A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps.

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of ß-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00; p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73; 95% CI: 0.50-1.08; p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.

Vitamin D supplementation reduces the occurrence of colorectal polyps in high-latitude locations.

There is suggestive evidence for the role of vitamin D in the development of colorectal cancer (CRC). Due to high latitudes in Canada, many Canadians are vitamin D deficient throughout winter. In this analysis, we examined the association between vitamin D supplement use and high-risk adenomatous polyps (HRAPs). The study population was drawn from the biorepository at the Forzani & MacPhail Colon Cancer Screening Centre (CCSC) in Calgary. Individuals enrolled between 2013 and 2016 between the age of 50 and 74 years (n = 1409) were included. When examining the association between any supplemental vitamin D use and HRAPs, a protective effect is observed with an ORadj of 0.57 (95% CI: 0.33-0.96). Similarly, meeting the recommended daily intake (RDI) of vitamin D (600 IU) is protective against HRAPs with an ORadj of 0.78 (95% CI: 0.62-0.99). This study suggests that adequate vitamin D supplementation reduces the occurrence of colorectal polyps in high-latitude locations.

Traditional Chinese medicine (Xiaoai Jiedu Decoction) as an adjuvant treatment for prevention new colorectal adenomatous polyp occurrence in post-polypectomy: Study protocol for a randomized controlled trial.

BACKGROUND: Colorectal Adenomatous Polyp (CAP) was one precursor of colorectal cancer (CRC) and having a high chance of developing into CRC. There was a lack of conclusive chemoprevention evidences to prevention new CAP occurrence in post-polypectomy. Xiaoai Jiedu Decoction, Chinese National Medical Professor (Zhou Zhongying)'s experience formula, has been used to treat new CAP occurrence in post-polypectomy from the 20th century in China. However, clinical research of Xiaoai Jiedu Decoction in the treatment of CAP recurrence was lack. We design this study to evaluate the efficacy and safety of Xiaoai Jiedu Decoction in the treatment of new CAP occurrence in post-polypectomy on colonoscopy. METHODS/DESIGN: A randomized, controlled, blind and multicenter trial to evaluate the efficacy and safety of Xiaoai Jiedu Decoction is proposed. CAP patients (after complete polypectomy under colonoscopy) will be randomly assigned into Xiaoai Jiedu Decoction group and Xiaoai Jiedu Decoction mimetic agent group. Patients will receive 6-course treatments and a 2-year follow-up. Follow-up colonoscopy will be anticipated to perform in 1 and 2 years after the baseline examinations. The primary outcome measure is the new CAP occurrence in 1 and 2 years. The secondary outcome measure is the occurrence of advanced adenoma in 1 and 2 years. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Xiaoai Jiedu Decoction as an adjuvant treatment for new CAP occurrence in post-polypectomy. TRIAL REGISTRATION: NCT03616444.

Celecoxib use and circulating oxylipins in a colon polyp prevention trial.

Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.

Do antioxidants prevent colorectal cancer? A meta-analysis.

BACKGROUND: Oxidative stress is the first step involved in mutagenesis, carcinogenesis and aging. There has been great interest in recent years in potentially health benefits of dietary and antioxidant supplements in cancer prevention. OBJECTIVES: Our primary objectives were to estimate the global effect of antioxidants on colorectal cancer incidence, adenomatous polyp recurrence, overall mortality and cancer related mortality. A secondary aim was to evaluate these effects across specific antioxidant compounds, dose and duration of antioxidant supplementation. METHODS: Using Cochrane Collaboration methodology we searched for all randomized controlled trials (RCTs) from 1966 till May 2009 (MEDLINE, Cochrane Controlled Clinical Trials Registry), comparing antioxidant supplements with placebo or no intervention on the occurrence of colorectal cancer or adenoma. The results expressed as relative risk (RR) and 95% confidence intervals (95% CI) were obtained using random and fixed effect meta-analysis. RESULTS: Twenty RCTs, including 26 8590 participants, were eligible: 12 analyzing the colorectal cancer incidence included 25 0676 participants and 8 analyzing colorectal adenoma recurrence included 17914 participants. Antioxidant supplements had no significant effect on colorectal cancer incidence or colorectal adenoma recurrence (RR = 0. 94, 95% CI, 0.84-1.06, p = 0.32) in a random-effect meta-analysis. The antioxidant supplements had no significant effect on overall mortality (RR = 1.03, 95% CI, 0.99-1.07, p = 0.12) or cancer related mortality (RR = 1.05, 95% CI, 0.94-1.16, p = 0.38) in a random effect meta-analysis. Selenium supplementation was associated with a trend in reducing colorectal cancer incidence, (RR = 0.88, 95% CI, 0.55-1.40, p = 0.59), colorectal adenoma recurrence (RR = 0.70, 95% CI, 0.43-1.14, p = 0.16) and overall mortality (RR = 0.91, 95% CI, 0.82-1.02, p = 0.09). Beta carotene alone was associated with a slight increase in colorectal cancer incidence (RR = 1.09, 95% CI, 0.92-1.29, p = 0.34) and in combination with other antioxidants it was associated with an increase in mortality (RR = 1.05, 95% CI, 0.99-1.11, p = 0.10). For both selenium and beta carotene, the effect was not statistically significant. Vitamin C and Vitamin E combination slightly reduced colorectal cancer incidence with no effect on overall mortality. CONCLUSIONS: This meta-analysis found no evidence in favor of a protective effect of the studied antioxidant supplements in the prevention of colorectal cancer or cancer related mortality. Only selenium supplementation might have anticarcinogenic effects and requires further research.

Antioxidant supplement and long-term reduction of recurrent adenomas of the large bowel. A double-blind randomized trial.

BACKGROUND: Patients who undergo polypectomy are at increased risk of adenoma recurrence. The preventive potential of vitamins (A, C and E) and selenium supplementation represent an interesting opportunity for colorectal cancer prevention. METHODS: To assess the efficacy of a combination of these micronutrients in reducing the incidence of recurrent adenomas in subjects on post-polypectomy endoscopic follow-up, a double-blind placebo-controlled randomized trial was started in Italy in 1988. A total of 411 patients were randomized to receive either an active compound (200 µg selenium, 30 mg zinc, 2 mg vitamin A, 180 mg vitamin C, 30 mg vitamin E) or a placebo daily for 5 years. Of them, 330 had follow-up colonoscopy (164 in the intervention and 166 in the placebo group). RESULTS: After a median follow-up of 4 years (range 1-15 years), 100 patients had recurrence: 38 in the intervention and 62 in the placebo arm. The 15-year cumulative incidence of recurrence was 48.3% in the intervention and 64.5% in the placebo arm (HR = 0.59; log-rank P = 0.009). A 39% reduction of the risk of recurrence was observed in the intervention compared to the placebo group (adjusted HR = 0.61; 95% CI 0.41-0.92): the risk reduction was similar for small tubular (adjusted HR = 0.61; 95% CI 0.37-0.99) and advanced adenomas (adjusted HR = 0.50; 95% CI 0.24-1.01). CONCLUSIONS: Our study showed a statistically significant effect of antioxidant supplementation on adenoma recurrence. Further clinical trials are needed to address the role of antioxidants in subgroups of subjects at increased risk for colorectal cancer.

Colorectal cancer screening in LHU4 Chiavarese, Italy: ethical, methodological and outcome evaluations at the end of the first round.

UNLABELLED: INTRODUCTION. The screening programmes are very challenging from the ethical perspective, and their impact in terms of morbidity and mortality make secondary colorectal cancer prevention a valuable public health intervention. METHODS: The target population people aged 50-69 years receive an invitation card with a test-tube for the fecal occult blood test (FOBT) and an immunochemical test is used for fecal occult blood. Subjects positive to FOBT are invited to perform a gastroenterologic examination and a full colonoscopy. RESULTS: In the firt round of screening, 100% of the target population has been invited with an adhesion rate of 41.3%. A total of 1739 FOBT-positive subjects have been invited to the second level of the screening. 1429 of them have performed the gastroenterologic examination (83.9%). To date 956 full colonoscopies have been completed and the rate of subjects affected by carcinoma, malignant polyp and advanced adenoma has been equal to 23.5%. DISCUSSION: Thanks to the reminders already sent, an increasing compliance has been registered with an increased rate of subjects with a low schooling that have performed a FOBT test. With the aim to optimize all the operative aspects of the screening programme it is already ongoing a set of meetings between health workers of Local Health Unit 4 and General Practioners.

Dietary intake of PUFAs and colorectal polyp risk.

BACKGROUND: Marine-derived n-3 (omega-3) PUFAs may reduce risk of developing colorectal cancer; however, few studies have investigated the association of n-3 PUFA intakes on colorectal polyp risk. OBJECTIVE: The objective of this study was to examine the associations of dietary PUFA intake on risk of colorectal adenomatous and hyperplastic polyps. DESIGN: This was a colonoscopy-based case-control study that included 3166 polyp-free control subjects, 1597 adenomatous polyp cases, and 544 hyperplastic polyp cases. Dietary PUFA intake was calculated from food-frequency questionnaires and tested for association by using unconditional logistic regression. The urinary prostaglandin E(2) metabolite, which is a biomarker of prostaglandin E(2) production, was measured in 896 participants by using liquid chromatography and tandem mass spectrometry. RESULTS: n-6 PUFAs were not associated with adenomatous or hyperplastic polyps in either men or women. Marine-derived n-3 PUFAs were associated with reduced risk of colorectal adenomas in women only, with an adjusted OR of 0.67 (95% CI: 0.47, 0.97) for the highest quintile of intake compared with the lowest quintile of intake (P-trend = 0.01). Dietary intake of α-linolenic acid was associated with an increased risk of hyperplastic polyps in men (P-trend = 0.03), which was not seen in women. In women, but not in men, dietary intake of marine-derived n-3 PUFAs was negatively correlated with urinary prostaglandin E(2) production (r = -0.18; P = 0.002). CONCLUSION: Higher intakes of marine-derived n-3 PUFAs are associated with lower risk of adenomatous polyps in women, and the association may be mediated in part through a reduction in the production of prostaglandin E(2). This trial was registered at clinicaltrials.gov as NCT00625066.

Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial.

Serum interleukin-6 (IL-6), a proinflammatory cytokine, is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis. Flavonols, which can be found in fruits and vegetables, may inhibit colorectal carcinogenesis partly by inhibiting inflammation. We estimated odds ratios and 95% confidence intervals (95% CI) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and thus may serve as a risk indicator and as a response indicator to dietary flavonols. Serum IL-6 concentrations at baseline, year 1, and year 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Intake of flavonols, especially of isorhamnetin, kaempferol, and quercetin, was inversely associated with serum IL-6 concentrations (highest versus lowest flavonol intake quartile, 1.80 versus 2.20 pg/mL) and high-risk (OR, 0.51; 95% CI, 0.26-0.98) and advanced adenoma recurrence (OR, 0.17; 95% CI, 0.06-0.50). A decrease in IL-6 concentration during the trial was inversely associated with high-risk (OR, 0.44; 95% CI, 0.23-0.84) and advanced adenoma recurrence (OR, 0.47; 95% CI, 0.19-1.18). Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high-risk and advanced adenoma. Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention.

Folic acid supplementation for the prevention of recurrence of colorectal adenomas: metaanalysis of interventional trials.

Conflicting data have emerged from preclinical and clinical studies that examined the relationship between folic acid and the risk of recurrence of colorectal adenomas. To determine precisely that relation, we planned this metaanalysis. We searched literature to identify interventional randomized, placebo-controlled studies where folic acid in specific dose and for specific duration was administered to evaluate its effect on the recurrence of adenomatous colorectal polyps. Five eligible trials were identified. The total number of patients with history of colorectal adenomas in the folate and the placebo groups was 805 and 775 patients, respectively. Our analysis showed that folate supplementation had no protective effects on the recurrence of colorectal adenomas [odds ratio = 1.08 (95% CI; 0.87, 1.33; P = 0.49)], nor has a positive outcome on the number of recurrent polyps per patient (P = 0.41). Examination of folic acid dose effect showed that the two studies that have used folic acid as 1 mg/day favored folic acid over placebo with an odds ratio of 0.62 (95% CI; 0.48, 0.80). However, the overall effect for all included studies was not significant [odds ratio = 0.78 (95% CI; 0.49, 1.24; P = 0.30)]. We found significant heterogeneity between trials, moreover, included trials exhibit inconsistency in methodological quality. The present metaanalysis has failed to show potential benefit for folate supplementation. Future trials should examine the effect of different dosage and duration. Moreover, the confounding effect of dietary and life style habits should be carefully controlled.

Lack of efficacy of blueberry in nutritional prevention of azoxymethane-initiated cancers of rat small intestine and colon.

BACKGROUND: Blueberries may lower relative risk for cancers of the gastrointestinal tract. Previous work indicated an inhibitory effect of consumed blueberry (BB) on formation of aberrant crypt foci (ACF) in colons of male Fisher F344 rats (inbred strain). However, effects of BB on colon tumors and in both genders are unknown. METHODS: We examined efficacy of BB in inhibition of azoxymethane (AOM)-induced colon ACF and intestine tumors in male and female Sprague-Dawley rats (outbred strain). Pregnant rats were fed a diet with or without 10% BB powder; progeny were weaned to the same diet as their dam and received AOM as young adults. RESULTS: Male and female rats on control diet had similar numbers of ACF at 6 weeks after AOM administration. BB increased (P < 0.05) ACF numbers within the distal colon of female but not male rats. There was a significant (P < 0.05) diet by gender interaction with respect to total colon ACF number. Colon and duodenum tumor incidences were less in females than males at 17 weeks after AOM. BB tended (0.1 > P > 0.05) to reduce overall gastrointestinal tract tumor incidence in males, however, tumor incidence in females was unaffected (P > 0.1) by BB. There was a tendency (0.1 > P > 0.05) for fewer adenocarcinomas (relative to total of adenomatous polyps plus adenocarcinomas) in colons of female than male tumor-bearing rats; in small intestine, this gender difference was significant (P < 0.05). BB favored (P < 0.05) fewer adenocarcinomas and more adenomatous polyps (as a proportion of total tumor number) in female rat small intestine. CONCLUSION: Results did not indicate robust cancer-preventive effects of BB. Blueberry influenced ACF occurrence in distal colon and tumor progression in duodenum, in gender-specific fashion. Data indicate the potential for slowing tumor progression (adenomatous polyp to adenocarcinoma) by BB.

Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.

BACKGROUND: Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries. Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake. Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in reviewing the existing evidence. OBJECTIVES: This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit , and Embase, to July 2007. The reference lists of identified studies were inspected for further studies, and the review literature was scrutinized. SELECTION CRITERIA: Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model. MAIN RESULTS: Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials, included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean duration of 4 years, and 2000 mg/day for three years. The rates of loss to follow -up were 14 % and 11%. For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both trials were combined. AUTHORS' CONCLUSIONS: Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.

Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.

BACKGROUND: Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries. Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake. Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in reviewing the existing evidence. OBJECTIVES: This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit, and Embase, to April 2002. The reference lists of identified studies were inspected for further studies, and the review literature was scrutinized. SELECTION CRITERIA: Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model. MAIN RESULTS: Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials, included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean duration of 4 years, and 2000 mg/day for three years. The rates of loss to follow -up were 14 % and 11%. For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both trials were combined. AUTHORS' CONCLUSIONS: Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.

Carotenoids, vitamin A and risk of adenomatous polyp recurrence in the polyp prevention trial.

One trial reported beta-carotene supplementation was protective of adenomatous polyp recurrence in nonsmokers. We now examine the relation of serum and dietary carotenoids and vitamin A to adenomatous polyp recurrence in a subcohort of 834 participants in a low fat, high fiber, high fruit and vegetable dietary intervention, the Polyp Prevention Trial. Multivariate odds ratio (OR) and 95% confidence intervals (CI) of polyp recurrence were obtained using baseline or the average (first 3 years of the trial) carotenoid and vitamin A values after adjustment for covariates. Compared to the lowest quartile of baseline alpha-carotene concentrations, the OR of multiple polyp recurrence for the highest quartile was 0.55 (95% CI = 0.30-0.99) and the OR of right-sided recurrence was 0.60 (95% CI = 0.37-0.95). Baseline dietary intakes of alpha-carotene and vitamin A from food with/without supplements were inversely associated with any recurrence (p for linear trend = 0.03-alpha-carotene; p = 0.004 and p = 0.007 -intakes of vitamin A). Compared to the lowest quartile of averaged beta-carotene concentrations, the OR of multiple adenomas for the highest quartile was 0.40 (95% CI = 0.22-0.75) with an inverse trend (p = 0.02). The risk was inversely related to averaged: alpha-carotene concentrations and right-sided polyps; alpha-carotene intake and recurrence of any, multiple and right-sided polyps; beta-carotene intake and multiple adenoma recurrence; vitamin A from food (with supplements) and each adverse endpoint. Thus, alpha-carotene and vitamin A may protect against recurrence in nonsmokers and nondrinkers or be indicative of compliance or another healthy lifestyle factor that reduces risk.

Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.

BACKGROUND: Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries. Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake. Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in reviewing the existing evidence. OBJECTIVES: This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit, and Embase, to April 2002. The reference lists of identified studies were inspected for further studies, and the review literature was scrutinized. SELECTION CRITERIA: Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model. MAIN RESULTS: Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials, included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean duration of 4 years, and 2000 mg/day for three years. The rates of loss to follow -up were 14 % and 11%. For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both trials were combined. REVIEWER'S CONCLUSIONS: Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.

Evaluation of 5-aminosalicylic acid (5-ASA) for cancer chemoprevention: lack of efficacy against nascent adenomatous polyps in the Apc(Min) mouse.

Recent experimental and epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the prevention of colorectal cancer. However, the toxicity associated with the long-term use of most classical NSAIDs has limited their usefulness for the purpose of cancer chemoprevention. Inflammatory bowel disease (IBD) patients, in particular, are sensitive to the adverse side effects of NSAIDs, and these patients also have an increased risk for the development of intestinal cancer. 5-Aminosalicylic acid (5-ASA) is an anti-inflammatory drug commonly used in the treatment of IBD and may provide protection against the development of colorectal cancer in these patients. To directly evaluate the ability of 5-ASA to suppress intestinal tumors, we studied several formulations of 5-ASA (free acid, sulfasalazine, and Pentasa) at multiple oral dosage levels [500, 2400, 4800, and 9600 parts/million (ppm)] in the adenomatous polyposis coli (Apc) mouse model of multiple intestinal neoplasia (Min). Although the ApcMin mouse is not a model of colitis-associated neoplasia, it is, nonetheless, a useful model for assessing the ability of anti-inflammatory agents to prevent tumor formation in a genetically preinitiated population of cells. We used a study design in which drug was provided ad libitum through the diet beginning at the time of weaning (28 days of age) until 100 days of age. We included 200 ppm of piroxicam and 160 ppm of sulindac as positive controls, and the negative control was AIN-93G diet alone. Treatment with either piroxicam or sulindac produced statistically significant reductions in intestinal tumor multiplicity (95% and 83% reductions in tumor number, respectively; P < 0.001 versus controls). By contrast, none of the 5-ASA drug formulations or dosage levels produced consistent dose-progressive changes in polyp number, distribution, or size, despite high luminal and serum concentrations of 5-ASA and its primary metabolite N-acetyl-5-ASA. Thus, 5-ASA does not seem to possess direct chemosuppressive activity against the development of nascent intestinal adenomas in the ApcMin mouse. However, because intestinal tumor development in the ApcMin mouse is driven by a germline mutation in the Apc gene rather than by chronic inflammation, we caution that these findings do not definitively exclude the possibility that 5-ASA may exert a chemopreventive effect in human IBD patients.

Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia.

INTRODUCTION: Although some have suggested that certain vitamins or calcium supplements may reduce adenoma recurrence, our own prior retrospective study found no such effects. The purpose of this case-control study was to further investigate whether regular vitamin or calcium supplement intake influenced the incidence of recurrent adenomatous polyps in patients with previous neoplasia who were undergoing follow-up colonoscopy. METHODS: This study enrolled 1,162 patients who underwent colonoscopy by one of three surgeons at Columbia-Presbyterian Medical Center in New York City between March 1993 and February 1997. Of these patients 448 (250 males) had a previous diagnosis of colorectal neoplasia (cancer, adenomas, or dysplasia). Of these, 183 (40.8 percent) had an adenoma at the index colonoscopy. Information was collected on personal and family history of colonic diseases, cigarette smoking, medication, and vitamin and micronutrient supplement usage on a questionnaire that was completed by the patients before the colonoscopy. Odds ratios were obtained by unconditional logistic regression analysis, adjusting for age and gender, and used adenoma recurrence at index colonoscopy as the outcome. RESULTS: The mean interval between colonoscopic examinations was 37 months for the recurrent adenoma group and 38 months for the nonrecurrent group of patients (P = not significant). In this case-control study we found a protective effect for the use of vitamin supplements in general (any vitamin) on the recurrence of adenomas (odds ratio, 0.41; 95 percent confidence interval, 0.27-0.61). Specifically, this protective effect was observed for the use of multivitamins (odds ratio, 0.47; 95 percent confidence interval, 0.31-0.72), vitamin E (odds ratio, 0.62; 95 percent confidence interval, 0.39-0.98), and for calcium supplementation (odds ratio, 0.51; 95 percent confidence interval, 0.27-0.96). Nonsignificant protective effects were noted for carotene/vitamin A, vitamin D, and vitamin C. CONCLUSIONS: The use of multivitamins, vitamin E, and calcium supplements were found to be associated with a lower incidence of recurrent adenomas in a population of patients with history of previous colonic neoplasia. Prospective, randomized trials are needed to better assess the impact of these agents and to determine whether the use of these supplements is associated with a protective effect against recurrent adenomas.

Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake.

We have evaluated the effect of folate supplementation (5 mg/day) on global deoxyribonucleic acid (DNA) methylation status of the rectal mucosa of 20 patients with resected colonic adenomas in a prospective, controlled, cross-over study. Baseline values of DNA methylation were inversely correlated with caloric (P = 0.03) and fat intake (P = 0.05) and patients harbouring multiple polyps consumed significantly more calories (P = 0.0006), fat (P = 0.009) and carbohydrates (P = 0.009) as compared to patients having one single lesion. Folate supplementation resulted in a significant decrease of DNA hypomethylation in 7/20 patients (P = 0.05) which returned to previous values after placebo treatment. This effect was significantly correlated with number of polyps, with all the responders presenting one single lesion, whereas 8/13 of the non-responders had multiple ones (chi2 = 7.17, P = 0.007). In conclusion, folate supplementation may decrease degree of DNA hypomethylation, but only in patients with one single polyp. In those with multiple lesions, other nutritional factors such as caloric and fat intake, may be more determinant.