Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Patients With Liver Metastases from Colorectal Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	18 and over	NCI	CALGB-9481 ECOG-C9481, NCT00002716

Objectives

1. 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.
2. Compare the quality of life of patients treated with these regimens.
3. 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.
4. Assess the p53 mutations, and correlate findings with objective response and survival in patients treated with these regimens.

Entry Criteria

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

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

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

Surgery:

• See Disease Characteristics

Patient Characteristics:

Age:

• 18 and over

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• See Disease Characteristics
• Bilirubin no greater than 2 times normal

Renal:

• Not specified

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

Expected Enrollment

Approximately 340 patients (170 per arm) will be accrued for this study within approximately 4.5 years.

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.

• Arm I: 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.
• Arm II: 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 on both arms 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.

Kemeny NE, Niedzwiecki D, Hollis DR, et al.: Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 24 (9): 1395-403, 2006.[PUBMED Abstract]

Kemeny NE, Niedzwiecki D, Hollis DR, et al.: Final analysis of hepatic arterial infusion (HAI) versus systemic therapy for hepatic metastases from colorectal cancer: a CALGB randomized trial of efficacy, quality of life (QOL), cost effectiveness, and molecular markers. [Abstract] American Society of Clinical Oncology 2005 Gastrointestinal Cancers Symposium, 27-29 January 2005, Miami, Florida. A-183, 2005.

Kemeny NE, Niedzwiecki D, Hollis DR, et al.: Hepatic arterial infusion (HAI) versus systemic therapy for hepatic metastases from colorectal cancer: a CALGB randomized trial of efficacy, quality of life (QOL), cost effectiveness, and molecular markers. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1010, 252, 2003.

Mandola MV, Stoehlmacher J, Muller-Weeks S, et al.: A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63 (11): 2898-904, 2003.[PUBMED Abstract]

Pullarkat ST, Stoehlmacher J, Ghaderi V, et al.: Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1 (1): 65-70, 2001.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Nancy Kemeny, MD, Protocol chair		Ph: 212-639-8068; 800-525-2225

Eastern Cooperative Oncology Group

Elin Ruth Sigurdson, MD, Protocol chair		Ph: 215-728-3519; 888-369-2427 Email: E_sigurdson@fccc.edu

Registry Information
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
Trial Start Date		1996-01-15
Registered in ClinicalTrials.gov		NCT00002716
Date Submitted to PDQ		1996-01-15
Information Last Verified		2004-04-15
NCI Grant/Contract Number		CA31946

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