RATIONALE: Drugs used in chemotherapy, such as leucovorin, fluorouracil, capecitabine, and oxaliplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether leucovorin and fluorouracil with or without oxaliplatin is more effective than capecitabine with or without oxaliplatin in treating patients who have metastatic colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of leucovorin and fluorouracil with or without oxaliplatin with that of capecitabine with or without oxaliplatin in treating patients who have metastatic colorectal cancer.

Condition	Treatment or Intervention	Phase
Colon Cancer Quality of Life Rectal Cancer	Drug: capecitabine  Drug: fluorouracil  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: chemotherapy  Procedure: quality-of-life assessment  Procedure: supportive care/therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare the progression-free survival of patients with metastatic colorectal adenocarcinoma treated with leucovorin calcium and fluorouracil with vs without oxaliplatin or capecitabine with vs without oxaliplatin.
• Compare the quality of life of patients treated with these fluorouracil-based vs capecitabine-based regimens.

Secondary

• Compare the failure-free and overall survival of patients treated with these regimens.
• Compare the toxic effects and adverse events associated with these regimens in these patients.
• Compare the limited health assessments of patients treated with these regimens.
• Compare the health economics associated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 4 treatment arms and receive 12 weeks of therapy.

• Patients receive leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm II.
• Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study.
• Patients receive oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm IV.
• Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study.

All patients are then re-evaluated at least every 6 weeks and begin another 12 weeks of therapy at any evidence (e.g., clinical, radiological, or tumor marker) of disease progression. Patients with chemo-sensitive disease may repeat alternating 12-week therapy sessions and evaluation periods indefinitely.

Quality of life is assessed at baseline, at 12-14 weeks, at 24 weeks, and then every 3 months thereafter.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 460 patients (115 per treatment arm) will be accrued for this study within 2 years.

Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:
• Prior or current histologically confirmed primary adenocarcinoma of the colon or rectum with clinical/radiological evidence of advanced/metastatic disease
• Histologically or cytologically confirmed metastatic adenocarcinoma with clinical/radiological evidence of colorectal primary tumor
• Unidimensionally measurable disease
• Unfit and unsuitable for full-dose combination chemotherapy, which would include 1 of the following circumstances:
• Unsuitable or unwilling to be entered into any full-dose chemotherapy protocol
• Ineligible or unsuitable for first-line standard combination as per National Institute of Clinical Excellence guidance

PATIENT CHARACTERISTICS: Age

• Not specified

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC greater than 3,000/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic

• Bilirubin no greater than 3 times upper limit of normal (ULN)
• AST or ALT no greater than 2.5 times ULN

Renal

• Creatinine clearance greater than 50 mL/min OR
• Glomerular filtration rate greater than 30 mL/min

Cardiovascular

• No uncontrolled angina
• No recent myocardial infarction

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No partial or complete bowel obstruction
• No concurrent severe uncontrolled medical illness that would preclude study treatment
• No psychiatric or neurological condition that would preclude giving informed consent or complying with oral study medication
• No other prior or concurrent malignant disease that would preclude study treatment or assessment of response
• No prior neuropathy greater than grade 1

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• More than 4 months since prior adjuvant chemotherapy with fluorouracil with or without leucovorin calcium
• More than 1 month since prior rectal chemoradiotherapy with fluorouracil with or without leucovorin calcium
• No prior systemic palliative chemotherapy for metastatic disease

Endocrine therapy

• Not specified

Radiotherapy

• See Chemotherapy

Surgery

• Not specified

Other

• No concurrent brivudine or sorivudine

United Kingdom, England
      Cookridge Hospital at Leeds Teaching Hospital NHS Trust, Leeds,  England,  LS16 6QB,  United Kingdom; Recruiting
      Medical Research Council Clinical Trials Unit, London,  England,  NW1 2DA,  United Kingdom; Recruiting
      University of Leeds, Leeds,  England,  LS2 9JT,  United Kingdom; Recruiting
United Kingdom, Wales
      Velindre Cancer Center at Velinde Hospital, Cardiff,  Wales,  CF14 2TL,  United Kingdom; Recruiting

Study chairs or principal investigators

Matthew T. Seymour, MA, MD, FRCP,  Cancer Research UK Clinical Centre at St. James's University Hospital   
Gareth Griffiths,  Medical Research Council   

Study ID Numbers:  CDR0000330142; NCRI-FOCUS2; MRC-CR09; EU-20303; NCT00070213
Record last reviewed:  December 2003
Last Updated:  December 6, 2004
Record first received:  October 3, 2003
ClinicalTrials.gov Identifier:  NCT00070213
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08