Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention
- Conditions
- Colorectal Adenomatous Polyps
- Interventions
- Procedure: Rectal biopsy during colonoscopyProcedure: Rectal biopsy at randomizationProcedure: Rectal biopsy at 1 yearProcedure: Rectal biopsy prior to colonoscopyProcedure: Biopsies during colonoscopy
- Registration Number
- NCT00399607
- Lead Sponsor
- Emory University
- Brief Summary
The study team has developed a set of biomarkers of risk for colon cancer; this study tests 1) whether or not calcium and/or vitamin D supplementation can favorably affect these biomarkers in persons who are at higher than average risk for colon cancer (ie, have already undergone the removal of colon growths, called adenomatous polyps, which are known to be precursors to developing colon cancer), and 2) whether effects on the biomarkers predict who will get new colon polyps or not.
- Detailed Description
This study is an add-on study ('adjunct study') to a clinical trial that is already being conducted (the 'parent study'). Study participants will be composed of persons who are already participating in the parent study, "Vitamin D/Calcium Polyp Prevention Study". In the parent study, a total of 1,964 people nationally are being randomly assigned to four different treatment groups: 1) calcium supplements, 600 mg twice a day; 2) vitamin D supplements, 500 IU twice a day; 3) both the calcium and vitamin D supplements twice a day; and 4) placebo tablets twice a day. The treatment period lasts three to five years at the end of which study participants undergo a follow-up colonoscopy to look for new polyps. The parent study began about a year prior to the start of this adjunct study, thus, there are already some patients in the trial who are receiving their study 'treatments' (i.e., have been 'randomized'), but more patients will be recruited into the parent study.
Depending on whether someone has already been randomized, participants of the parent study will be invited to take part in the adjunct study in one of two ways: 'Aim 1' only, or 'All Aims'. First, patients who have already been randomized will be asked to allow biopsies to be made of their rectal tissue during their 3- or 5-year follow-up colonoscopy (Aim 1). Biopsies, which will be used for our biomarker measurements, are very tiny pieces of tissue that can be examined under the microscope. Second, patients who have not yet been randomized will be invited to participate more fully (All Aims) in the adjunct study. This involves having outpatient rectal biopsies taken immediately after their first phone call, their 1-year follow-up visit, and 7 - 21 days before their 3- or 5-year follow-up colonoscopy. Finally, during their 3- or 5-year colonoscopy, biopsies will be taken from three areas of the colon: the rectum (same area as the outpatient biopsies), the sigmoid colon, and the ascending colon. From all of the biopsies taken from all of the visits and colon sites, biomarker measurements will be of normal proteins that occur in the surface cells lining the colon. Study researchers will then analyze whether calcium and/or vitamin D affect these biomarkers and whether the effects predict who gets new polyps.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 264
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description All aims Biopsies during colonoscopy Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study. All aims Rectal biopsy at 1 year Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study. All aims Rectal biopsy prior to colonoscopy Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study. Aim 1 Rectal biopsy during colonoscopy Participants previously randomized for the parent study will be eligible for a portion of the adjunct biomarker study. All aims Rectal biopsy at randomization Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study.
- Primary Outcome Measures
Name Time Method β-catenin Levels Baseline to end of intervention (up to 5 years) β-catenin is a protein encoded by the CTNNB1 gene and is part of the APC Pathway of colon cancer development. Overexpression and mutations of β-catenin are associated with multiple cancers, including colorectal cancer. An increase in the ratio of APC to β-catenin is indicative of a decrease of adenoma recurrence.
E-cadherin Levels Baseline to end of intervention (up to 5 years) E-cadherin is a calcium-dependent cell adhesion molecule necessary for colon crypt structure and function. Regulated by β-catenin, E-cadherin is part of the APC Pathway of colon cancer development. An increase in the ratio of APC to E-cadherin is indicative of a decrease of adenoma recurrence.
Bax Levels Baseline to end of intervention (up to 5 years) Bax (bcl-2-like protein 4) is a protein that promotes apoptosis of cancer cells and is involved in the DNA Mismatch Repair (MMR) Pathway. Apoptosis is higher in colon neoplasms than in normal colon tissue so a lower expression of bax is indicative of decreased adenoma recurrence.
TGFβ1 Levels Baseline to end of intervention (up to 5 years) Transforming growth factor beta 1 (TGFβ1), a potent inhibitor of colonocyte growth/proliferation, inhibits c-myc19,26 and induces p21,26 and the growth suppressive activity of TGFβ1 is inhibited by β-catenin (part of the APC Pathway of colon cancer development). A decrease in the ratio of TGFα to TGFβ1 may be associated with a decrease in adenoma recurrence.
Bcl-2 Levels Baseline to end of intervention (up to 5 years) B-cell CLL/lymphoma 2 (bcl-2) is a protein encoded by the BCL2 gene which regulates apoptosis. Bcl-2 inhibits apoptosis of abnormal cells. A decrease in the ratio of bax to bcl-2 may be associated with a decrease in adenoma recurrence.
APC Protein Levels Baseline to end of intervention (up to 5 years) Adenomatous polyposis coli (APC) is a protein encoded by the APC gene and is part of the APC Pathway of colon cancer development. The APC Pathway accounts for familial adenomatosis polyposis (FAP) and approximately 80% of sporadic cancers. The APC protein regulates β-catenin.
hTERT Levels Baseline to end of intervention (up to 5 years) hTERT is a catalytic subunit of telomerase. Telomerase is normally present primarily in stem cells and at least some early daughter cells and is expressed in colon and other cancers. A decrease of hTERT is associated in decreased adenoma recurrence.
COX-2 Levels Baseline to end of intervention (up to 5 years) Cyclo-oxygenase-2 (COX-2) is an enzyme that is elevated during periods of inflammation. Inflammation and inflammation regulation likely have important roles in colon cancer development. Control of inflammatory response suppresses COX-2.
MLH1 Protein Levels Baseline to end of intervention (up to 5 years) MutL homolog 1 (MLH1) is a protein in the DNA Mismatch Repair (MMR) Pathway. MLH1 protein deficiencies have been found to be related multiple types of cancer, including colorectal cancer. The MMR Pathway accounts for hereditary non-polyosis colon cancer (HNPCC) and approximately 15% of sporadic cancers.
TGFα Levels Baseline to end of intervention (up to 5 years) Transforming growth factor alpha (TGFα), a potent stimulator of colonocyte growth/proliferation, can synergize with c-myc to promote malignant transformation in vitro. A decrease in the ratio of TGFα to TGFβ1 may be associated with a decrease in adenoma recurrence.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (9)
Dartmouth-Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
USC/Norris Comprehensice Cancer Center
🇺🇸Los Angeles-, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
University of Iowa Hospitals & Clinic
🇺🇸Iowa City, Iowa, United States
University of South Carolina
🇺🇸West Columbia, South Carolina, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
University of Colorado Health Sciences Center
🇺🇸Denver, Colorado, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States