Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

Study Overview
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Brief Summary
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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 regimen of combination chemotherapy is most effective in treating advanced colorectal cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients who have advanced, recurrent, or metastatic colorectal cancer that cannot be treated with surgery or radiation therapy.

Detailed Description
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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.)

Official Title
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A Randomized Phase III Trial of Three Different Regimens of CPT-11 Plus 5-Fluorouracil and Leucovorin Compared to 5-Fluorouracil and Leucovorin in Patients With Advanced Adenocarcinoma of the Colon and Rectum

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: irinotecan
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: irinotecan + leucovorin + fluorouracil<br>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. 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. | Drug: irinotecan<br> <br> Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> |
| Experimental: oxaliplatin + leucovorin + fluorouracil<br>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. 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. | Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> Drug: oxaliplatin<br> <br> |
| Experimental: oxaliplatin + irinotecan<br>Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 30 minutes on day 1. Courses repeat every 3 weeks. 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. | Drug: irinotecan<br> <br> Drug: oxaliplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to progression |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | Up to 5 years | 
| time to treatment failure |  | Up to 5 years | 
| response rate |  | Up to 5 years | 
| quality of life |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III colon cancer, stage IV colon cancer, stage III rectal cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum