RATIONALE: Drugs used in chemotherapy 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 which chemotherapy regimen is more effective for colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of irinotecan with that of combination chemotherapy in treating patients who have advanced colorectal cancer that has not responded to previous treatment.

OBJECTIVES:

• Compare the overall survival of patients with locally advanced, locally recurrent, or metastatic colorectal cancer treated with oxaliplatin, fluorouracil, and leucovorin calcium versus irinotecan, after initial therapy with fluorouracil.
• Determine the time to progression, time to treatment failure, and overall response rate in patients treated with these 2 regimens.
• Determine the toxic effects of these 2 regimens in these patients.
• Compare the quality of life of patients treated with these 2 regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to performance status (ECOG 0-1 vs 2), primary indicator lesion (hepatic vs pulmonary vs other), age (less than 65 vs at least 65 years), alkaline phosphatase (less than 2 vs at least 2 times ULN), fluorouracil failure (adjuvant vs metastatic), and membership (intergroup vs expanded participation project).

Patients are randomized to one of two treatment arms:

• Arm I: Patients receive irinotecan IV over 90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on days 1 and 2, and fluorouracil IV bolus followed by IV infusion over 22 hours on days 1 and 2. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Patients who experience progression or toxicity on the initial regimen may crossover to the other regimen. At least 3 weeks must elapse between regimens.

Quality of life is assessed at baseline, prior to each chemotherapy course, at crossover, and at the end of the study.

Patients are followed every 6 months for 3 years or until death.

PROJECTED ACCRUAL: A total of 560 patients will be accrued for this study within 2 years.

• Drug: FOLFOX regimen
• Drug: fluorouracil
• Drug: irinotecan hydrochloride
• Drug: leucovorin calcium
• Drug: oxaliplatin

• Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20.
• Goldberg R. Oxaliplatin in colorectal cancer: current studies. Oncology (Huntingt). 2000 Dec;14(12 Suppl 11):42-7. Review.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or radiotherapy

• Progressive disease following:

  • One prior fluorouracil based chemotherapy regimen for metastatic disease OR
  • Failure during or within 6 months after fluorouracil based adjuvant therapy
• Measurable or evaluable disease
• No CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 12 weeks

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL (transfusion allowed)

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST no greater than 5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 5 times ULN

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No uncontrolled high blood pressure
• No unstable angina
• No symptomatic congestive heart failure
• No myocardial infarction with the past 6 months
• No serious uncontrolled cardiac arrhythmias
• No New York Heart Association class III or IV heart disease

Pulmonary:

• No pleural effusion or ascites that cause respiratory compromise (e.g., dyspnea grade 2 or greater)
• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• Fluent in English
• No active or uncontrolled infection
• No other prior malignancy within the past 5 years, except:
• Adequately treated basal or squamous cell skin cancer
• Adequately treated noninvasive carcinomas
• No sensory neuropathy grade 2 or greater
• No uncontrolled colonic or small bowel disorders (greater than 3 loose stools daily)

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent sargramostim (GM-CSF)

Chemotherapy:

• At least 4 weeks since prior chemotherapy and recovered
• No more than 1 prior chemotherapy regimen for advanced colorectal cancer
• No prior irinotecan or other camptothecin derivative (e.g., topotecan)
• No prior oxaliplatin
• No other concurrent investigational chemotherapy agents

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior major radiotherapy
• No prior radiotherapy to greater than 25% of bone marrow

Surgery:

• At least 4 weeks since prior major surgery and recovered
• At least 2 weeks since prior minor surgery and recovered

• National Cancer Institute (NCI)
• Southwest Oncology Group
• Eastern Cooperative Oncology Group