Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery
A Phase III Trial of 6 Versus 12 Treatments of Adjuvant FOLFOX Plus Celecoxib or Placebo for Patients With Resected Stage III Colon Cancer
PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin calcium,
and fluorouracil together to compare how well they work when given together with or without
celecoxib in treating patients with stage III colon cancer previously treated with surgery.
RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and
fluorouracil, work in different ways to stop the growth of tumor cells, either by killing
the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. It is not yet known whether giving
oxaliplatin, leucovorin calcium, and fluorouracil is more effective with or without
celecoxib in treating colon cancer.
OUTLINE: This is a multicenter study. Patients are stratified according to number of
positive lymph nodes* (1-3 vs 4 or more) and concurrent regular low-dose of aspirin (yes vs
no). Patients are randomized to 1 of 4 treatment arms. Please see the "Arms" section for
more information. In all arms, treatment with celecoxib or placebo continues for 3 years in
the absence of disease progression or unacceptable toxicity. Blood and tissue samples maybe
collected for biomarker analysis and pharmacogenomic studies. The primary and secondary
objectives for the research study are described below.
1. To compare disease-free survival of patients with stage III colon cancer randomized to
standard chemotherapy only FOLFOX or standard chemotherapy FOLFOX with 3 years of celecoxib
400 mg daily.
1. To contribute to an international prospective pooled analysis that will compare
disease-free survival of patients with stage III colon cancer randomized to 6
treatments of adjuvant FOLFOX chemotherapy or 12 treatments of adjuvant FOLFOX
2. To compare overall survival of patients with stage III colon cancer randomized to
standard chemotherapy only (FOLFOX) or standard chemotherapy (FOLFOX) with 3 years of
celecoxib 400 mg daily.
3. To contribute to an international prospective pooled analysis that will compare overall
survival of patients with stage III colon cancer randomized to 6 treatments of adjuvant
FOLFOX chemotherapy or 12 treatments of adjuvant FOLFOX chemotherapy or 12 treatments
of adjuvant FOLFOX chemotherapy.
4. To assess toxicities of celecoxib as maintenance adjuvant therapy in patients with
stage III colon cancer.
5. To assess differences in cardiovascular-specific events with celecoxib versus placebo
in a population of stage III colon cancer survivors.
6. To evaluate differences in toxicities, particularly cumulative peripheral neuropathy,
for patients treated with 6 treatments of FOLFOX compared to those treated with 12
treatments of FOLFOX.
After completion of study therapy, patients are followed up every 6 months for up to 6
1. Requirements for tumor parameters
1. Histologically documented adenocarcinoma of the colon. The gross inferior
(caudad) margin of the primary tumor must lie above the peritoneal reflection
(i.e., patients with rectal cancer are not eligible). Surgeon confirmation that
the entire tumor was above the peritoneal reflection is only required in cases
where it is important to establish if the tumor is a rectal or colon primary.
2. Tumors must have been completely resected. In patients with tumor adherent to
adjacent structures, en bloc R0 resection must be documented in the operative
report or otherwise confirmed by the surgeon. Near or positive radial margin are
not exclusions as long as en bloc resection was performed. Positive proximal
margin or distal margin is an exclusion.
3. Node positive disease (N1 or N2) as designated in AJCC version 7. Either at
least one pathologically confirmed positive lymph node or N1C (defined as tumor
deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or
perirectal tissues without regional lymph node metastases). Patients with
resected stage IV disease are not eligible.
4. No evidence of residual involved lymph node disease or metastatic disease at the
time of registration.
5. Patients with synchronous colon cancers are eligible and staging for
stratification will be based on higher N stage of the more advanced primary
tumor. However, patients with synchronous colon and rectal primary tumors are
2. NSAID use
Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2
times per week (on average) or aspirin at more than 325 mg at least three times per
week, on average. Low-dose aspirin not exceeding 100 mg/day is permitted. Patients
who agree to stop regular NSAIDs or higher dose aspirin are eligible and no was out
period is required.
3. Patient history
1. No previous or concurrent malignancy, except treated basal cell or squamous cell
cancer of skin, treated in situ cervical cancer, treated lobular or ductal
carcinoma in situ in one breast, or any other cancer for which the patient has
been disease-free for at least 5 years.
2. No neurosensory or neuromotor toxicity ≥ grade 2 at the time of registration.
3. No known allergy to platinum compounds.
4. No prior allergic reaction or hypersensitivity to sulfonamides, celecoxib or
5. No history of upper gastrointestinal ulceration, upper gastrointestinal
bleeding, or upper gastrointestinal perforation within the past 3 years.
Patients with ulceration, bleeding or perforation in the lower bowel are not
6. No symptomatic pulmonary fibrosis or interstitial pneumonitis ≥ grade 2.
7. No cardiac risk factors including:
- Uncontrolled high blood pressure (systolic blood pressure > 150).
- Unstable angina.
- History of documented myocardial infarction or cerebrovascular accident.
- New York Heart Association class III or IV heart failure.
4. Pregancy/nursing status
Non-pregnant and not nursing. Men and women of childbearing potential must agree to
employ adequate contraception for the duration of chemotherapy and for as many as 8
weeks after the completion of chemotherapy due to the unknown teratogenic effects of
FOLFOX on the developing fetus.
5. Age and performance status
1. ECOG performance status 0, 1 or 2.
2. Age at least 18 years.
6. Required initial laboratory values
1. Granulocytes ≥ 1,500/μL
2. Platelet count ≥ 100,000/μL
3. Creatinine ≤ 1.5 times upper limit of normal (ULN)
4. Total Bilirubin ≤ 1.5 times ULN in the absence of Gilbert's disease
5. Direct bilirubin ≤ 1.5 x upper limit of normal for patients with Gilbert's