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Bernard F Cole,
John A Baron,
Robert S Sandler,
Robert W Haile,
Dennis J Ahnen,
Robert S Bresalier,
Gail McKeown-Eyssen,
Robert W Summers,
Richard I Rothstein,
Carol A Burke, [......],
Tim Byers, Jack S Mandel,
Leila A Mott,
Loretta H Pearson,
Elizabeth L Barry,
Judy R Rees,
Norman Marcon,
Fred Saibil,
Per Magne Ueland,
E Robert Greenberg
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ABSTRACT: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine.
To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas.
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.
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).
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).
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.
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.
clinicaltrials.gov Identifier: NCT00272324.
JAMA The Journal of the American Medical Association 06/2007; 297(21):2351-9. · 30.03 Impact Factor
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Maria V Grau,
John A Baron,
Robert S Sandler,
Kristin Wallace,
Robert W Haile,
Timothy R Church,
Gerald J Beck,
Robert W Summers,
Elizabeth L Barry,
Bernard F Cole,
Dale C Snover,
Richard Rothstein, Jack S Mandel
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ABSTRACT: 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.
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.
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.
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.
CancerSpectrum Knowledge Environment 02/2007; 99(2):129-36. · 14.07 Impact Factor
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ABSTRACT: Experimental studies have consistently shown a protective effect of nonsteroidal antiinflammatory drugs (NSAIDs) against nonmelanoma skin cancers (NMSC). However, little human epidemiological research has been done in this regard. We used data from the Skin Cancer Chemoprevention Study to explore the association of NSAID use and with the risk of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). 1,805 subjects with a recent history of NMSC were randomized to placebo or 50 mg of daily beta-carotene. Participants were asked about their use of over-the-counter and prescription medications at baseline and every 4 months during the trial. Skin follow-up examinations were scheduled annually with a study dermatologist; confirmed lesions were the endpoints in the study. We used a risk set approach to the analysis of grouped times survival data and unconditional logistic regression to compute odds ratios [ORs] for various exposures to NSAIDs. The use of NSAIDs was reported in over 50% of questionnaires. For BCC, NSAIDs exhibited a weak protective effect in crude analyses, which attenuated markedly after adjustment. For SCC, the use of NSAIDs in the year previous to diagnosis reduced the odds by almost 30% (adjusted OR=0.71, 95% CI 0.48-1.04). When we accounted for frequency of use, results for BCC were not striking, and there were inconsistent suggestions of an inverse association with SCC. There were some indications of a modest, nonsignificant reduction on the number of BCCs and SCCs with NSAID use. Our data suggest a weak and inconsistent chemopreventive effect of NSAIDs on BCC and SCC.
International Journal of Cancer 09/2006; 119(3):682-6. · 5.44 Impact Factor
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ABSTRACT: 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.
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.
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.
Data from two different randomized clinical trials suggest that calcium and NSAIDs may act synergistically to lower the risk of advanced colorectal neoplastic polyps.
Cancer Epidemiology Biomarkers & Prevention 11/2005; 14(10):2353-8. · 4.12 Impact Factor
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Douglas J Robertson,
E Robert Greenberg,
Michael Beach,
Robert S Sandler,
Dennis Ahnen,
Robert W Haile,
Carol A Burke,
Dale C Snover,
Robert S Bresalier,
Gail McKeown-Eyssen, Jack S Mandel,
John H Bond,
Rosalind U Van Stolk,
Robert W Summers,
Richard Rothstein,
Timothy R Church,
Bernard F Cole,
Tim Byers,
Leila Mott,
John A Baron
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ABSTRACT: Colonoscopic polypectomy is considered effective for preventing colorectal cancer (CRC), but the incidence of cancer in patients under colonoscopic surveillance has rarely been investigated. We determined the incidence of CRC in patients under colonoscopic surveillance and examined the circumstances and risk factors for CRC and adenoma with high-grade dysplasia.
Patients were drawn from 3 adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of at least one adenoma and were deemed free of remaining lesions. We identified patients subsequently diagnosed with invasive cancer or adenoma with high-grade dysplasia. The timing, location, and outcome of all cases of cancer and high-grade dysplasia identified are described and risks associated with their development explored.
CRC was diagnosed in 19 of the 2915 patients over a mean follow-up of 3.7 years (incidence, 1.74 cancers/1000 person-years). The cancers were located in all regions of the colon; 10 were at or proximal to the hepatic flexure. Although most of the cancers (84%) were of early stage, 2 participants died of CRC. Seven patients were diagnosed with adenoma with high-grade dysplasia during follow-up. Older patients and those with a history of more adenomas were at higher risk of being diagnosed with invasive cancer or adenoma with high-grade dysplasia.
CRC is diagnosed in a clinically important proportion of patients following complete colonoscopy and polypectomy. More precise and representative estimates of CRC incidence and death among patients undergoing surveillance examinations are needed.
Gastroenterology 08/2005; 129(1):34-41. · 11.68 Impact Factor
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ABSTRACT: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue.
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.
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.
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.
Cancer Epidemiology Biomarkers & Prevention 03/2005; 14(3):586-9. · 4.12 Impact Factor
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Kristin Wallace,
John A Baron,
Bernard F Cole,
Robert S Sandler,
Margaret R Karagas,
Michael A Beach,
Robert W Haile,
Carol A Burke,
Loretta H Pearson, Jack S Mandel,
Richard Rothstein,
Dale C Snover
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ABSTRACT: Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas. However, few studies have examined the effect of calcium on the risk of different types of colorectal lesions or dietary determinants of this effect.
Our analysis used patients from the Calcium Polyp Prevention Study, a randomized, double-blind, placebo-controlled chemoprevention trial among patients with a recent colorectal adenoma. Nine hundred thirty patients were randomly assigned to calcium carbonate (1200 mg/day) or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years after the qualifying examination. We used general estimating equation (GEE) and generalized linear regression analyses to compute risk ratios and 95% confidence intervals (CIs) to assess the effect of calcium treatment versus placebo on the risk of hyperplastic polyps, tubular adenomas, and more advanced lesions. Additionally, we used GEE analyses to compare the calcium treatment effects for various types of polyps with that for tubular adenomas. We also examined the interaction between calcium treatment and baseline intake of dietary calcium, fat, and fiber. All P values were obtained using Wald tests based on the corresponding models. All tests of statistical significance were two-sided.
The calcium risk ratio for hyperplastic polyps was 0.82 (95% CI = 0.67 to 1.00), that for tubular adenomas was 0.89 (95% CI = 0.77 to 1.03), and that for histologically advanced neoplasms was 0.65 (95% CI = 0.46 to 0.93) compared with patients assigned to placebo. There were no statistically significant differences between the risk ratio for tubular adenomas and that for other types of polyps. The effect of calcium supplementation on adenoma risk was most pronounced among individuals with high dietary intakes of calcium and fiber and with low intake of fat, but the interactions were not statistically significant.
Our results suggest that calcium supplementation may have a more pronounced antineoplastic effect on advanced colorectal lesions than on other types of polyps.
CancerSpectrum Knowledge Environment 07/2004; 96(12):921-5. · 14.07 Impact Factor
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John A Baron,
Bernard F Cole,
Robert S Sandler,
Robert W Haile,
Dennis Ahnen,
Robert Bresalier,
Gail McKeown-Eyssen,
Robert W Summers,
Richard Rothstein,
Carol A Burke, [......],
Gerald J Beck,
John H Bond,
Tim Byers,
E Robert Greenberg, Jack S Mandel,
Norman Marcon,
Leila A Mott,
Loretta Pearson,
Fred Saibil,
Rosalind U van Stolk
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[hide abstract]
ABSTRACT: Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel.
We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals.
Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23).
Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel.
New England Journal of Medicine 04/2003; 348(10):891-9. · 53.30 Impact Factor
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JNCI Journal of the National Cancer Institute 07/2002; 94(11):861; author reply 865-6. · 13.76 Impact Factor
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ABSTRACT: Objective.
—To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes.
JAMA The Journal of the American Medical Association 275(9):699-703. · 30.03 Impact Factor
