Celecoxib Combined With Fluorouracil and Leucovorin in Treating Patients With Resected Stage III Adenocarcinoma (Cancer) of the Colon

OBJECTIVES:

Primary

• Compare disease-free survival of patients with curatively resected stage III adenocarcinoma of the colon treated with adjuvant fluorouracil and leucovorin calcium with or without celecoxib.

Secondary

• Compare the overall survival, the occurrence of new primary colon cancer, and the development of new polyps in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to ≥ 4 tumor-positive lymph nodes (yes vs no), form of adjuvant chemotherapy (infusional vs bolus), low-dose aspirin for cardiovascular prophylaxis (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fluorouracil and leucovorin calcium IV for up to 6 courses in the absence of disease recurrence or unacceptable toxicity. Patients also receive oral celecoxib twice daily.
• Arm II: Patients receive oral placebo twice daily and fluorouracil and leucovorin calcium as in arm I.

In both arms, treatment with celecoxib or placebo continues for 3 years in the absence of disease recurrence or unacceptable toxicity.

Patients are followed annually for 2 years.

PROJECTED ACCRUAL: A total of 1,450 patients (725 per treatment arm) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon

• 15 cm above anal verge
• Stage III disease (any pT, N1-2, M0)
• No rectal cancer
• Must have undergone curative radical resection (R0 resection) within the past 6 weeks

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• AST ≤ 5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• None of the following conditions within the past 6 months:

• Myocardial infarction
• Unstable angina
• Symptomatic congestive heart failure
• Serious uncontrolled cardiac arrhythmia
• Cerebrovascular accident or transient ischemic attack
• Deep vein thrombosis
• Other significant thromboembolic event

Pulmonary

• No pulmonary embolism within the past 6 months

Gastrointestinal

• No active gastric or duodenal ulceration within the past year
• No gastrointestinal bleeding within the past year
• No partial or complete bowel obstruction
• No known chronic malabsorption
• No active inflammatory bowel disease or chronic diarrhea (more than 4 stools/day)

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• No AIDS-related illness
• No prior hypersensitivity to fluorouracil, leucovorin calcium, celecoxib, other COX-2 inhibitors, NSAIDs, salicylates, or sulfonamides
• No other severe acute or chronic medical condition or laboratory abnormality that would preclude study participation, study drug administration, or study results interpretation
• No psychological, familial, sociological, or geographical condition that would preclude study compliance
• No concurrent active infection
• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or basal cell or squamous cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent sargramostim (GM-CSF) or molgramostim

Chemotherapy

• Not specified

Endocrine therapy

• No more than 4 weeks of concurrent orally/nasally inhaled steroids over a 6-month period

• Concurrent mometasone (or fluticasone) allowed if patients require ≥ 4 weeks of inhaled steroid therapy
• At least 30 days since other prior steroids
• No concurrent hormonal therapy

Radiotherapy

• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• No prior total colectomy or other major surgery that would result in substantial alteration in transit to absorption of oral medication

Other

• More than 30 days since prior investigational medication
• No prior systemic anticancer treatment for colon cancer
• No concurrent prophylactic fluconazole
• No concurrent lithium
• No concurrent chronic* use of full dose aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase-2 (COX-2) inhibitors

• Aspirin at cardioprotective doses (i.e., 80 mg daily or equivalent) allowed
• No concurrent participation in any other clinical study
• No other concurrent experimental agents (e.g., other COX-2 inhibitors, matrix metalloproteinase inhibitors, inhibitors of the vascular endothelial growth factor/Flk-1 pathway, or inhibitors of the epidermal growth factor receptor pathway) NOTE: *Chronic use is defined as a frequency of 7 consecutive days (1 week) for more than 3 weeks/year or more than 21 days throughout the year