Supplemental calcium in the chemoprevention of colorectal cancer: A systematic review and meta-analysis

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      Objective: The aim of the review was to assess the evidence for the effectiveness of calcium in reducing the recurrence of adenomas and the occurrence of colorectal cancer among populations at high, intermediate, and low risk of the disease.
      Methods: A systematic review of randomized controlled trials (RCTs) was performed to compare calcium alone, and with other agents, versus placebo. Nine databases (Cochrane Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE, Web of Science, Biological Abstracts, the National Research Register, and Current Controlled Trials) were searched for published and unpublished trials. Searches were not restricted by either language or date of publication. All searches were completed in January 2010. Database thesaurus and free text terms for calcium and adenomas or colorectal cancer were used to search for trial reports; additional terms were used to search for other agents of interest, such as NSAIDs and folic acid. Search terms consisted of a combination of terms for colorectal cancer (eg, colon or colorectal and neoplasm or cancer or adenoma) and terms for calcium and RCTs. The initial searches were conducted in June 2008, with update searches in January 2010 to identify more recent studies. The reference lists of relevant studies were also searched for additional papers not identified by the search of electronic databases. Studies had to satisfy the following criteria to be included: RCTs about calcium, with or without other chemopreventive agents, in adults with familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer, or a history of colorectal adenomas, or with no increased baseline risk of colorectal cancer. Meta-analysis was performed. For discrete and numerical outcomes, relative risks (RRs) and risk differences were reported with 95% CIs. The random-effects model was used to account for clinical and methodologic variations between trials.
      Results: The original and update searches of electronic databases produced 3835 citations, of which 6 studies (8 papers) met the inclusion criteria. Supplemental calcium had no effect on the number of adenomas in 1 small trial of patients with FAP. Meta-analysis of 3 trials in individuals with a history of adenomas showed a statistically significant reduction in the RR for adenoma recurrence (RR = 0.80 [95% CI, 0.69–0.94], P = 0.006) for those receiving calcium 1200 to 2000 mg/d, but no effect was seen in advanced adenoma (RR = 0.77 [95% CI, 0.501.17], P = NS). Meta-analysis of 2 trials in populations with no increased baseline risk for colorectal cancer suggested that calcium, with or without vitamin D, had no effect on the RR for colorectal cancer (RR = 0.62 [95% CI, 0.11-3.40], P = NS).
      Conclusion: Published reports indicated that supplemental calcium was effective for the prevention of adenoma recurrence in populations with a history of adenomas, but no similar effect was apparent in populations at higher or lower risk.

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        • Bond JH
        Colorectal cancer update. Prevention, screening, treatment, and surveillance for high-risk groups.
        Med Clin North Am. 2000; 84: 1163-1182
        • Ferlay J
        • Autier P
        • Boniol M
        • et al.
        Estimates of the cancer incidence and mortality in Europe in 2006.
        Ann Oncol. 2007; 18: 581-592
        • Office for National Statistics
        Cancer statistics registration: Registrations of cancer diagnosed in 2006, England. Series MB1, No. 37.
        (Accessed March 30, 2010)
        • Welsh Cancer Intelligence and Surveillance Unit
        Cancer incidence in Wales. 2003–2007; (Accessed March 30, 2010)
        • Giovannucci E
        • Stampfer MJ
        • Colditz GA
        • et al.
        Folate, methionine, and alcohol intake and risk of colorectal adenoma.
        J Natl Cancer Inst. 1993; 85: 875-884
        • National Institute for Health and Clinical Excellence
        Improving outcomes in colorectal cancers: Manual update.
        (Accessed March 30, 2010)
        • Bishop DT
        • Hall NR
        The genetics of colorectal cancer.
        Eur J Cancer. 1994; 30A: 1946-1956
        • Aaltonen LA
        • Salovaara R
        • Kristo P
        • et al.
        Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.
        N Engl J Med. 1998; 338: 1481-1487
        • Hill MJ
        • Morson BC
        • Bussey HJ
        Aetiology of adenomacarcinoma sequence in large bowel.
        Lancet. 1978; 1: 245-247
        • Ramsoekh D
        • Van Leerdam ME
        • Wagner A
        • Kuipers EJ
        Review article: Detection and management of hereditary non-polyposis colorectal cancer (Lynch syndrome).
        Aliment Pharmacol Ther. 2007; 26: 101-111
        • University of York Centre for Reviews and Dissemination
        The management of colorectal cancers.
        Effect Health Care. 2004; 8: 1-12
        • Leslie A
        • Carey FA
        • Pratt NR
        • Steele RJ
        The colorectal adenoma-carcinoma sequence.
        Br J Surg. 2002; 89: 845-860
        • Stryker SJ
        • Wolff BG
        • Culp CE
        • et al.
        Natural history of untreated colonic polyps.
        Gastroenterology. 1987; 93: 1009-1013
        • Flossmann E
        • Rothwell PM
        • British Doctors Aspirin Trial and the UK-TIA Aspirin Trial
        Effect of aspirin on long-term risk of colorectal cancer: Consistent evidence from randomised and observational studies.
        Lancet. 2007; 369: 1603-1613
        • Atkin WS
        • Saunders BP
        • British Society for Gastroenterology and the Association of Coloproctology for Great Britain and Ireland
        Surveillance guidelines after removal of colorectal adenomatous polyps.
        Gut. 2002; 51: V6-V9
        • Cancer Research UK
        Bowel cancer: Survival statistics.
        (Accessed April 23, 2010)
      1. Cooper K, Pilgrim H, Carroll C, et al. Chemoprevention of colorectal cancer: Systematic review and economic evaluation. Health Technol Assess. In press.

        • Dubé C
        • Rostom A
        • Lewin G
        • et al.
        The use of aspirin for primary prevention of colorectal cancer: A systematic review prepared for the US Preventive Services Task Force.
        Ann Intern Med. 2007; 146: 365-375
        • Rostom A
        • Dubé C
        • Lewin G
        • et al.
        Nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: A systematic review prepared for the US Preventive Services Task Force.
        Ann Intern Med. 2007; 146: 376-389
        • Asano TK
        • McLeod RS
        Non steroidal anti-inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas.
        Cochrane Database Syst Rev. 2004; : CD004079
        • Carroll C
        • Cooper K
        • Papaioannou D
        • et al.
        Meta-analysis: Folic acid in the prevention of colorectal adenomas and the chemoprevention of colorectal cancer.
        Aliment Pharmacol Ther. 2010; 31: 708-718
        • Bjelakovic G
        • Nikolova D
        • Simonetti RG
        • Gluud C
        Antioxidant supplements for preventing gastrointestinal cancers.
        Cochrane Database Syst Rev. 2008; : CD004183
        • Bjelakovic G
        • Nagorni A
        • Nikolova D
        • et al.
        Meta-analysis: Antioxidant supplements for primary and secondary prevention of colorectal adenoma.
        Aliment Pharmacol Ther. 2006; 24: 281-291
        • Weingarten MA
        • Zalmanovici A
        • Yaphe J
        Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps.
        Cochrane Database Syst Rev. 2008; : CD003548
        • Shaukat A
        • Scouras N
        • Schünemann HJ
        Role of supplemental calcium in the recurrence of colorectal adenomas: A meta-analysis of randomized controlled trials.
        Am J Gastroenterol. 2005; 100: 390-394
        • Scottish Intercollegiate Guidelines Network
        Search filters: Randomised controlled trials.
        (Accessed March 30, 2010)
        • National Health Service Centre for Reviews and Dissemination
        Systematic reviews: CRD's guidance for undertaking reviews in healthcare.
        (Accessed March 30, 2010)
        • Higgins J
        • Green S
        Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2.
        (Accessed April 23, 2010)
        • Thomas MG
        • Thomson JP
        • Williamson RC
        Oral calcium inhibits rectal epithelial proliferation in familial adenomatous polyposis.
        Br J Surg. 1993; 80: 499-501
        • Baron JA
        • Beach M
        • Mandel JS
        • et al.
        • Calcium Polyp Prevention Study Group
        Calcium supplements for the prevention of colorectal adenomas.
        N Engl J Med. 1999; 340: 101-107
        • Baron JA
        • Beach M
        • Mandel JS
        • et al.
        • Polyp Prevention Study Group
        Calcium supplements and colorectal adenomas.
        Ann N Y Acad Sci. 1999; 889: 138-145
        • Bonithon-Kopp C
        • Kronborg O
        • Giacosa A
        • et al.
        • European Cancer Prevention Organisation Study Group
        Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: A randomised intervention trial.
        Lancet. 2000; 356: 1300-1306
        • Hofstad B
        • Vatn M
        • Hoff G
        • et al.
        Growth of colorectal polyps: Design of a prospective, randomized, placebo-controlled intervention study in patients with colorectal polyps [published correction appears in Eur J Cancer Prev. 1993;2:189].
        Eur J Cancer Prev. 1992; 1: 415-422
        • Hofstad B
        • Almendingen K
        • Vatn M
        • et al.
        Growth and recurrence of colorectal polyps: A double-blind 3-year intervention with calcium and antioxidants.
        Digestion. 1998; 59: 148-156
        • Lappe JM
        • Travers-Gustafson D
        • Davies KM
        • et al.
        Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial [published correction appears in Am J Clin Nutr. 2008;87:794].
        Am J Clin Nutr. 2007; 85: 1586-1591
        • Wactawski-Wende J
        • Kotchen JM
        • Anderson GL
        • et al.
        • Women's Health Initiative Investigators
        Calcium plus vitamin D supplementation and the risk of colorectal cancer [published correction appears in N Engl J Med. 2006;354:1102].
        N Engl J Med. 2006; 354: 684-696
        • Tierney JF
        • Stewart LA
        Investigating patient exclusion bias in meta-analysis.
        Int J Epidemiol. 2005; 34: 79-87
        • Bjelakovic G
        • Nikolova D
        • Simonetti RG
        • Gluud C
        Antioxidant supplements for prevention of gastrointestinal cancers: A systematic review and meta-analysis.
        Lancet. 2004; 364: 1219-1228
        • Grau MV
        • Baron JA
        • Sandler RS
        • et al.
        Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial.
        J Natl Cancer Inst. 2007; 99: 129-136
        • Hollis S
        • Campbell F
        What is meant by intention to treat analysis? Survey of published randomised controlled trials.
        BMJ. 1999; 319: 670-674
        • Montori V
        • Guyatt G
        Intention-to-treat principle.
        CMAJ. 2001; 165: 1339-1341
        • Martfnez ME
        • Sampliner R
        • Marshall JR
        • et al.
        Adenoma characteristics as risk factors for recurrence of advanced adenomas.
        Gastroenterology. 2001; 120: 1077-1083
        • Bonithon-Kopp C
        • Piard F
        • Fenger C
        • et al.
        • European Cancer Prevention Organisation Study Group
        Colorectal adenoma characteristics as predictors of recurrence.
        Dis Colon Rectum. 2004; 47: 323-333
        • Grau MV
        • Baron JA
        • Sandler RS
        • et al.
        Vitamin D, calcium supplementation, and colorectal adenomas: Results of a randomized trial.
        J Natl Cancer Inst. 2003; 95: 1765-1771
        • Ding EL
        • Mehta S
        • Fawzi WW
        • Giovannucci EL
        Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women's Health Initiative randomized trial.
        Int J Cancer. 2008; 122: 1690-1694
        • McAlister FA
        • Straus SE
        • Sackett DL
        • Altman DG
        Analysis and reporting of factorial trials: A systematic review.
        JAMA. 2003; 289: 2545-2553
      2. Stajner Comment on interaction of hormone replacement therapy with calcium and vitamin D supplementation on colorectal cancer risk.
        Int J Cancer. 2009; 124: 1736
      3. Stajner Comment on interaction of hormone replacement therapy with calcium and vitamin D supplementation on colorectal cancer risk.
        Int J Cancer. 2009; 124 (author reply): 1737-1738