Adenomatous Colorectal Polyps, Colorectal Cancer, Precancerous Condition
Conditions
Keywords
colon cancer, rectal cancer, colorectal cancer, adenomatous polyp
Brief summary
RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Selenium may be effective in preventing the recurrence of adenomatous colorectal polyps. PURPOSE: This randomized phase III trial is studying selenium to see how well it works in preventing the recurrence of polyps in patients with adenomatous colorectal polyps.
Detailed description
OBJECTIVES: Primary * Compare the effects of selenium vs placebo on the recurrence of adenomatous colorectal polyps, in terms of histologic type, degree of dysplasia, number, size, and location, in patients with adenomatous colorectal polyps. * Compare the type, incidence, and outcome of side effects in patients treated with these regimens. * Determine patient adherence to long-term treatment with these regimens. Secondary * Determine the effects of regimen modification by baseline blood selenium level, low-dose aspirin, selenoprotein genetic marker polymorphisms (e.g., GPx-1, GPx-2, and SEP15) * Determine the effects of low-dose aspirin (81 mg/day) modification by ornithine decarboxylase promoter genotype, and toxicity by slow-metabolizer genotypes of the cytochrome p450 2C9 and UT1A6 loci in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to use of low-dose (≤ 81 mg/day) aspirin (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral selenium once daily. * Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for up to 5 years\* in the absence of disease progression or unacceptable toxicity. Patients undergo follow-up colonoscopy approximately 5 years\* after baseline colonoscopy. NOTE: Some patients will continue participation for up to 7 and a half years PROJECTED ACCRUAL: A total of 1,600 patients with an adenoma will be randomized to this study, followed by a second group of randomization of 200 patients with at least one advanced adenoma (at baseline) for a substudy. Total planned randomizations = 1,800 participants.
Interventions
DRUGSelenium
Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.
Sponsors
National Cancer Institute (NCI)
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed colorectal adenomatous polyps * Meets the following criteria by colonoscopy (performed within the past 6 months): * Cecum was totally visualized or reached * At least 90% visualization of colon surface area * Removed at least 1 adenomatous polyp of at least 3 mm in size during procedure (For the Advanced Adenoma Sub-study: Removal of at least 1 advanced colorectal adenomatous polyp during procedure. An adenoma is considered advanced if it is 10 mm or greater in size, and/or has villous histology and/or shows high grade dysplasia) * Removed no more than 10 adenomatous polyps of any size by endoscopy * All other neoplastic and non-neoplastic colon polyps must have been completely removed (except for diminutive \[less than 3 mm\] sessile rectal polyps) * For the sub-study, at least 1 advanced adenomatous polyp defined as 10 mm or greater in size and/or has villous histology and/or shows high grade dysplasia * No prior diagnosis of any of the following: * Colorectal cancer * Familial adenomatous polyposis * Ulcerative colitis * Crohn's disease * Hereditary non-polyposis colon cancer (HNPCC), defined as: * Histologically confirmed colorectal cancer in at least 3 relatives, 1 of whom is a first-degree relative of the other 2 * Disease occurrence in at least 2 consecutive generations * Colorectal cancer diagnosis in at least 1 family member who is less than 50 years of age * Patients with a family history of colorectal cancer but who are not diagnosed with HNPCC are allowed * No more than 1 prior segmental colon resection PATIENT CHARACTERISTICS: Age * 40 to 80 Performance status * SWOG 0-1 Life expectancy * Not specified Hematopoietic * Hemoglobin \> 11 g/dL * WBC 3,000 - 11,000/mm\^3 Hepatic * AST and ALT \< 2 times upper limit of normal * Bilirubin \< 2.0 mg/dL Renal * Creatinine \< 1.9 mg/dL Cardiovascular * No unstable\* cardiac disease despite medication (e.g., diuretics or digitalis) * No uncontrolled hypertension (i.e., systolic blood pressure ≥ 170 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) despite medication NOTE: \*Unstable defined as unable to walk across the room without chest pain or shortness of breath Other * Not pregnant or nursing * Fertile patients must use effective contraception for at least 2 months before and during study treatment * Resident of a clinical center metropolitan area or obtaining regular health care in a clinical metropolitan area for at least 6 months out of the year * Must be able to swallow pills * No unexpected weight loss of 10% or more within the past 6 months * No prior rheumatoid arthritis * No poorly controlled diabetes mellitus despite medication, defined as: * Blood sugar level ≥ 200 mg/dL on more than half of the readings taken within the past month * No invasive malignancy within the past 5 years that required medical excision, radiotherapy, or chemotherapy except basal cell or squamous cell carcinoma PRIOR CONCURRENT THERAPY: Biologic therapy * No concurrent drugs that regulate the immune system Chemotherapy * No concurrent chemotherapy Endocrine therapy * Not specified Radiotherapy * No concurrent radiotherapy Surgery * See Disease Characteristics Other * Prior enrollment in another adenoma prevention study allowed * Concurrent routine aspirin (≤ 81 mg/day) allowed * No regular use of non-steroidal anti-inflammatory drugs (NSAIDs) * No concurrent enrollment in another research study using pharmacological cancer drugs, a cyclo-oxygenase-2 inhibitor, or selenium * No other concurrent selenium unless dosage is ≤ 50 µg/day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Recurrent Adenomas at Surveillance Colonoscopy | 3 to 5 years after baseline colonoscopy | Detection of metachronous colorectal adenomas during follow-up, by treatment, in the original cohort. Surveillance colonoscopy is recommended 3 to 5 years after removal of colorectal adenoma(s). Participants will remain on the study intervention until their surveillance colonoscopy. Surveillance colonoscopy is determined by participants' GI physician. |
| Median Selenium Blood Levels at One Year. | One year | Adequate adherence to long-term selenium treatment as measured by blood selenium levels (ng/mL) at one year. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through clinical centers in Arizona, Colorado, Texas, and New York following ambulatory colonoscopies. Eligible participants were between age 40 and 80 years and had undergone colonoscopic removal of one or more colorectal adenomas 3 mm or larger within six months prior to random assignment.
Participants by arm
| Arm | Count |
|---|---|
| Selenium Participants receive oral selenium 200 mcg once daily.
Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled. | 685 |
| Placebo Participants receive oral placebo once daily.
Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled. | 689 |
| Total | 1,374 |
Baseline characteristics
| Characteristic | Selenium | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 8.9 | 63.4 years STANDARD_DEVIATION 8.8 | 63.1 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 64 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 660 Participants | 1310 Participants | 650 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 33 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 20 Participants | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 652 Participants | 1302 Participants | 650 Participants |
| Region of Enrollment United States | 685 participants | 1374 participants | 689 participants |
| Sex: Female, Male Female | 242 Participants | 476 Participants | 234 Participants |
| Sex: Female, Male Male | 443 Participants | 898 Participants | 455 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 685 | 10 / 689 |
| other Total, other adverse events | 0 / 685 | 0 / 689 |
| serious Total, serious adverse events | 228 / 685 | 226 / 689 |
Outcome results
Primary
Median Selenium Blood Levels at One Year.
Adequate adherence to long-term selenium treatment as measured by blood selenium levels (ng/mL) at one year.
Time frame: One year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selenium | Median Selenium Blood Levels at One Year. | 205.4 ng/mL |
| Placebo | Median Selenium Blood Levels at One Year. | 140.0 ng/mL |
p-value: 0.6895% CI: [0.91, 1.16]Negative binomial regression
Primary
Number of Recurrent Adenomas at Surveillance Colonoscopy
Detection of metachronous colorectal adenomas during follow-up, by treatment, in the original cohort. Surveillance colonoscopy is recommended 3 to 5 years after removal of colorectal adenoma(s). Participants will remain on the study intervention until their surveillance colonoscopy. Surveillance colonoscopy is determined by participants' GI physician.
Time frame: 3 to 5 years after baseline colonoscopy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selenium | Number of Recurrent Adenomas at Surveillance Colonoscopy | 302 Adenomas |
| Placebo | Number of Recurrent Adenomas at Surveillance Colonoscopy | 295 Adenomas |