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 cancer cells. It is not yet known which chemotherapy regimen is more effective for metastatic colorectal cancer.

PURPOSE: Randomizedphase III trial to compare the effectiveness of intrahepaticfloxuridine, leucovorin, and dexamethasone with that of systemicfluorouracil and leucovorin in treating patients who have unresectableliver metastases from colorectal cancer.

Condition	Treatment or Intervention	Phase
Colon Cancer liver metastases Rectal Cancer	Drug: dexamethasone  Drug: floxuridine  Drug: fluorouracil  Drug: leucovorin calcium  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: drug modulation  Procedure: surgery	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the efficacy, toxicity, and cost of hepatic artery infusion of floxuridine, leucovorin calcium (CF), and dexamethasone vs IV fluorouracil and IV CF after resection of primary disease in patients with hepatic metastases secondary to colorectal cancer.
• Compare the quality of life of patients treated with these regimens.
• Measure the level of thymidylate synthase present in liver metastases, and correlate these levels with objective response and survival in patients treated with these regimens.
• Assess the p53 mutations, and correlate findings with objective response and survival in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center, percentage of liver involvement on CT scan or MRI (less than 30% vs 30% to under 70%), prior chemotherapy (none vs adjuvant chemotherapy comprising fluorouracil (5-FU) and leucovorin calcium (CF) or 5-FU, CF, and levamisole (LEV) completed at least 1 year before study vs adjuvant chemotherapy comprising 5-FU with or without LEV completed at least 6 months before study), and synchronous disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo laparotomy for placement of a hepatic artery catheter and then subcutaneous placement of a hepatic artery infusion pump. Patients with unresected primary disease also undergo resection at the time of catheter and pump placement. Beginning within 1-2 weeks after surgery, patients receive floxuridine, dexamethasone, and leucovorin calcium (CF) via continuous hepatic artery infusion on days 1-14.
• Arm II: Patients receive CF IV and fluorouracil IV on days 1-5. Patients with unresected primary disease undergo resection within 3-4 weeks before initiation of chemotherapy. Treatment for patients on both arms continues every 4 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life and medical resource utilization are assessed at baseline, every 3 months for 1 year, and then at 18 months.

Patients are followed every 3 months.

PROJECTED ACCRUAL: Approximately 340 patients (170 per arm) will be accrued for this study within approximately 4.5 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Unresectable liver metastases secondary to colorectal cancer
• Less than 70% liver involvement on CT scan or MRI
• Liver biopsy required before study unless 1 of the following conditions are met:
• Carcinoembryonic antigen greater than 30
• 5 or more liver metastases visible on CT scan or MRI
• Greater than 50% to under 70% liver involvement on CT scan or MRI
• Histologically proven primary colorectal cancer that is resected or appears resectable on CT scan and physical exam
• Documentation of previously resected primaries must be based on pathologic results of the resected tumor
• Histological documentation of synchronous disease must be based on 1 of the following:
• Biopsy of primary colorectal tumor before study
• Suspicious lesion on barium enema, colonoscopy, or sigmoidoscopy, and a liver biopsy positive for adenocarcinoma consistent with the primary colorectal tumor
• Measurable disease
• Clearly defined liver mass measuring at least 2 cm or at least 3 liver masses on CT scan or MRI
• No evidence of extrahepatic disease on CT scan and physical exam
• No portal vein occlusion or ascites

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• See Disease Characteristics
• Bilirubin no greater than 2 times normal

Renal:

• Not specified

Other:

• No other malignancy within the past 5 years except inactive nonmelanomatous skin cancer, carcinoma in situ of the cervix, or grade 1 bladder cancer
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

• Not specified

Chemotherapy:

• At least 1 year since prior adjuvant chemotherapy comprising fluorouracil (5-FU) and leucovorin calcium (CF) or 5-FU, CF, and levamisole (LEV)
• At least 6 months since prior adjuvant chemotherapy comprising 5-FU with or without LEV
• No other prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy:

• No concurrent hormonal therapy except for nondisease-related conditions, e.g.:
• Steroids for adrenal failure
• Insulin for diabetes
• Intermittent dexamethasone as an antiemetic

Radiotherapy:

• No prior radiotherapy to the liver

Surgery:

• See Disease Characteristics

Iowa
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States
      CCOP - Iowa Oncology Research Association, Des Moines,  Iowa,  50309-1016,  United States
      Iowa Lutheran Hospital, Des Moines,  Iowa,  50316-2301,  United States
      John Stoddard Cancer Center at Iowa Methodist Medical Center, Des Moines,  Iowa,  50309,  United States
      Mercy Cancer Center at Mercy Medical Center-Des Moines, Des Moines,  Iowa,  50314,  United States
Nebraska
      Midlands Cancer Center at Midlands Community Hospital, Papillion,  Nebraska,  68128-4157,  United States
New Mexico
      MBCCOP - University of New Mexico HSC, Albuquerque,  New Mexico,  87131,  United States
Ohio
      MetroHealth Medical Center, Cleveland,  Ohio,  44109,  United States
Pennsylvania
      Fox Chase Cancer Center, Philadelphia,  Pennsylvania,  19111-2497,  United States
      Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey,  Pennsylvania,  17033-0850,  United States
Wisconsin
      CCOP - St. Vincent Hospital Cancer Center, Green Bay, Green Bay,  Wisconsin,  54307-3453,  United States
Australia, New South Wales
      Westmead Hospital, Westmead,  New South Wales,  2145,  Australia
Peru
      Instituto de Enfermedades Neoplasicas, Lima,  34,  Peru
Puerto Rico
      San Juan City Hospital, San Juan,  00936-7344,  Puerto Rico

Study chairs or principal investigators

Nancy E. Kemeny, MD,  Study Chair,  Memorial Sloan-Kettering Cancer Center   
Elin Ruth Sigurdson, MD,  Study Chair,  Fox Chase Cancer Center   

Study ID Numbers:  CDR0000064553; CALGB-9481; ECOG-C9481
Record last reviewed:  May 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002716
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08