Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

OBJECTIVES:

- Compare the time to progression in patients with locally advanced, locally recurrent,
or metastatic colorectal adenocarcinoma treated with combinations of oxaliplatin,
fluorouracil, leucovorin calcium, and irinotecan.

- Compare the quality of life, response rate, time to treatment failure, and overall
survival in patients treated with these regimens.

- Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG
performance status (0-1 vs 2), prior adjuvant chemotherapy (yes vs no), prior immunotherapy
(yes vs no), and age (under 65 vs 65 and over). Patients are randomized to one of three
treatment arms.

Only arm II remains open to accrual.

- Arm I (Saltz regimen): Patients receive irinotecan IV over 90 minutes followed by
leucovorin calcium IV over 15 minutes and fluorouracil IV once a week for 4 weeks
followed by 2 weeks of rest. Courses repeat every 6 weeks. (Arm I closed to accrual as
of March 15, 2002.)

- Arm II (FOLFOX4 regimen): Patients receive oxaliplatin IV over 2 hours on day 1 and
leucovorin calcium IV over 2 hours plus fluorouracil IV over 22 hours on days 1 and 2.
Courses repeat every 2 weeks.

- Arm III (oxaliplatin plus irinotecan): Patients receive oxaliplatin IV over 2 hours and
irinotecan IV over 30 minutes on day 1. Courses repeat every 3 weeks. (Arm III closed
to accrual as of March 15, 2002.) Treatment continues in the absence of disease
progression or unacceptable toxicity.

Quality of life is assessed before treatment, during treatment (arm specific), and after
completion of treatment.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then
annually thereafter.

PROJECTED ACCRUAL: A total of 825 patients (275 per arm) have been accrued for this study
thus far. Additional patients are being accrued on arm II. (Arms I and III closed to accrual
as of March 15, 2002.)

DISEASE CHARACTERISTICS:

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

- Histological or cytological requirement waived in patients who developed
radiological or clinical evidence of metastatic cancer after a prior surgical
resection unless:

- More than 5 years has elapsed since primary surgery OR

- Primary cancer was stage I or II

- Site of primary lesion must be or have been confirmed endoscopically, radiologically,
or surgically to be or have been in the large bowel

- 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 granulocyte count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 9.0 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 hypertension

- No unstable angina

- No symptomatic congestive heart failure

- No myocardial infarction within the past 6 months

- No serious uncontrolled arrhythmia

- No New York Heart Association class III or IV cardiac disease

Pulmonary:

- No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

- No pleural effusion or ascites that cause respiratory compromise (grade 2 or worse
dyspnea)

Other:

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No active or uncontrolled infection

- No symptomatic sensory peripheral neuropathy

- No known allergy to platinum compounds

- No history of gastrointestinal bleeding unless it is determined to be acceptable by
the enrolling physician

- No other prior or concurrent malignancy within the past 3 years except nonmelanoma
skin cancer, carcinoma in situ of the uterine cervix, or other resected malignant
tumor with less than a 10% probability of tumor relapse within 3 years of diagnosis

- No medical or psychiatric conditions that would preclude study

- No colonic or small bowel disorders with uncontrolled symptoms of more than 3 loose
stools per day

- Colostomy or ileostomy allowed at investigator's discretion

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Prior adjuvant immunotherapy for resected stage II-IV disease allowed if adjuvant
therapy concluded at least 1 year before documentation of recurrent disease

- No concurrent sargramostim (GM-CSF)

Chemotherapy:

- No prior chemotherapy for advanced colorectal cancer

- No prior standard adjuvant chemotherapy for rectal cancer

- Prior adjuvant fluorouracil for resected stage II-IV disease allowed if adjuvant
therapy concluded at least 1 year before documentation of recurrent disease

Radiotherapy:

- See Disease Characteristics

- At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative
radiotherapy)

- No prior radiotherapy to more than 15% of bone marrow

- No prior standard adjuvant radiotherapy for rectal cancer

Surgery:

- See Disease Characteristics

- At least 4 weeks since prior major surgery (e.g., laparotomy) (2 weeks for minor
surgery) and recovered

- Insertion of a vascular access device not considered major or minor surgery

Other:

- No other concurrent investigational agents