OBJECTIVES:

• Compare the survival of patients with liver-dominant metastatic colorectal adenocarcinoma treated with irinotecan, fluorouracil, and leucovorin calcium with or without hepatic chemoembolization.
• Compare response in the liver, time to hepatic tumor progression, and time to extrahepatic tumor progression in patients treated with these regimens.
• Compare the possible treatment differences with respect to morbidity, toxic effects of chemoembolization, toxic effects of chemotherapy, and death from cancer-related complications in these patients.

OUTLINE: This is a phase I dose-escalation study followed by a phase III randomized, multicenter study. (Phase I closed as of 10/14/02.)

• Phase I: Patients in phase I are sequentially enrolled to 1 of 3 treatment regimens. (Phase I closed as of 10/14/02.)

  • Regimen A: Patients receive irinotecan IV over 60-90 minutes, leucovorin calcium IV, and fluorouracil IV over 10 minutes on days 1, 8, 15, and 22. Patients undergo hepatic embolization with embolic suspension only on day 36.
  • Regimen B: Patients receive chemotherapy as in regimen A. Patients undergo hepatic chemoembolization with lower-dose cisplatin, doxorubicin, and mitomycin on day 36.
  • Regimen C: Patients receive chemotherapy as in regimen A. Patients undergo hepatic chemoembolization with higher-dose cisplatin, doxorubicin, and mitomycin on day 36.

After 1 week of rest, patients in all regimens receive a second 4-week course of systemic chemotherapy.

Cohorts of 3-10 patients are sequentially enrolled until the maximum tolerated dose (MTD) of chemotherapy and chemoembolization is determined. The MTD is defined as the dose preceding that at which at least 4 of 10 patients experience dose-limiting toxicity.

• Phase III: Patients are stratified according to liver volume involvement (less than 25% vs 25-50% vs more than 50% to less than 75%) and participating center. Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive irinotecan IV over 60-90 minutes, leucovorin calcium IV, and fluorouracil IV over 10 minutes on days 1, 8, 15, and 22. Courses repeat every 6 weeks in the absence of disease progression.
  • Arm II: Patients receive chemotherapy as in arm I. Patients undergo hepatic chemoembolization with cisplatin, doxorubicin, and mitomycin on day 36. Chemotherapy repeats every 6 weeks in the absence of disease progression. Chemoembolization may repeat every 6 weeks for 2-4 courses as necessary.

Patients in phase III are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 9-18 patients will be accrued for phase I of this study. (Phase I closed to accrual as of 10/14/02.) Approximately 315 patients will be accrued for phase III of this study within 2.5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic colorectal adenocarcinoma

  • Measurable metastasis to liver at least 1.0 cm

    • Less than 75% of total liver volume
  • Known extrahepatic disease limited to lymph nodes and less than 2 cm
  • No ascites
• Ineligible for surgery

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute granulocyte count at least 2,000/mm^3
• Platelet count at least 90,000/mm^3
• No bleeding diathesis not correctable by standard therapy

Hepatic:

• Ineligible if all of the following criteria are concurrently present:

  • High risk of hepatic failure (more than 50% liver involvement by tumor)
  • Bilirubin greater than 2.0 mg/dL
  • SGOT greater than 100 U/L
  • Lactate dehydrogenase greater than 425 U/L
• No hepatic encephalopathy
• No portal vein occlusion without hepatopedal collateral flow demonstrated by angiography
• No portal hypertension with hepatofugal flow

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• No myocardial infarction within the past 6 months
• No evidence of congestive heart failure
• No severe peripheral vascular disease that would preclude catheterization

Other:

• No severe allergy or intolerance to contrast media, narcotics, sedatives, or atropine
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No more than 1 prior adjuvant immunotherapy regimen for colon cancer

Chemotherapy:

• At least 6 months since prior adjuvant chemotherapy and recovered
• No more than 1 prior adjuvant chemotherapy regimen for colon cancer
• No prior hepatic arterial infusion chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 1 month since prior radiotherapy
• No prior hepatic radiotherapy

Surgery:

• At least 1 month since prior surgery
• Prior surgical resection or ablation of liver metastases allowed

Other:

• No other concurrent therapy