Liver Resection and Floxuridine Plus Fluorouracil and Leucovorin in Treating Patients With Liver Metastases From Colorectal Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00002842
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 49
• Location: 1
• Arm: 1
• Duration (Months): 236
• Patients Per Site Per Month: 0.2

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 and giving drugs in different ways may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of surgery followed by floxuridine plus systemic fluorouracil and leucovorin in treating patients with liver metastases from colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer; Metastatic Cancer	Drug: floxuridine; Drug: fluorouracil; Drug: leucovorin calcium; Procedure: adjuvant therapy; Procedure: conventional surgery	Phase 2

Detailed Description

OBJECTIVES:

• Evaluate the efficacy of hepatic resection followed by portal vein infusion of floxuridine plus systemic fluorouracil/leucovorin calcium in patients with metastatic colorectal cancer.

• Study the toxic effects of adjuvant chemotherapy following hepatic resection.

• Evaluate mRNA expression of enzymes that may be important to the cytotoxicity of fluoropyrimidines in tumor cells, including thymidylate synthase, ribonucleotide reductase, and folylglutamyl synthetase, by polymerase chain reaction and immunohistochemistry.

OUTLINE: Following resection of the liver and all extrahepatic colorectal cancer, patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks.

If biopsy-proven metastatic disease develops, treatment may be stopped at the investigator's discretion. Continuation of regional therapy should be considered for extrahepatic failure. No concurrent radiotherapy is permitted.

Patients are followed every 3 months for 3 years, then every 6 months for survival.

PROJECTED ACCRUAL: It is expected that 50 patients will be entered over approximately 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Hepatic Resection Followed by Concurrent Adjuvant Portal Vein Infusion of Fluorodeoxyuridine and Systemic 5-Fluorouracil and Folinic Acid for Metastatic Colorectal Carcinoma
• Study Start Date: Sep 1, 1994
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin Patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks

Drug: floxuridine; Starting dose of 0.2 mg/kg/day for 14 consecutive days.; Drug: fluorouracil; 300 mg/m2/day by intravenous bolus 24 hours apart for 5 consecutive days.; Drug: leucovorin calcium; 500 mg/m2/day by continuous intravenous infusion beginning 24 hours prior to the first dose of 5-FU and continuing until 12 hours following the last dose of 5-FU.; Procedure: adjuvant therapy; Chemotherapy given after hepatic resection; Procedure: conventional surgery; Hepatic resection

Outcome Measures

Primary Outcome Measures

1. 2 Year Disease-free Survival . [2 years after treatment]

   Estimated using the product-limit method of Kaplan and Meier. Disease free survival, defined as first documented evidence of treatment failure. Acceptable evidence includes: Anastomotic - positive cytology or biopsy; Abdominal, pelvic and retroperitoneal nodes - progressively enlarging node as evidenced by 2 CT scans separated by at least a 4 week interval, ureteral obstruction in the presence of a mass as documented on CT scan; Peritoneum - positive cytology or biopsy, progressively enlarged intraperitoneal solid mass as evidenced by 2 CT scans separated by at least 4 weeks; Ascites - positive cytology or biopsy; Liver - positive cytology or biopsy; Pelvic mass - positive cytology or biopsy, progressively enlarging intrapelvic solid mass as evidenced by 2 CT scans separated by at least 4 weeks; Abdominal wall - positive cytology or biopsy; Lung - positive cytology or biopsy or presence of multiple pulmonary nodules; Bone marrow - positive cytology, aspiration or biopsy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal carcinoma or radiologically confirmed colorectal carcinoma in a synchronous metastasis

• Intrahepatic metastases required

• No more than 15 metastases involving no more than 60% of functioning liver

• No extrahepatic disease unless:

• Resectable anastomotic or locally recurrent tumor

• Resectable mesenteric lymph node involvement in patients undergoing initial resection of primary colorectal carcinoma

• Disease extension from liver metastasis amenable to en bloc resection (e.g., diaphragm wall, kidney, abdominal wall)

• No biopsy-proven chronic active hepatitis

PATIENT CHARACTERISTICS:

Age:

• Physiologic 18 to 70

Performance status:

• Karnofsky 60%-100%

Hematopoietic:

• AGC at least 1,500

• Platelets at least 100,000

Hepatic:

• Bilirubin no greater than 2.0 mg/dL (unless reversibly obstructed by metastasis)

Renal:

• Creatinine no greater than 2.0 mg/dL

Other:

• No second malignancy within 5 years except adequately treated:

• Nonmelanomatous skin cancer

• In situ bladder cancer

• In situ cervical cancer

• No pregnant women

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Prior mitomycin or nitrosoureas allowed

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to the liver

• At least 3 weeks since radiotherapy and recovered

• Prior pelvic radiotherapy allowed

• No planned concurrent radiotherapy

Surgery:

• Not specified

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Lucille A. Leong, MD, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00002842
• Other Study ID Numbers: 94080; P30CA033572; CHNMC-IRB-94080; NCI-V96-1031; CDR0000065077
• First Posted: Jan 27, 2003
• Last Update Posted: Apr 11, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by City of Hope Medical Center: stage IV colon cancer; stage IV rectal cancer; recurrent colon cancer; recurrent rectal cancer; liver metastases
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Floxuridine; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
Arm/Group Description	Patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks floxuridine: Starting dose of 0.2 mg/kg/day for 14 consecutive days. fluorouracil: 300 mg/m2/day by intravenous bolus 24 hours apart for 5 consecutive days. leucovorin calcium: 500 mg/m2/day by continuous intravenous infusion beginning 24 hours prior to the first dose of 5-FU and continuing until 12 hours following the last dose of 5-FU. adjuvant therapy: Chemotherapy given after hepatic resection conventional surgery: Hepatic resection
Period Title: Overall Study
STARTED	49
COMPLETED	22
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
Arm/Group Description	Patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks floxuridine: Starting dose of 0.2 mg/kg/day for 14 consecutive days. fluorouracil: 300 mg/m2/day by intravenous bolus 24 hours apart for 5 consecutive days. leucovorin calcium: 500 mg/m2/day by continuous intravenous infusion beginning 24 hours prior to the first dose of 5-FU and continuing until 12 hours following the last dose of 5-FU. adjuvant therapy: Chemotherapy given after hepatic resection conventional surgery: Hepatic resection
Overall Participants	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	9 40.9%
Male	13 59.1%
Region of Enrollment (participants) [Number]
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	2 Year Disease-free Survival .
Description	Estimated using the product-limit method of Kaplan and Meier. Disease free survival, defined as first documented evidence of treatment failure. Acceptable evidence includes: Anastomotic - positive cytology or biopsy; Abdominal, pelvic and retroperitoneal nodes - progressively enlarging node as evidenced by 2 CT scans separated by at least a 4 week interval, ureteral obstruction in the presence of a mass as documented on CT scan; Peritoneum - positive cytology or biopsy, progressively enlarged intraperitoneal solid mass as evidenced by 2 CT scans separated by at least 4 weeks; Ascites - positive cytology or biopsy; Liver - positive cytology or biopsy; Pelvic mass - positive cytology or biopsy, progressively enlarging intrapelvic solid mass as evidenced by 2 CT scans separated by at least 4 weeks; Abdominal wall - positive cytology or biopsy; Lung - positive cytology or biopsy or presence of multiple pulmonary nodules; Bone marrow - positive cytology, aspiration or biopsy.
Time Frame	2 years after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
Arm/Group Description	Patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks floxuridine: Starting dose of 0.2 mg/kg/day for 14 consecutive days. fluorouracil: 300 mg/m2/day by intravenous bolus 24 hours apart for 5 consecutive days. leucovorin calcium: 500 mg/m2/day by continuous intravenous infusion beginning 24 hours prior to the first dose of 5-FU and continuing until 12 hours following the last dose of 5-FU. adjuvant therapy: Chemotherapy given after hepatic resection conventional surgery: Hepatic resection
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	9 40.9%

Adverse Events

Time Frame	Adverse events occurring over a period of 7 years and 6 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
Arm/Group Description	Patients receive floxuridine via portal vein infusion from days 1-14. Systemic chemotherapy consists of leucovorin calcium on days 8-14 and fluorouracil on days 9-13. Courses repeat every 4 weeks for a total of 12 weeks floxuridine: Starting dose of 0.2 mg/kg/day for 14 consecutive days. fluorouracil: 300 mg/m2/day by intravenous bolus 24 hours apart for 5 consecutive days. leucovorin calcium: 500 mg/m2/day by continuous intravenous infusion beginning 24 hours prior to the first dose of 5-FU and continuing until 12 hours following the last dose of 5-FU. adjuvant therapy: Chemotherapy given after hepatic resection conventional surgery: Hepatic resection
All Cause Mortality
	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
	Affected / at Risk (%)	# Events
Total	8/22 (36.4%)
Gastrointestinal disorders
Diarrhea	2/22 (9.1%)	2
Investigations
AGC	2/22 (9.1%)	2
Activated partial thromboplastin time prolonged	1/22 (4.5%)	1
Lymphopenia	1/22 (4.5%)	1
Neutrophil count decreased	2/22 (9.1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Hepatic Resection/Portal Vein FUdr/Systemic 5-FU & Leucovorin
	Affected / at Risk (%)	# Events
Total	22/22 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	11/22 (50%)	26
Cardiac disorders
Dysrhythmias	2/22 (9.1%)	3
Pericardial	1/22 (4.5%)	1
Arrhythmia supraventricular	1/22 (4.5%)	1
Sinus bradycardia	1/22 (4.5%)	1
Gastrointestinal disorders
Abdominal pain	5/22 (22.7%)	8
Ascites	1/22 (4.5%)	1
Colitis	1/22 (4.5%)	1
Constipation	4/22 (18.2%)	4
Diarrhea	20/22 (90.9%)	66
Gastrointestinal disorder	2/22 (9.1%)	2
Mucositis oral	7/22 (31.8%)	10
Nausea	15/22 (68.2%)	31
	3/22 (13.6%)	6
Proctitis	1/22 (4.5%)	1
Rectal pain	1/22 (4.5%)	1
Vomiting	12/22 (54.5%)	19
General disorders
Other Misc	9/22 (40.9%)	14
Stomatitis	7/22 (31.8%)	10
Chills	1/22 (4.5%)	1
Fatigue	12/22 (54.5%)	20
Fever	3/22 (13.6%)	3
Fever (no infection)	7/22 (31.8%)	15
Oedema NOS	2/22 (9.1%)	7
Pain	2/22 (9.1%)	5
Infections and infestations
Catheter related infection	1/22 (4.5%)	1
Infection	2/22 (9.1%)	2
Injury, poisoning and procedural complications
Bruising	1/22 (4.5%)	1
Investigations
AGC	5/22 (22.7%)	14
Alanine aminotransferase increased	11/22 (50%)	41
Alkaline Phosphatase	5/22 (22.7%)	18
Alkaline phosphatase increased	8/22 (36.4%)	26
Aspartate aminotransferase increased	12/22 (54.5%)	32
Bilirubin	1/22 (4.5%)	1
Creatinine	1/22 (4.5%)	2
Creatinine increased	1/22 (4.5%)	3
HGB/HCT	8/22 (36.4%)	32
Hyperbilirubinemia	2/22 (9.1%)	9
INR increased	5/22 (22.7%)	8
Leukopenia	10/22 (45.5%)	21
Lymphopenia	1/22 (4.5%)	3
Neutrophil count decreased	4/22 (18.2%)	7
Platelet count decreased	6/22 (27.3%)	12
Platelets	4/22 (18.2%)	17
Prothrombin Time	4/22 (18.2%)	6
SGOT/SGT	9/22 (40.9%)	39
WBC	7/22 (31.8%)	19
Weight gain	1/22 (4.5%)	1
Weight loss	3/22 (13.6%)	5
Metabolism and nutrition disorders
Weight (Food Intake)	1/22 (4.5%)	2
Anorexia	7/22 (31.8%)	8
Dehydration	6/22 (27.3%)	6
Hypercalcemia	1/22 (4.5%)	1
Hyperglycemia	10/22 (45.5%)	31
Hypoalbuminemia	8/22 (36.4%)	25
Hypocalcemia	11/22 (50%)	29
Hypoglycemia	2/22 (9.1%)	2
Hypokalemia	3/22 (13.6%)	6
Hypomagnesemia	3/22 (13.6%)	4
Hyponatremia	3/22 (13.6%)	3
Musculoskeletal and connective tissue disorders
Muscle weakness	1/22 (4.5%)	1
Nervous system disorders
Cortical/State of Consciousness	1/22 (4.5%)	1
Depressed level of consciousness	1/22 (4.5%)	1
Dizziness	3/22 (13.6%)	3
Headache	2/22 (9.1%)	4
Motor Activity	1/22 (4.5%)	1
Peripheral Nervous System Sensory	1/22 (4.5%)	1
Peripheral motor neuropathy	5/22 (22.7%)	7
Taste alteration	1/22 (4.5%)	1
Psychiatric disorders
Anxiety	4/22 (18.2%)	7
Depression	1/22 (4.5%)	1
Insomnia	1/22 (4.5%)	1
Mood	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory disorder	2/22 (9.1%)	2
Skin and subcutaneous tissue disorders
Alopecia	3/22 (13.6%)	6
Extensive Skin Rash	1/22 (4.5%)	1
Hand-and-foot syndrome	1/22 (4.5%)	1
Local Skin Rash	3/22 (13.6%)	4
Nail disorder	1/22 (4.5%)	1
Rash desquamating	9/22 (40.9%)	12
Sweating	1/22 (4.5%)	2
Vascular disorders
Hypertension	1/22 (4.5%)	1
Hypotension	4/22 (18.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.