Combination Chemotherapy After Surgery in Treating Patients With High-Risk Stage II or Stage III Colorectal Cancer

OBJECTIVES:

• To assess the efficacy and compare the associated toxicity of adjuvant chemotherapy lasting 12 weeks vs 24 weeks in patients with fully resected high-risk stage II or III colorectal cancer.
• To conduct an economic analysis of the cost effectiveness of these regimens.
• To compare the randomization methodologies used in this study.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center's recruitment potential. Patients are randomized (within 10 weeks after surgery and before or after receiving 12 weeks of chemotherapy) to 1 of 2 treatment arms. The treatment regimen that a patient receives (Oxaliplatin Modified DeGramont [OxMdG] or XELOX) is determined by the participating center.

• Arm I: Patients receive 12 courses of OxMdG (described below) or XELOX (described below)combination chemotherapy (6 additional courses if patient already received 6 courses) for treatment lasting a total of 24 weeks.
• Arm II: Patients receive 6 courses of OxMdG or XELOX combination chemotherapy (no additional courses if patient already received 6 courses) for treatment lasting a total of 12 weeks.

The two adjuvant combination chemotherapy regimens are administered as follows:

• OxMdG: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• XELOX: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality-of-life assessments periodically using the EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and GOG Ntx4 questionnaires.

After completion of study treatment, patients are followed periodically for up to 7 years.

Peer Reviewed and Funded by Medical Research Council (MRC)

DISEASE CHARACTERISTICS:

• Diagnosis of colorectal cancer meeting 1 of the following criteria:

• High-risk stage IIB disease, defined as T4 disease, perforation, obstruction, < 10 nodes examined, poorly differentiated histology, extramural venous invasion, or extramural lymphatic invasion
• Fully resected stage III disease
• Patients with rectal cancer must meet the following criteria:

• Underwent prior total mesorectal excision surgery with negative resection (R0) margins
• No prior pre-operative or scheduled post-operative combined chemotherapy and radiotherapy
• No evidence of residual or metastatic disease
• Deemed suitable for adjuvant chemotherapy

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Life expectancy > 5 years with reference to noncancer-related diseases
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• AST and ALT ≤ 2.5 times upper limit of normal
• Carcinoembryonic antigen (CEA) levels normal
• Glomerular filtration rate ≥ 30 mL/min (no moderate or severe renal impairment)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must effective contraception
• More than 12 months since prior and no active clinically significant cardiovascular disease, including any of the following:

• Cerebrovascular accident
• Myocardial infarction
• Unstable angina
• New York Heart Association class II-IV congestive heart failure
• Serious cardiac arrhythmia requiring medication
• Uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg)
• Disease-free interval of ≥ 5 years for previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal cell or squamous cell carcinoma of the skin
• No known or suspected dihydropyrimidine dehydrogenase deficiency

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No more than 10 weeks since prior surgery and recovered
• No prior chemotherapy (except in patients randomized after 12 weeks of adjuvant therapy)
• No prior abdomino-pelvic radiotherapy, with the exception of short-course pre-operative radiotherapy for rectal cancer
• No concurrent brivudine or sorivudine for patients taking capecitabine