Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT00002716

Collaborator

National Cancer Institute (NCI) (NIH)

135

Enrollment

Locations

Arms

127

Duration (Months)

9.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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: Randomized phase III trial to compare the effectiveness of intrahepatic floxuridine, leucovorin, and dexamethasone with that of systemic fluorouracil and leucovorin in treating patients who have unresectable liver metastases from colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic Cancer	Drug: dexamethasone Drug: floxuridine Drug: fluorouracil Drug: leucovorin calcium Procedure: laparotomy Procedure: conventional surgery	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

135 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

PHASE III STUDY OF HEPATIC ARTERY FLOXURIDINE (FUDR), LEUCOVORIN (LV), AND DEXAMETHASONE (DEX) VERSUS SYSTEMIC 5-FLUOROURACIL (5-FU) AND LEUCOVORIN (LV) AS TREATMENT FOR HEPATIC METASTASES FROM COLORECTAL CANCER

Study Start Date :

Jan 1, 1996

Actual Primary Completion Date :

Mar 1, 2006

Actual Study Completion Date :

Aug 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I - laparotomy + conventional surgery + chemotherapy 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. Treatment for patients 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.	Drug: dexamethasone Drug: floxuridine Drug: leucovorin calcium Procedure: laparotomy Procedure: conventional surgery
Experimental: Arm II - conventional surgery + chemotherapy 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 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.	Drug: fluorouracil Drug: leucovorin calcium Procedure: conventional surgery

Arm

Intervention/Treatment

Experimental: Arm I - laparotomy + conventional surgery + chemotherapy

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. Treatment for patients 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.

Drug: dexamethasone

Drug: floxuridine

Drug: leucovorin calcium

Procedure: laparotomy

Procedure: conventional surgery

Experimental: Arm II - conventional surgery + chemotherapy

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 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.

Drug: fluorouracil

Drug: leucovorin calcium

Procedure: conventional surgery

Outcome Measures

Primary Outcome Measures

Overall survival [Up to 5 years]
Time to progression [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Hepatic:

Bilirubin no greater than 2 times normal

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

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

Contacts and Locations

Locations

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