Chemotherapy With or Without Isolated Hepatic Perfusion With Melphalan in Treating Patients With Colorectal Cancer That Has Spread to the Liver

OBJECTIVES:

• Compare the disease-free and overall survival of patients with unresectable colorectal cancer metastatic to the liver treated with regional and systemic chemotherapy with or without isolated hepatic perfusion with melphalan.
• Compare the response rate and duration of response in patients treated with these regimens.
• Compare the patterns of recurrence (liver vs systemic) in patients treated with these regimens.
• Compare the health-related quality of life (QOL) of patients treated with these regimens.
• Determine whether baseline QOL correlates with length of survival of patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are stratified according to prior chemotherapy for liver metastasis (yes vs no) and percentage of hepatic replacement (less than 25% vs at least 25%). All patients undergo laparotomy to determine final eligibility. Eligible patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo hyperthermic isolated hepatic perfusion with melphalan over 60 minutes. Patients then undergo placement of an intrahepatic pump or port. At 6 weeks post hepatic perfusion, patients receive systemic chemotherapy comprising irinotecan IV over 90 minutes on day 1 followed by fluorouracil IV over 15 minutes and leucovorin calcium (CF) IV over 15 minutes on days 1-3. Patients receive local chemotherapy comprising floxuridine (FUDR) and CF by hepatic arterial infusion (HAI) continuously on days 14-28.
• Arm II: Patients undergo placement of an intrahepatic pump or port at laparotomy. At 7 days post laparotomy, patients receive FUDR and CF by HAI continuously for 14 days. Beginning 2 weeks after completion of HAI, patients receive systemic and local chemotherapy as in arm I.

Treatment with combined systemic and local chemotherapy repeats every 35 days for a maximum of 6 courses. Treatment with local chemotherapy alone repeats every 28 days for a maximum of 6 additional courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, postoperatively, every third course of chemotherapy, every 3 months for 2 years, and then every 6 months thereafter.

Patients are followed every 3 months for 2 years and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 168 patients (84 per treatment arm) will be accrued for this study within 54 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic colorectal cancer of the parenchyma of the liver

• No evidence of extrahepatic disease (limited resectable extrahepatic disease allowed)
• Unresectable liver metastasis, as defined by the following:

• More than 3 sites of disease
• Bilobar disease
• Tumor abutting major vascular or ductal structures
• Measurable disease
• No biopsy-proven cirrhosis or evidence of significant portal hypertension manifested by ascites, esophageal varices, or collateral vessels around organs drained by the portal venous system

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Platelet count greater than 100,000/mm^3
• Hematocrit greater than 27.0%
• WBC greater than 3,000/mm^3

Hepatic:

• Bilirubin less than 2.0 mg/dL
• PT no greater than 2 seconds over upper limit of normal
• Elevations in transaminases secondary to metastatic disease allowed
• No veno-occlusive disease
• No active chronic hepatitis

• Hepatitis B or C allowed provided there is no evidence of cirrhosis

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• No ischemic cardiac disease
• No prior congestive heart failure with LVEF less than 40%

Pulmonary:

• No chronic obstructive pulmonary disease or other chronic pulmonary disease with pulmonary function test less than 50% of predicted

Other:

• No active infections
• Not pregnant or nursing
• Negative pregnancy test
• Weight greater than 30 kg

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 4 weeks since prior biologic therapy for disease and recovered

Chemotherapy:

• At least 4 weeks since prior chemotherapy for disease and recovered
• No prior intrahepatic artery infusion therapy with floxuridine

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy for disease and recovered

Surgery:

• Not specified

Other:

• No concurrent immunosuppressive drugs
• No concurrent chronic anticoagulants