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Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

Primary Purpose

Colorectal Cancer, Metastatic Cancer

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
dexamethasone
floxuridine
fluorouracil
leucovorin calcium
laparotomy
conventional surgery
Sponsored by
Alliance for Clinical Trials in Oncology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring stage IV colon cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum, liver metastases

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • CCOP - Cedar Rapids Oncology Project
  • CCOP - Iowa Oncology Research Association
  • John Stoddard Cancer Center at Iowa Methodist Medical Center
  • Mercy Cancer Center at Mercy Medical Center-Des Moines
  • Iowa Lutheran Hospital
  • Midlands Cancer Center at Midlands Community Hospital
  • MBCCOP - University of New Mexico HSC
  • MetroHealth Medical Center
  • Penn State Cancer Institute at Milton S. Hershey Medical Center
  • Fox Chase Cancer Center
  • CCOP - St. Vincent Hospital Cancer Center, Green Bay
  • Westmead Hospital
  • Instituto de Enfermedades Neoplasicas
  • San Juan City Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I - laparotomy + conventional surgery + chemotherapy

Arm II - conventional surgery + chemotherapy

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Overall survival
Time to progression

Secondary Outcome Measures

Full Information

First Posted
November 1, 1999
Last Updated
July 12, 2016
Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00002716
Brief Title
Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer
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 Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
January 1996 (undefined)
Primary Completion Date
March 2006 (Actual)
Study Completion Date
August 2006 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer, Metastatic Cancer
Keywords
stage IV colon cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum, liver metastases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
135 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I - laparotomy + conventional surgery + chemotherapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm II - conventional surgery + chemotherapy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Intervention Type
Drug
Intervention Name(s)
floxuridine
Intervention Type
Drug
Intervention Name(s)
fluorouracil
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Intervention Type
Procedure
Intervention Name(s)
laparotomy
Intervention Type
Procedure
Intervention Name(s)
conventional surgery
Primary Outcome Measure Information:
Title
Overall survival
Time Frame
Up to 5 years
Title
Time to progression
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy E. Kemeny, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Study Chair
Facility Information:
Facility Name
CCOP - Cedar Rapids Oncology Project
City
Cedar Rapids
State/Province
Iowa
ZIP/Postal Code
52403-1206
Country
United States
Facility Name
CCOP - Iowa Oncology Research Association
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50309-1016
Country
United States
Facility Name
John Stoddard Cancer Center at Iowa Methodist Medical Center
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50309
Country
United States
Facility Name
Mercy Cancer Center at Mercy Medical Center-Des Moines
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50314
Country
United States
Facility Name
Iowa Lutheran Hospital
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50316-2301
Country
United States
Facility Name
Midlands Cancer Center at Midlands Community Hospital
City
Papillion
State/Province
Nebraska
ZIP/Postal Code
68128-4157
Country
United States
Facility Name
MBCCOP - University of New Mexico HSC
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
MetroHealth Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Penn State Cancer Institute at Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033-0850
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111-2497
Country
United States
Facility Name
CCOP - St. Vincent Hospital Cancer Center, Green Bay
City
Green Bay
State/Province
Wisconsin
ZIP/Postal Code
54307-3453
Country
United States
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Instituto de Enfermedades Neoplasicas
City
Lima
ZIP/Postal Code
34
Country
Peru
Facility Name
San Juan City Hospital
City
San Juan
ZIP/Postal Code
00936-7344
Country
Puerto Rico

12. IPD Sharing Statement

Citations:
PubMed Identifier
16505413
Citation
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.
Results Reference
result
Citation
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.
Results Reference
result
PubMed Identifier
12782596
Citation
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.
Results Reference
result
PubMed Identifier
11913730
Citation
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.
Results Reference
result

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Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

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