Profiles of Patients Who Use Marijuana for Inflammatory Bowel Disease.

BACKGROUND: Marijuana is legal in a number of states for indications that include inflammatory bowel diseases (IBD), and patients are interested in its potential benefits. AIMS: We aimed to describe the legal use of marijuana in individuals with IBD in the USA who participate within the CCFA Partners internet-based cohort. METHODS: A total of 2357 participants who lived in states where prescription or recreational marijuana was legal, were offered the opportunity to complete a survey on marijuana use and IBD symptoms including perceived benefits of therapy. Bivariate statistics and logistic regression models were used to determine factors associated with marijuana use. RESULTS: Surveys were completed by 1666 participants (71%) with only 214 (12.8%) indicating they had asked their medical doctor about its use and 73 actually using prescribed marijuana (4.4%). Within the respondent group (N = 1666), 234 participants lived where both medical and recreational marijuana is legal and 49 (20.9%) reported recreational marijuana use specifically for IBD. Users reported positive benefits (80.7%), but users also reported more depression, anxiety, pain interference, and lower social satisfaction than non-users. Those prescribed marijuana reported more active disease, and more use of steroids, narcotics, and zolpidem. CONCLUSIONS: Few IBD patients consulted their medical doctors about marijuana use or used prescription marijuana. Where recreational marijuana was available, usage rates were higher. Users reported benefits but also more IBD symptoms, depression, anxiety, and pain. Marijuana use may be higher in patients with IBD symptoms not well treated by conventional medical approaches.

Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome.

BACKGROUND & AIMS: Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations. METHODS: We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy. RESULTS: A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy. CONCLUSIONS: Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy.

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas.

BACKGROUND: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).

Calcium supplementation increases blood creatinine concentration in a randomized controlled trial.

BACKGROUND: Calcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied. METHODS: We investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004-2013 at 11 clinical centers in the United States. Healthy participants (N = 1,675) aged 45-75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total calcium concentration were measured after one year of treatment and multiple linear regression was used to estimate effects on creatinine concentrations. RESULTS: After one year of treatment, blood creatinine was 0.013±0.006 mg/dL higher on average among participants randomized to calcium compared to placebo after adjustment for other determinants of creatinine (P = 0.03). However, the effect of calcium treatment appeared to be larger among participants who consumed the most alcohol (2-6 drinks/day) or whose estimated glomerular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 at baseline. The effect of calcium treatment on creatinine was only partially mediated by a concomitant increase in blood total calcium concentration and was independent of randomized vitamin D treatment. There did not appear to be further increases in creatinine after the first year of calcium treatment. CONCLUSIONS: Among healthy adults participating in a randomized clinical trial, daily supplementation with 1200 mg of elemental calcium caused a small increase in blood creatinine. If confirmed, this finding may have implications for clinical and public health recommendations for calcium supplementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00153816.

C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study.

Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 ± 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85-2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps.

Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial.

BACKGROUND: Randomized controlled trials testing the association between vitamin D status and upper respiratory tract infection (URTI) have given mixed results. During a multicenter, randomized controlled trial of colorectal adenoma chemoprevention, we tested whether 1000 IU/day vitamin D(3) supplementation reduced winter episodes and duration of URTI and its composite syndromes, influenza-like illness (ILI; fever and ≥2 of sore throat, cough, muscle ache, or headache) and colds (no fever, and ≥2 of runny nose, nasal congestion, sneezing, sore throat, cough, swollen or tender neck glands). METHODS: The 2259 trial participants were aged 45-75, in good health, had a history of colorectal adenoma, and had a serum 25-hydroxyvitamin D level ≥12 ng/mL. They were randomized to vitamin D(3) (1000 IU/day), calcium (1200 mg/day), both, or placebo. Of these, 759 participants completed daily symptom diaries. Secondary data included semiannual surveys of all participants. RESULTS: Among those who completed symptom diaries, supplementation did not significantly reduce winter episodes of URTI (rate ratio [RR], 0.93; 95% confidence interval [CI], .79-1.09) including colds (RR, 0.93; 95% CI, .78-1.10) or ILI (RR, 0.95; 95% CI, .62-1.46), nor did it reduce winter days of illness (RR, 1.13; 95% CI, .90-1.43). There was no significant benefit according to adherence, influenza vaccination, body mass index, or baseline vitamin D status. Semiannual surveys of all participants (N = 2228) identified no benefit of supplementation on ILI (odds ratio [OR], 1.14; 95% CI, .84-1.54) or colds (OR, 1.03; 95% CI, .87-1.23). CONCLUSIONS: Supplementation with 1000 IU/day vitamin D(3) did not significantly reduce the incidence or duration of URTI in adults with a baseline serum 25-hydroxyvitamin D level ≥12 ng/mL.

Ciprofloxacin for the prevention of postoperative recurrence in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: The commensal bacterial flora plays a critical role in the postoperative recurrence of Crohn's disease (CD). We conducted a randomized, double-blind, placebo-controlled 6-month pilot trial of ciprofloxacin for the prevention of endoscopic recurrence in patients with CD who underwent surgery. METHODS: Thirty-three patients with CD, who had undergone surgery with ileocolonic anastomosis within the previous 2 weeks, were randomized to treatment with ciprofloxacin (500 mg twice daily) or placebo tablets for 6 months. Endpoints were endoscopic recurrence at 6 months and safety and tolerability of long-term ciprofloxacin therapy. RESULTS: Thirty-three patients were randomized; 14 patients discontinued the study early. Significant endoscopic recurrence was observed in 3 of 9 patients (33%) in the ciprofloxacin group and 5 of 10 patients (50%) in the placebo group at 6 months after surgery (P < 0.578). The intention-to-treat analysis demonstrated endoscopic recurrence in 11 of 17 patients (65%) in the ciprofloxacin group and 11 of 16 patients (69%) in the placebo group at month 6 (P < 0.805). Thirty-six adverse events occurred in 19 of 33 patients (58%). Possible drug-associated adverse events occurred significantly more often in the ciprofloxacin group (P < 0.043), leading to study drug discontinuation in 24% (4 of 17) and 6% of patients (1 of 16) in the ciprofloxacin and placebo groups, respectively (P < 0.166). CONCLUSIONS: In this pilot study, ciprofloxacin was not more effective than placebo for the prevention of postoperative recurrence in patients with CD. Long-term ciprofloxacin therapy is limited by drug-associated side effects. Future studies in postoperative prevention of CD should evaluate antibiotic approaches with a more favorable safety profile.

Serum salicylate levels and risk of recurrent colorectal adenomas.

BACKGROUND: Intake of aspirin is associated with reduction in risk of colorectal adenoma and carcinoma. Some plants contain salicylates, and individuals not taking aspirin may have measurable salicylate levels. However, the association between serum salicylate level and recurrence of adenoma in nonusers of aspirin has not been studied. METHODS: We measured serum salicylate levels in participants in a randomized controlled trial with calcium supplementation for the prevention of colorectal adenomas. Generalized linear models were used to assess the association between serum levels and adenoma risk during the follow-up period of the trial. RESULTS: We did not find an association with recurrence of adenomas or advanced adenomas with serum salicylate levels at year 1 among nonusers of aspirin. There was no effect modification of the chemopreventive effect of calcium supplementation in reducing risk of recurrent adenomas or advanced adenomas. CONCLUSIONS: Among nonusers of ASA, serum salicylate levels are not associated with risk of recurrence of adenomas. IMPACT: Serum salicylate levels can be detected in individuals not taking aspirin, but the levels may be too low to confer protection from risk of recurrent adenomas.

Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans.

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) may have antineoplastic properties in the colon. The authors examined the association between intakes of different PUFAs and distal large bowel cancer in a population-based case-control study of 1,503 whites (716 cases; 787 controls) and 369 African Americans (213 cases; 156 controls) in North Carolina (2001-2006). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals for distal large bowel cancer risk in relation to quartiles of PUFA intake. Increased consumption of long-chain omega-3 PUFAs was associated with reduced risk of distal large bowel cancer in whites (multivariable odds ratios = 0.88 (95% confidence interval (CI): 0.63, 1.22), 0.69 (95% CI: 0.49, 0.98), and 0.49 (95% CI: 0.34, 0.71) for second, third, and highest vs. lowest quartile) (P(trend) < 0.01). Intake of individual eicosapentaenoic acids and docosahexaenoic acids was inversely related to distal large bowel cancer risk, whereas the ratio of omega-6 to long-chain omega-3 PUFAs was associated with increased risk of distal large bowel cancer in whites, but not among African Americans (P(interaction) < 0.05). Study results support the hypothesis that long-chain omega-3 PUFAs have beneficial effects in colorectal carcinogenesis. Whether or not the possible benefit of long-chain omega-3 PUFAs varies by race warrants further evaluation.

Antioxidant and DNA methylation-related nutrients and risk of distal colorectal cancer.

OBJECTIVE: To investigate the relationship between antioxidant nutrients (vitamins C and E, beta-carotene, selenium) and DNA methylation-related nutrients (folate, vitamins B6 and B12) and distal colorectal cancer risk in whites and African Americans and to examine intakes from food only versus total (food plus dietary supplements) intakes. METHODS: Data are from the North Carolina Colon Cancer Study-Phase II, a case-control study of 945 distal colorectal cancer (including sigmoid, rectosigmoid, and rectum) cases and 959 controls. In-person interviews captured usual dietary intake and various covariates. Multivariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: High intakes of each antioxidant and DNA methylation-related nutrient were significantly associated with lower risk in whites. In African Americans, the highest category of selenium from food only had a marginally significant inverse association with distal colorectal cancer risk (Q4 vs. Q1 OR: 0.55, 95% CI 0.29-1.02). Supplements did not provide additional risk reduction beyond intakes from food. CONCLUSIONS: Our findings provide evidence that antioxidant and DNA methylation-related nutrients may lower the risk of distal colorectal cancer in whites, and selenium may lower risk in African Americans. Optimal micronutrient intakes from food alone may be more beneficial than supplementation.

Surgeons' volume of colorectal cancer procedures and collaborative decision-making about adjuvant therapies.

BACKGROUND: Few studies have assessed associations of surgeons' practice volume with processes of care that lead to better outcomes. OBJECTIVE: We surveyed surgeons treating colorectal cancer to determine whether high-volume surgeons were more likely to collaborate with other physicians in decisions about adjuvant therapies. SUBJECTS AND METHODS: Surgeons caring for patients with colorectal cancer in multiple regions and health-care organizations were surveyed to assess their volume of colorectal cancer resections and participation in decisions about adjuvant chemotherapy and radiation therapy. We used logistic regression to assess physician and practice characteristics associated with surgical volume and the relation of surgical volume and these other characteristics to collaborative decision-making regarding adjuvant therapies. RESULTS: Of 635 responding surgeons, those who identified themselves as surgical oncologists or colorectal surgeons were more likely than others to report high volume of colorectal cancer resections (P < 0.001), as were those who practiced at a comprehensive cancer center (P = 0.06) and attended tumor board meetings weekly (vs. quarterly or less, P = 0.09). Most surgeons reported a collaborative role in decisions about chemotherapy and radiation therapy. However, in adjusted analyses, higher-volume surgeons more often reported a collaborative role with other physicians in decisions about chemotherapy (P < 0.001) and radiation therapy (P < 0.001). CONCLUSIONS: Higher-volume surgeons are more likely to report collaborating with other physicians in decisions about adjuvant therapies for patients following colorectal cancer surgery. This collaborative decision-making of higher-volume surgeons may contribute to outcome differences by surgeon volume.

Folic acid and risk of prostate cancer: results from a randomized clinical trial.

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.

Selenium, folate, and colon cancer.

Selenium is an essential trace element that has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer, 2) evaluate possible effect measure modifiers, and 3) evaluate potential biases associated with the use of postdiagnostic serum selenium measures. The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n = 1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens, which were used to measure serum selenium. Individuals who had both high serum selenium (> 140 mcg/l) and high reported folate (> 354 mcg/day) had a reduced relative risk of colon cancer [odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.4-0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR = 1.1, 95% CI = 0.7-1.5) as was the risk for those with low selenium and high folate (OR = 0.9, 95% CI = 0.7-1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study.

Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels.

The Aspirin/Folate Polyp Prevention Study is a randomized, placebo-controlled trial of aspirin use and folic acid supplementation and incidence of colorectal adenomas in individuals with a history of these lesions. The trial showed that folic acid supplementation does not prevent the occurrence of new adenomas and may increase risk. We extend these results by investigating whether the effect of folic acid treatment differed by baseline dietary and circulating folate levels. Diet and supplement use were ascertained at baseline through a food-frequency questionnaire; a blood sample was used to determine plasma and RBC folate levels. Individuals were followed for 3 years (first follow-up) and subsequently for an additional 3 to 5 years (second follow up). We used generalized linear regression to estimate risk ratios and 95% confidence limits as measures of association. There was little evidence that baseline dietary and total folate intake, and plasma and RBC folate modified the association between folic acid treatment and risk of any adenomas or advanced lesions. However, there was a protective association of the highest tertile of dietary and total intake as well as circulating folate with risk of any adenomas among those in the placebo group but no association among individuals in the folic acid group. Our findings support the idea that although moderate doses of folate may be protective compared with deficiency, at some point of sufficiency, supplementation provides no additional benefit.

Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation.

BACKGROUND: Folate, other vitamin B cofactors, and genes involved in folate-mediated one-carbon metabolism all may play important roles in colorectal neoplasia. In this study, we examined the associations between dietary and circulating plasma levels of vitamins B(2), B(6), and B(12) and risk colorectal adenomas. METHODS: The Aspirin/Folate Polyp Prevention Study is a randomized clinical trial of folic acid supplementation and incidence of new colorectal adenomas in individuals with a history of adenomas (n = 1,084). Diet and supplement use were ascertained through a food frequency questionnaire administered at baseline. Blood collected at baseline was used to determine plasma B-vitamin levels. We used generalized linear regression to estimate risk ratios (RR) and 95% confidence intervals (95% CI) as measures of association. RESULTS: We found a borderline significant inverse association with plasma B(6) [pyridoxal 5'-phosphate (PLP)] and adenoma risk (adjusted RR Q4 versus Q1, 0.78; 95% CI, 0.61-1.00; P(trend) = 0.08). This association was not modified by folic acid supplementation or plasma folate. However, the protective association of PLP with adenoma risk was observed only among subjects who did not drink alcohol (P(interaction) = 0.03). Plasma B(2) (riboflavin) was inversely associated with risk of advanced lesions (adjusted RR Q4 versus Q1, 0.51; 95% CI, 0.26-0.99; P(trend) = 0.12). No significant associations were observed between adenoma risk and plasma vitamin B(12) or dietary intake of vitamin B(2) and B(6). When we examined specific gene-B-vitamin interactions, we observed a possible interaction between methylenetetrahydrofolate reductase -C677T and plasma B(2) on risk of all adenomas. CONCLUSION: Our results suggest that high levels of PLP and B(2) may protect against colorectal adenomas.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

CONTEXT: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. OBJECTIVE: To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later). MAIN OUTCOME MEASURES: The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas). RESULTS: During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. CONCLUSIONS: Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00272324.

Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial.

BACKGROUND: Calcium supplementation has been shown to decrease the risk of recurrence of colorectal adenomas in randomized trials. However, the duration of this protective effect after cessation of active supplementation is not known. METHODS: In the Calcium Polyp Prevention Study, 930 subjects with a previous colorectal adenoma were randomly assigned from November 1988 through April 1992 to receive placebo or 1200 mg of elemental calcium daily for 4 years. The Calcium Follow-up Study was an observational phase of the trial that tracked adenoma occurrence for an average of 7 years after the end of randomized treatment and gathered information regarding the use of medications, vitamins, and supplements during that time. We obtained follow-up information for 822 subjects, 597 of whom underwent at least one colonoscopy after the end of study treatment and are included in this analysis. Generalized linear models were used to compute relative risks (RRs) and 95% confidence intervals (CIs) for the effect of randomized calcium treatment on risk of adenoma recurrence during the first 5 years after study treatment ended and during the subsequent 5 years. Statistical tests were two-sided. RESULTS: During the first 5 years after randomized treatment ended, subjects in the calcium group still had a substantially and statistically significantly lower risk of any adenoma than those in the placebo group (31.5% versus 43.2%; adjusted RR = 0.63, 95% CI = 0.46 to 0.87, P = .005) and a smaller and not statistically significant reduction in risk of advanced adenomas (adjusted RR = 0.85, 95% CI = 0.43 to 1.69, P = .65). However, the randomized treatment was not associated with the risk of any type of polyp during the next 5 years. The findings were broadly similar when the analysis was restricted to subjects who did not report use of any calcium supplements after the treatment phase of the trial ended. CONCLUSION: The protective effect of calcium supplementation on risk of colorectal adenoma recurrence extends up to 5 years after cessation of active treatment, even in the absence of continued supplementation.

Selenium, apoptosis, and colorectal adenomas.

BACKGROUND: Selenium is an essential trace element found in cereals, wheat, dairy products, meat, and fish. This micronutrient may prevent carcinogenesis through several biochemical pathways; one suggested pathway is enhanced apoptosis. OBJECTIVES: The relation between selenium and colorectal adenomas was evaluated because the colorectal adenoma is the established precursor lesion of most colorectal cancers. Apoptosis was a pathway of interest because decreased apoptosis has been associated with an increased prevalence of adenomas. Our objectives were as follows: to investigate the association between (a) selenium and colorectal adenomas and (b) selenium and apoptosis. METHODS: The study population was assembled for the Diet and Health Study III (n = 803), a cross-sectional study conducted at the University of North Carolina Hospital (Chapel Hill, NC). There were 451 participants in the analysis of selenium and adenoma prevalence and 351 participants in the analysis of selenium and apoptosis. Selenium was measured from serum collected at the time of colonoscopy. Apoptosis was measured in biopsies from normal rectal epithelium obtained during the colonoscopy procedure. RESULTS: Participants in the highest fifth of serum selenium were less likely to have adenomas in comparison with those in the lowest fifth (prevalence ratio, 0.6; 95% confidence interval, 0.4-1.1). Selenium and apoptosis (>2.76 cells per crypt) were not strongly related, but results collectively suggested a roughly inverse association. CONCLUSIONS: High selenium was associated with a reduced prevalence of colorectal adenomas. Apoptosis, however, did not seem to be the mechanism by which selenium was related to adenoma prevalence in our data.

Interaction of calcium supplementation and nonsteroidal anti-inflammatory drugs and the risk of colorectal adenomas.

BACKGROUND: Calcium and aspirin have both been found to be chemopreventive against colorectal neoplasia. However, the joint effect of the two agents has not been well investigated. METHODS: To explore the separate and joint effects of calcium and aspirin/nonsteroidal anti-inflammatory drugs (NSAID), we used data from two large randomized clinical trials among patients with a recent history of colorectal adenomas. In the Calcium Polyp Prevention Study, 930 eligible subjects were randomized to receive placebo or 1,200 mg of elemental calcium daily for 4 years. In the Aspirin/Folate Polyp Prevention Study, 1,121 eligible subjects were assigned to take placebo, 81 mg of aspirin, or 325 mg of aspirin daily for 3 years. In each study, subjects completed a validated food frequency questionnaire at enrollment and were asked periodically about medications and supplements used. Recurrent adenomas and advanced adenomas were the end points considered. We used generalized linear models to assess the separate and combined effects of aspirin (or NSAIDs) and calcium supplementation (or dietary calcium) and the interactions between these exposures. RESULTS: In the Calcium Trial, subjects randomized to calcium who also were frequent users of NSAIDs had a reduction of risk for advanced adenomas of 65% [adjusted risk ratio (RR), 0.35; 95% confidence interval (95% CI), 0.13-0.96], and there was a highly significant statistical interaction between calcium treatment and frequent NSAID use (P(interaction) = 0.01). Similarly, in the Aspirin Trial, 81 mg aspirin and calcium supplement use together conferred a risk reduction of 80% for advanced adenomas (adjusted RR, 0.20; 95% CI, 0.05-0.81); there was a borderline significant statistical interaction between the two treatments (P(interaction) = 0.09). In this trial, we found similar trends when we considered baseline dietary calcium intake instead of calcium supplements. For all adenomas considered together, the interactive patterns were not consistent. CONCLUSION: Data from two different randomized clinical trials suggest that calcium and NSAIDs may act synergistically to lower the risk of advanced colorectal neoplastic polyps.

Risk of prostate cancer in a randomized clinical trial of calcium supplementation.

BACKGROUND: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. METHODS: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. RESULTS: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. CONCLUSION: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.