Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

NCT ID: NCT00002716

Last Updated: 2016-07-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 135 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1996-01-31
• Study Completion Date: 2006-08-31

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.

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.

Conditions

Colorectal Cancer; Metastatic Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

dexamethasone

Intervention Type: DRUG

floxuridine

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

laparotomy

Intervention Type: PROCEDURE

conventional surgery

Intervention Type: PROCEDURE

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.

Group Type: EXPERIMENTAL

fluorouracil

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

conventional surgery

Intervention Type: PROCEDURE

Interventions

dexamethasone

Intervention Type: DRUG

floxuridine

Intervention Type: DRUG

fluorouracil

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

laparotomy

Intervention Type: PROCEDURE

conventional surgery

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion 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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Alliance for Clinical Trials in Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nancy E. Kemeny, MD

Role: STUDY_CHAIR

Memorial Sloan Kettering Cancer Center

Locations

CCOP - Cedar Rapids Oncology Project

Cedar Rapids, Iowa, United States

CCOP - Iowa Oncology Research Association

Des Moines, Iowa, United States

John Stoddard Cancer Center at Iowa Methodist Medical Center

Des Moines, Iowa, United States

Mercy Cancer Center at Mercy Medical Center-Des Moines

Des Moines, Iowa, United States

Iowa Lutheran Hospital

Des Moines, Iowa, United States

Midlands Cancer Center at Midlands Community Hospital

Papillion, Nebraska, United States

MBCCOP - University of New Mexico HSC

Albuquerque, New Mexico, United States

MetroHealth Medical Center

Cleveland, Ohio, United States

Penn State Cancer Institute at Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

CCOP - St. Vincent Hospital Cancer Center, Green Bay

Green Bay, Wisconsin, United States

Westmead Hospital

Westmead, New South Wales, Australia

Instituto de Enfermedades Neoplasicas

Lima, , Peru

San Juan City Hospital

San Juan, , Puerto Rico

Countries

United States; Australia; Peru; Puerto Rico

References

Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, Weeks JC, Sigurdson ER, Herndon JE 2nd, Zhang C, Mayer RJ. 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. 2006 Mar 20;24(9):1395-403. doi: 10.1200/JCO.2005.03.8166. Epub 2006 Feb 27.

Reference Type: RESULT

PMID: 16505413 (View on PubMed)

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.

Reference Type: RESULT

Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD. 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. 2003 Jun 1;63(11):2898-904.

Reference Type: RESULT

PMID: 12782596 (View on PubMed)

Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65-70. doi: 10.1038/sj.tpj.6500012.

Reference Type: RESULT

PMID: 11913730 (View on PubMed)

Other Identifiers

U10CA031946

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000064553

Identifier Type: REGISTRY

Identifier Source: secondary_id

CALGB-9481

Identifier Type: -

Identifier Source: org_study_id