Program Official

Principal Investigator

John Anthony
Baron
Awardee Organization

Univ Of North Carolina Chapel Hill
United States

Fiscal Year
2015
Activity Code
R01
Project End Date

Colorectal Chemoprevention with Calcium and Vitamin D

In this application we propose to complete CA098286, a double-blind, randomized, controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. The study builds on extensive epidemiological and experimental data indicating that both vitamin D and calcium have anti-neoplastic effects in the large bowel and that these agents interact, each requiring the other for full effect. Despite the strong supporting data, randomized trials are needed to confirm the purported efficacy of vitamin D, clarify its persistence, and assess the possible interaction with calcium. Experience with previous candidate chemopreventive agents for large bowel neoplasia shows that observation of a single colonoscopic surveillance cycle provides an incomplete evaluation of efficacy. Some agents have shown maximal effects only with longer follow-up; others have shown "rebound" increases in adenoma risk after treatment ends. Eligible subjects for the trial had a recent adenoma and no known polyps remaining in the large bowel. A total of 2259 subjects have been randomized to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. Women were offered the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up is either 3 years or 5 years after the qualifying exam, as planned by each subject's gastroenterologist. The main endpoint of the study is one or more neoplastic polyps of the bowel on follow-up; advanced lesions and multiple lesions are secondary endpoints. After completion of study treatment, subjects are followed for one subsequent colonoscopic surveillance cycle. The study has successfully met its milestones during the first 10 years of funding. Enrollment proceeded according to schedule and subjects have shown very good compliance with study procedures and agents. Recruitment into the post-treatment follow-up has been excellent. We now request funds for the final phases of the study: completion of treatment for a few subjects, post- treatment follow-up, and analyses of on-treatment and post-treatment adenoma occurrence. In our main analyses, we will assess the effect of vitamin D alone vs. placebo and that of vitamin D + calcium vs. calcium alone and also test whether there is a "rebound" in adenoma risk after cessation of vitamin D treatment. Under conservative assumptions, we will have greater than 95% power to detect a 20% reduction in adenoma recurrence with vitamin D vs. placebo, 89% power to detect a 25% reduction with calcium plus vitamin D vs. calcium alone and 80% power to reject a non-inferiority hypothesis regarding vitamin D vs. placebo, with an inferiority margin of 0.065 during post-treatment follow-up. Our secondary analyses will address advanced and multiple lesions, the interaction of calcium and vitamin D, and the modifying effects of baseline 25-OH vitamin D levels and polymorphisms in the vitamin D receptor on vitamin D treatment effects.

Publications

  • Passarelli MN, McDonald JG, Thompson BM, Arega EA, Palys TJ, Rees JR, Barry EL, Baron JA. Association of demographic and health characteristics with circulating oxysterol concentrations. Journal of clinical lipidology. 2022 May-Jun;16(3):345-355. Epub 2022 Apr 9. PMID: 35461764
  • Gibbs DC, Fedirko V, Baron JA, Barry EL, Flanders WD, McCullough ML, Yacoub R, Raavi T, Rutherford RE, Seabrook ME, Bostick RM. Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial. Cancer prevention research (Philadelphia, Pa.). 2021 Jan;14(1):65-76. Epub 2020 Sep 11. PMID: 32917645
  • Crockett SD, Mott LA, Barry EL, Figueiredo JC, Burke CA, Baxter GJ, Sandler RS, Baron JA. C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study. Cancer prevention research (Philadelphia, Pa.). 2014 Nov;7(11):1122-7. Epub 2014 Aug 21. PMID: 25145487
  • Rees JR, Hendricks K, Barry EL, Peacock JL, Mott LA, Sandler RS, Bresalier RS, Goodman M, Bostick RM, Baron JA. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013 Nov;57(10):1384-92. Epub 2013 Sep 6. PMID: 24014734
  • Crockett SD, Barry EL, Mott LA, Ahnen DJ, Robertson DJ, Anderson JC, Wallace K, Burke CA, Bresalier RS, Figueiredo JC, Snover DC, Baron JA. Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial. Gut. 2019 Mar;68(3):475-486. Epub 2018 Mar 1. PMID: 29496722
  • Bischoff-Ferrari HA, Rees JR, Grau MV, Barry E, Gui J, Baron JA. Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. The American journal of clinical nutrition. 2008 Jun;87(6):1945-51. PMID: 18541589
  • Vermandere K, Bostick RM, Tran HQ, Gewirtz AT, Barry EL, Rutherford RE, Seabrook ME, Fedirko V. Effects of Supplemental Calcium and Vitamin D on Circulating Biomarkers of Gut Barrier Function in Patients with Colon Adenoma: A Randomized Clinical Trial. Cancer prevention research (Philadelphia, Pa.). 2021 Mar;14(3):393-402. Epub 2020 Nov 23. PMID: 33229339
  • Barry EL, Mott LA, Melamed ML, Rees JR, Ivanova A, Sandler RS, Ahnen DJ, Bresalier RS, Summers RW, Bostick RM, Baron JA. Calcium supplementation increases blood creatinine concentration in a randomized controlled trial. PloS one. 2014 Oct 15;9(10):e108094. doi: 10.1371/journal.pone.0108094. eCollection 2014. PMID: 25329821
  • Kwan AK, Um CY, Rutherford RE, Seabrook ME, Barry EL, Fedirko V, Baron JA, Bostick RM. Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial. Molecular carcinogenesis. 2019 Apr;58(4):511-523. Epub 2018 Dec 21. PMID: 30499618
  • Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ (Clinical research ed.). 2010 Jul 29;341:c3691. PMID: 20671013
  • Anderson JC, Baron JA, Ahnen DJ, Barry EL, Bostick RM, Burke CA, Bresalier RS, Church TR, Cole BF, Cruz-Correa M, Kim AS, Mott LA, Sandler RS, Robertson DJ. Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome. Gastroenterology. 2017 Jun;152(8):1933-1943.e5. Epub 2017 Feb 20. PMID: 28219690
  • Barry EL, Lund JL, Westreich D, Mott LA, Ahnen DJ, Beck GJ, Bostick RM, Bresalier RS, Burke CA, Church TR, Rees JR, Robertson DJ, Baron JA. Body mass index, calcium supplementation and risk of colorectal adenomas. International journal of cancer. 2019 Feb 1;144(3):448-458. Epub 2018 Oct 30. PMID: 30117164
  • Passarelli MN, Mott LA, Barry EL, Rees JR, Baron JA. Oral Antibiotics and Risk of New Colorectal Adenomas During Surveillance Follow-up. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021 Oct;30(10):1974-1976. Epub 2021 Jul 21. PMID: 34289971
  • Barry EL, Peacock JL, Rees JR, Bostick RM, Robertson DJ, Bresalier RS, Baron JA. Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial. JAMA oncology. 2017 May 1;3(5):628-635. PMID: 27978548
  • Obuch JC, Pigott CM, Ahnen DJ. Sessile serrated polyps: detection, eradication, and prevention of the evil twin. Current treatment options in gastroenterology. 2015 Mar;13(1):156-70. PMID: 25623474
  • Figueiredo JC, Gresham G, Barry EL, Mott LA, Passarelli MN, Bradshaw PT, Anderson CW, Baron JA. Circulating Sex Hormones and Risk of Colorectal Adenomas and Serrated Lesions in Men. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jan;31(1):293-295. Epub 2021 Nov 10. PMID: 34758968
  • Dai Q, Sandler R, Barry E, Summers R, Grau M, Baron J. Calcium, magnesium, and colorectal cancer. Epidemiology (Cambridge, Mass.). 2012 May;23(3):504-5. PMID: 22475836
  • Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, Burckhardt P, Li R, Spiegelman D, Specker B, Orav JE, Wong JB, Staehelin HB, O'Reilly E, Kiel DP, Willett WC. Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. The American journal of clinical nutrition. 2007 Dec;86(6):1780-90. PMID: 18065599
  • Peery AF, Sandler RS, Galanko JA, Bresalier RS, Figueiredo JC, Ahnen DJ, Barry EL, Baron JA. Risk Factors for Hemorrhoids on Screening Colonoscopy. PloS one. 2015 Sep 25;10(9):e0139100. doi: 10.1371/journal.pone.0139100. eCollection 2015. PMID: 26406337
  • Crockett SD, Barry EL, Mott LA, Snover DC, Wallace K, Baron JA. Predictors of Incident Serrated Polyps: Results from a Large Multicenter Clinical Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 May 4;31(5):1058-1067. PMID: 35506244
  • Passarelli MN, Thompson BM, McDonald JG, Snover DC, Palys TJ, Rees JR, Barry EL, Baron JA. Circulating 27-hydroxycholesterol and Risk of Colorectal Adenomas and Serrated Polyps. Cancer prevention research (Philadelphia, Pa.). 2021 Apr;14(4):479-488. Epub 2021 Jan 6. PMID: 33408073
  • Peery AF, Sandler RS, Ahnen DJ, Galanko JA, Holm AN, Shaukat A, Mott LA, Barry EL, Fried DA, Baron JA. Constipation and a low-fiber diet are not associated with diverticulosis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2013 Dec;11(12):1622-7. Epub 2013 Jul 23. PMID: 23891924
  • Liu S, Barry EL, Baron JA, Rutherford RE, Seabrook ME, Bostick RM. Effects of supplemental calcium and vitamin D on the APC/β-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients. Molecular carcinogenesis. 2017 Feb;56(2):412-424. Epub 2016 Jun 14. PMID: 27254743
  • Grau MV, Baron JA, Sandler RS, Wallace K, Haile RW, Church TR, Beck GJ, Summers RW, Barry EL, Cole BF, Snover DC, Rothstein R, Mandel JS. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. Journal of the National Cancer Institute. 2007 Jan 17;99(2):129-36. PMID: 17227996
  • Hodge R, Mandle HB, Ray S, Tandon S, Peterson M, Henry A, Jahan FA, Bostick RM, Baron JA, Barry EL, Yacoub R, Rutherford RE, Seabrook ME, Fedirko V. Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/β in the Normal Rectal Mucosa of Colorectal Adenoma Patients. Cancer prevention research (Philadelphia, Pa.). 2018 Nov;11(11):707-716. Epub 2018 Sep 12. PMID: 30209117
  • Gao Y, Um CY, Fedirko V, Rutherford RE, Seabrook ME, Barry EL, Baron JA, Bostick RM. Effects of supplemental vitamin D and calcium on markers of proliferation, differentiation, and apoptosis in the normal colorectal mucosa of colorectal adenoma patients. PloS one. 2018 Dec 17;13(12):e0208762. doi: 10.1371/journal.pone.0208762. eCollection 2018. PMID: 30557404
  • Rees JR, Mott LA, Barry EL, Baron JA, Figueiredo JC, Robertson DJ, Bresalier RS, Peacock JL. Randomized controlled trials: who fails run-in? Trials. 2016 Jul 29;17:374. PMID: 27474021
  • Calderwood AH, Baron JA, Mott LA, Ahnen DJ, Bostick RM, Figueiredo JC, Passarelli MN, Rees JR, Robertson DJ, Barry EL. No Evidence for Posttreatment Effects of Vitamin D and Calcium Supplementation on Risk of Colorectal Adenomas in a Randomized Trial. Cancer prevention research (Philadelphia, Pa.). 2019 May;12(5):295-304. Epub 2019 Mar 4. PMID: 30833381
  • Anderson JC, Morris CB, Robertson DJ, Barry ELR, Figueiredo JC, Cruz-Correa M, Bostick RM, Ahnen DJ, Baron JA. Can the Sum of Adenoma Diameters (Adenoma Bulk) on Index Examination Predict Risk of Metachronous Advanced Neoplasia? Journal of clinical gastroenterology. 2018 Aug;52(7):628-634. PMID: 28767463
  • Mandle HB, Jahan FA, Bostick RM, Baron JA, Barry EL, Yacoub R, Merrill J, Rutherford RE, Seabrook ME, Fedirko V. Effects of supplemental calcium and vitamin D on tight-junction proteins and mucin-12 expression in the normal rectal mucosa of colorectal adenoma patients. Molecular carcinogenesis. 2019 Jul;58(7):1279-1290. Epub 2019 Apr 2. PMID: 30938860
  • Barry EL, Rees JR, Peacock JL, Mott LA, Amos CI, Bostick RM, Figueiredo JC, Ahnen DJ, Bresalier RS, Burke CA, Baron JA. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. The Journal of clinical endocrinology and metabolism. 2014 Oct;99(10):E2133-7. Epub 2014 Jul 29. PMID: 25070320
  • Passarelli MN, Karagas MR, Mott LA, Rees JR, Barry EL, Baron JA. Risk of keratinocyte carcinomas with vitamin D and calcium supplementation: a secondary analysis of a randomized clinical trial. The American journal of clinical nutrition. 2020 Dec 10;112(6):1532-1539. PMID: 33022713
  • Peery AF, Baron JA. Reply: To PMID 23891924. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014 Jul;12(7):1201-2. Epub 2014 May 10. PMID: 24823290
  • Wei JW, Suriawinata AA, Vaickus LJ, Ren B, Liu X, Lisovsky M, Tomita N, Abdollahi B, Kim AS, Snover DC, Baron JA, Barry EL, Hassanpour S. Evaluation of a Deep Neural Network for Automated Classification of Colorectal Polyps on Histopathologic Slides. JAMA network open. 2020 Apr 1;3(4):e203398. PMID: 32324237
  • Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, Bostick RM, Ivanova A, Cole BF, Ahnen DJ, Beck GJ, Bresalier RS, Burke CA, Church TR, Cruz-Correa M, Figueiredo JC, Goodman M, Kim AS, Robertson DJ, Rothstein R, Shaukat A, Seabrook ME, Summers RW. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. The New England journal of medicine. 2015 Oct 15;373(16):1519-30. PMID: 26465985
  • Grau MV, Sandler RS, McKeown-Eyssen G, Bresalier RS, Haile RW, Barry EL, Ahnen DJ, Gui J, Summers RW, Baron JA. Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study. Journal of the National Cancer Institute. 2009 Feb 18;101(4):267-76. Epub 2009 Feb 10. PMID: 19211442

Clinical Trials

Study Name Clinical Trial ID
Vitamin D/Calcium Polyp Prevention Study NCT00153816