OBJECTIVES:

• Determine the percentage change in colorectal aberrant crypt foci (ACF) in patients with a history of colorectal cancer or at high risk for colorectal cancer when treated with sulindac vs aspirin vs ursodiol.
• Determine the safety and efficacy of these drugs, in terms of ability to cause regression of existing colorectal ACF and prevent new ACF development, in these patients.

OUTLINE: This is a partially blinded, randomized, placebo-controlled study. Patients are stratified according to colorectal neoplasia (adenoma vs carcinoma). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive oral sulindac twice daily.
• Arm II: Patients receive oral aspirin once daily.
• Arm III: Patients receive oral ursodiol three times daily.
• Arm IV: Patients receive oral sulindac placebo twice daily. In all arms, treatment continues for 12 months in the absence of disease progression or unacceptable toxicity.

Patients undergo a colonoscopy at baseline and at the end of treatment.

Patients are followed at 2 months after the end of treatment.

PROJECTED ACCRUAL: A total of 172 patients (43 per treatment arm) with a history of colorectal cancer or adenomas will be accrued for this study. A total of 20 additional patients with no elevated risk of colorectal neoplasia will be accrued, but not randomized, for this study.

DISEASE CHARACTERISTICS:

• Presence of at least 5 colorectal aberrant crypt foci

• Meets 1 of the following criteria:

  • Recent or current history of colorectal cancer* defined by 1 of the following:

    • Dukes' A/B1 carcinoma within the past 5 years
    • Any stage of colorectal cancer if at least 5 years after surgical resection NOTE: *No rectal cancer except for transanal excision without radiotherapy

  • Recent or current history of colorectal adenoma(s) defined by 1 of the following:

    • One adenomatous polyp at least 1 cm
    • Two or more adenomatous polyps of any size
    • One adenomatous polyp of any size and a documented history of prior adenomatous polyps
  • No elevated risk of colorectal cancer or adenoma
• No known familial adenomatous polyposis
• No hereditary nonpolyposis colon cancer
• No inflammatory bowel disease

PATIENT CHARACTERISTICS:

Age

• 40 to 80

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• WBC greater than 3,000/mm^3
• Platelet count greater than 100,000/mm^3
• Hemoglobin greater than 10.0 g/dL
• No bleeding diathesis

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• AST and ALT less than 2 times upper limit of normal
• No unexplained elevation of transaminases
• No acute liver disease

Renal

• No history of renal stones

Pulmonary

• No asthma

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to participate in scheduled follow-up tests
• No history of gastroduodenal ulcers by endoscopy
• No history of hypersensitivity to cyclo-oxygenase-2 inhibitors, sulfonamides, NSAIDs, salicylates, or ursodiol
• No hypersensitivity to sulindac products
• No significant medical or psychiatric problem that would preclude study participation
• No other invasive carcinoma within the past 5 years except Dukes' A/B1 carcinoma or any stage of colorectal cancer that is at least 5 years post-surgical resection

• No "unacceptable clinical risk" to proceed including:

  • New diagnosis of carcinoma
  • Suspicion of need for colectomy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• More than 6 months since prior chemotherapy

  • Topical chemotherapy may be allowed on a case-by-case basis

Endocrine therapy

• At least 30 days since prior nasal steroids
• No concurrent nasal steroids (mometasone allowed)
• No concurrent oral corticosteroids

Radiotherapy

• No prior radiotherapy to the pelvis or rectum

Surgery

• See Disease Characteristics
• No prior colectomy

Other

• More than 3 months since prior investigational agents
• At least 3 months since prior nonsteroidal anti-inflammatory drugs (NSAIDs) (including aspirin)
• Concurrent acetaminophen allowed
• No concurrent aspirin (including as a cardioprotectant)
• No concurrent NSAIDs (e.g., ibuprofen or naproxen)