Selenium for Prevention of Adenomatous Colorectal Polyps

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.

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