Combination Chemotherapy in Treating Patients With Unresectable Liver Metastases From Colorectal Cancer

OBJECTIVES:

• Determine the maximum tolerated dose of oxaliplatin and fluorouracil when given with leucovorin calcium and hepatic intra-arterial floxuridine and dexamethasone with or without cryosurgery (group I cryosurgery closed to accrual as of 10/13/03) in patients with unresectable liver metastases from colorectal cancer.
• Determine, preliminarily, the anti-tumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of oxaliplatin and fluorouracil. Patients are assigned to one of two treatment groups. (Group I closed to accrual as of 10/13/03.)

• Group I (closed to accrual as of 10/13/03): Patients with no more than 8 hepatic metastases and no metastases greater than 5 cm in diameter undergo cryosurgery prior to chemotherapy. Chemotherapy is delayed for at least 4 weeks after cryosurgery.
• Group II: Patients with more than 8 hepatic metastases or at least one metastases greater than 5 cm in diameter do not undergo cryosurgery prior to chemotherapy.

Beginning 2 weeks after pump placement surgery, all patients receive floxuridine and dexamethasone by hepatic intra-arterial infusion continuously on days 1-14; oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on days 15 and 29; and fluorouracil IV continuously over 48 hours on days 15-16 and 29-30. Courses repeat every 36 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of oxaliplatin and fluorouracil until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 4-72 patients will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum with unresectable liver metastases that comprise less than 70% of liver parenchyma

• No extrahepatic disease
• No ascites

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 2.0 mg/dL
• No hepatic encephalopathy

Renal:

• Creatinine no greater than 1.5 mg/dL

Other:

• Not pregnant or nursing
• Negative pregnancy test
• No obstruction of gastrointestinal tract or genitourinary tract
• No symptomatic peripheral sensory neuropathy
• No active infection
• No other malignancy except resectable primary colorectal carcinoma

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior floxuridine
• If undergoing cryosurgery (group I cryosurgery closed to accrual as of 10/13/03), must have received one of the following:

• Systemic chemotherapy for metastatic disease
• Adjuvant therapy within the past 6 months comprising fluorouracil with or without levamisole for resected primary colorectal carcinoma
• Adjuvant therapy within the past 12 months comprising fluorouracil and leucovorin calcium with or without levamisole for resected primary colorectal carcinoma

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to liver

Surgery:

• Not specified