Combination Chemotherapy for 3 Months or 6 Months in Treating Patients With Stage III Colon Cancer

A Phase III Randomized Trial Investigating the Duration of Adjuvant Therapy(3 Versus 6 Months) With the Modified FOLFOX 6 or XELOX Regimens for Patients With Stage III Colon Cancer

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. It is not yet known whether giving more than one drug (combination chemotherapy) is more effective when given for 3 months or 6 months in treating patients with colon cancer.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy for 3 months to see how well it works compared with giving combination chemotherapy for 6 months in treating patients with stage III colon cancer.

OBJECTIVES:

Primary Objective

• To assess whether a 3-month modified FOLFOX 6 or XELOX treatment is not inferior to a 6-month modified FOLFOX 6 or XELOX treatment in terms of disease free survival (DFS) in patients with radically resected stage III colon cancer.

Secondary Objectives

• To assess whether 3-month modified FOLFOX 6 (6 cycles) or XELOX (4 cycles) treatment is not inferior to 6-month modified FOLFOX 6 (12 cycles) or XELOX (8 cycles) treatment in terms of overall survival (OS) in patients with radically resected stage III colon cancer
• To evaluate the safety profiles of the treatment groups

Tertiary Objectives

• For patients who signed a specific informed consent, blood and tumour tissue samples will be stored, registered, and centralized in a data bank for translational research projects that will be further determined according to the literature and scientific knowledge at the time of the end of inclusion. (exploratory)
• An economic evaluation at the country level will be conducted alongside the clinical evaluation. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to center, T stage (1 or 2 vs 3 vs 4), N stage (1 vs 2), performance status (0 vs 1 vs 2), and age (< 70 years vs ≥ 70 years). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive modified FOLFOX 6 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1. Treatment repeats every 14 days for 6 courses (3 months).
• Arm II: Patients receive modified FOLFOX 6 as in arm I. Treatment repeats every 14 days for 12 courses (6 months).

Blood and tumor samples may be collected at baseline for pharmacogenetic and other analyses.

After completion of study treatment, patients are followed up every 6 months for 8 years.

Inclusion criteria:

• Patients who have undergone surgery for colon cancer, defined as a tumor location >12 cm from the anal verge by endoscopy and/or above the peritoneal reflection at surgery (high rectum), without gross or microscopic evidence of residual disease after surgery with curative intent.
• Histologically confirmed AJCC/UICC stage III adenocarcinoma colon cancer.
• Age >18 years.
• Curative surgery and no more than 8 weeks prior to randomization.
• ECOG performance Status (ECOG-PS) <2.
• Signed written informed consent obtained prior to any study specific procedures.
• CEA ≤ 10 ng/ml (2 X normal value).
• Post-menopausal women or women willing to accept the use of an effective contraceptive regimen during the treatment period and up to 1 month after the end of the study treatment. All non postmenopausal women should have a negative pregnancy test within 72 hours prior to randomization. Men should accept to use an effective contraception during the treatment period, and up to 1 month after the end of the study treatment.
• Registration in a national health care system (CMU included).

Exclusion criteria:

Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in ascites or peritoneal carcinomatosis resected "en bloc").

• Cancer of low or medium rectum with tumor location < 12 cm from the anal verge by endoscopy.
• Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
• Pregnant or lactating women
• Clinically relevant cardiovascular disease (for example: ischemic myocardial infarction in the last year and/or unstable ischemic cardiopathy).
• History or current evidence on physical examination of central nervous system disease or peripheral neuropathy ≥ grade 1 Common Toxicity Criteria for Adverse Events (CTCAE) v.3.0.
• Known hypersensitivity reaction to any of the components of study treatments.
• Current or recent (within 28 days prior to randomization) treatment with another investigational drug.
• Subject unwilling or unable to comply with study requirements.