Capecitabine and Oxaliplatin or Standard Follow-Up Care in Treating Patients Who Have Undergone Surgery for Locally Advanced Rectal Cancer

OBJECTIVES:

• Compare the efficacy of adjuvant chemotherapy comprising capecitabine and oxaliplatin vs standard follow-up care, in terms of disease-free and overall survival, in patients with clear margins after complete resection of locally advanced rectal cancer.

OUTLINE: This is an open-label, randomized, controlled, prospective, multicenter study. Patients are stratified according to surgeon and nodal status (node positive vs node negative vs unknown). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo standard follow up.
• Arm II: Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum

• Within 15 cm of the anal verge
• Locally advanced disease
• Underwent complete resection of primary tumor within the past 12 weeks

• ypT0-4, N0-2 with definitive histology at surgery
• Circumferential resection margin > 1 mm
• No gross evidence of residual disease
• Received neoadjuvant fluoropyrimidine-based chemoradiotherapy with ≥ 45 Gy planned total radiation dose, given in 1 of the following fashions:

• Prolonged fluorouracil IV during radiotherapy
• Low-dose leucovorin calcium and fluorouracil (days 1-5 and 29-33) concurrently with radiotherapy
• Oral capecitabine concurrently with radiotherapy
• No evidence of metastatic disease

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine clearance ≥ 50 mL/min
• Bilirubin ≤ 1.25 times upper limit of normal (ULN)
• AST and ALT ≤ 1.25 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
• No known dihydropyrimidine dehydrogenase deficiency
• No hypersensitivity to platinum compounds
• No preexisting peripheral neuropathy ≥ grade 1
• No lack of physical integrity of the upper gastrointestinal tract
• No malabsorption syndrome
• No other serious uncontrolled medical condition or concurrent medical illness that would compromise life expectancy and/or preclude study compliance, including any of the following:

• Serious uncontrolled infections
• Significant cardiac disease (e.g., uncontrolled angina, congestive heart failure, cardiomyopathy, or arrhythmias) or myocardial infarction within the past 12 months
• Interstitial pneumonia or symptomatic lung fibrosis
• No other malignancies except adequately treated in situ carcinoma of the cervix or basal cell or squamous cell carcinoma of the skin, unless disease-free for ≥ 10 years
• No history of uncontrolled seizures, CNS disorders, or psychiatric disability that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy exceeding 6 weeks in duration

• Prior chemotherapy given as part of neoadjuvant treatment (i.e., chemoradiotherapy) may last a maximum of 11-12 weeks
• No prior oxaliplatin
• Prior mitomycin C, irinotecan hydrochloride, or cetuximab allowed
• No concurrent warfarin, antiviral agents, or phenytoin