 1,000 IU of vitamin D and 25-hydroxyvitamin D serum concentration of 33 ng/mL were each associated with a 50% risk reduction of colorectal cancer [73]. A population- based case-control study found an inverse relationship between vitamin D intake and colorectal cancer risk [74]. More recent research is focused on the role of vitamin D as an adjunct treatment after a diagnosis of colorectal cancer. For example, two randomized, placebo-controlled trials of vitamin D in patients with metastatic colorectal cancer are underway to assess patient survival as a primary endpoint. The first study is a phase II trial comparing high-dose vitamin D3 (8,000 IU/day for two weeks followed by 4,000 IU/day) versus a standard dose (400 IU/day). The second study is a phase I–II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80–100 ng/mL versus 2,000 IU/day. The results of these and subsequent phase III trials may provide more definitive answers about the role of vitamin D in the treatment of colorectal cancer [75]. Folate An observational study of women with a family history of colon cancer found use of folic acid supplements for more than 15 years was associated with a 75% lower risk of colorectal cancer [76]. One hypothesis is that folate is required for DNA synthesis, and suboptimal amounts may cause abnormalities in DNA synthesis or repair [77]. However, a trial that randomized 1,021 men and women with recent colorectal adenoma history to daily folic acid 1 mg or placebo found folic acid was associated with greater risks of developing ≥1 advanced adenoma, ≥3 adenomas, and extra-colonic malignancy compared with placebo [78]. General population studies have not found benefit of folic acid on colorectal cancer risk, but outcomes obtained over relatively short duration may have missed detection of benefit from longer exposure and/or follow-up [57]. Calcium Researchers have suggested that calcium’s action of binding bile acids and fatty acids may lower colon cancer risks through reducing exposure to toxic intraluminal compounds [79]. To study the effects of calcium on adenoma recurrence, persons with a recent history of colorectal adenomas were randomized to daily 3 g calcium carbonate (1,200 mg elemental
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