Combination Chemotherapy With or Without Chemoembolization in Treating Patients With Colorectal Cancer Metastatic to the Liver (6655)

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as irinotecan, fluorouracil, and leucovorin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. It is not yet known if chemoembolization is more effective than standard chemotherapy in treating metastatic cancer. PURPOSE: This phase I trial and randomized phase III trial is studying the effectiveness of chemoembolization in treating patients who have colorectal cancer metastatic to the liver.

Detailed Description
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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.

Official Title
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A Randomized Phase I/III Study Of Systematic Chemotherapy With Or Without Hepatic Chemoembolization For Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: FOLFIRI regimen
* Drug: cisplatin
* Drug: doxorubicin hydrochloride
* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: mitomycin C


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: FOLFIRI regimen|nan|
|Drug: cisplatin|nan|
|Drug: doxorubicin hydrochloride|nan|
|Drug: fluorouracil|nan|
|Drug: irinotecan hydrochloride|nan|
|Drug: leucovorin calcium|nan|
|Drug: mitomycin C|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

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