Protocol Number: 01-C-0093

Title:

A Phase III Prospective Random Assignment Trial of Regional and Systemic Chemotherapy with or without Initial Isolated Hepatic Perfusion for Patients with Metastatic Unresectable Colorectal Cancers of the Liver

Number:

01-C-0093

Summary:

This study will test whether isolated hepatic (liver) perfusion (IHP) enhances treatment with local and systemic chemotherapy for colorectal tumors that have spread to the liver. IHP is a major operation in which the liver's blood supply is separated from that of the rest of the body. The procedure allows chemotherapy to be administered directly to the liver in amounts that would not be safe if it circulated throughout the body. The study will also assess participants' quality of life over a 2-year period, starting from the beginning of the study.

Patients 18 years of age or older with colorectal cancer that has spread to the liver, but not further, and cannot be removed surgically may be eligible for this study. Candidates will be screened with a physical examination, blood tests, electrocardiogram (EKG), chest X-ray, and imaging studies, such as X-ray studies, CT scan of the chest, abdomen and pelvis and MRI scan of the liver, to evaluate the tumor.

All patients will undergo laparotomy-abdominal surgery to examine the tumor-and will then be randomized to one of two treatment groups. Group 1 will undergo liver perfusion and then receive local (direct to the liver) and systemic (through the bloodstream) chemotherapy. Group 2 will have local and systemic chemotherapy without prior liver perfusion. During either the laparotomy or IHP operation, patients will have a small catheter placed in the artery to the liver. This will be connected to either a liver port or pump (depending on what's best suited for the individual) for administration of the local chemotherapy.

Group 1

After the laparotomy, group 1 patients will undergo IHP. In this procedure, catheters (plastic tubes) are placed into the large artery and vein that supply blood to the liver and carry blood away from it. This creates a separate circulation for the liver, similar to the heart-lung bypass in open-heart surgery. During the perfusion the pump pushes blood and melphalan (anti-cancer drug) through the liver for 1 hour. After the perfusion, the catheter for local chemotherapy is put in place. The entire operation takes between 6 and 8 hours. About 6 weeks after IHP, patients will receive systemic chemotherapy with irinotecan followed by fluorouracil (5-FU) through a catheter in a vein. 5-FU and leucovorin will also be given for the next 2 days. This regimen will be repeated every 48 days for 6 cycles unless the disease progresses or the treatment side effects are too severe to continue. Local therapy will begin 2 weeks after the first cycle of systemic therapy. This will consist of a combination of floxuridine and leucovorin given directly to the liver through the catheter placed during the IHP surgery. Heparin will also be given to prevent clot formation in the catheter, and the steroid dexamethasone will be given to reduce swelling in the liver. The drugs will be infused for 14 days. This treatment will be repeated every 48 days for 6 cycles and then every 28 days for another 6 cycles.

[Note: The protocol (page14) says the systemic and local chemotherapy are given in 35-day cycles for 6 cycles; the consent form (pages 4 and 5) says the systemic chemotherapy is given in 48-day cycles for 6 cycles and the local chemotherapy is given in 48-day cycles for 6 cycles and then 28-day cycles for another 6 cycles for a total of 12 cycles.]

Group 2

Seven days after the laparotomy, patients in this group will receive one cycle of local chemotherapy. Two weeks later they will begin systemic and local chemotherapy according to the same schedule as group 1.

All patients will return to NIH 10 to 11 times the first year for treatment and evaluation. They will have X-rays and blood tests to assess side effects and treatment response.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Histologically or cytologically proven measurable metastatic colorectal cancer limited to the parenchyma of the liver with no evidence of unresectable extrahepatic disease by preoperative radiological studies. Limited resectable extrahepatic disease is acceptable.

Patients must have had no chemotherapy, radiotherapy, or biologic therapy for their malignancy in the 4 weeks prior to the liver perfusion and must have recovered from all side effects.

Patients must have an ECOG performance standard of 0, 1 or 2 for 24 hours prior to surgery and then again 24 hours prior to post perfusion chemotherapy.

Patients must have adequate hepatic function as evidenced by bilirubin less than 2.0 mg/dL and a PT less than or equal to 2 seconds of the upper limit of normal.

Patients must be greater than or equal to 18 years of age and greater than 30 kg.

Patients must have a platelet count greater than 100,000, a Hct greater than 27.0, a white blood count greater than 3000/microliter, and a creatinine less than or equal to 1.5 mg/dL or a creatinine clearance of greater than 60 mL/min. Patients with elevations in hepatic transaminases secondary to the presence of metastatic disease in the liver are eligible.

Patients must be aware of the neoplastic nature of his/her illness, the experimental nature of the therapy, alternative treatments, potential benefits, and risks. The patient must be willing to sign an informed consent.

The patient's disease in the liver must be considered unresectable as defined by greater than three sites of disease in the liver, bilobar disease, tumor abutting major vascular or ductal structures making anatomic resection with preservation of liver function impossible.

EXCLUSION CRITERIA:

Pregnant patients and nursing mothers will be excluded due to the unknown effects of melphalan on the fetus or newborn.

Patients previously treated with intrahepatic artery infusional therapy using FUDR will be excluded.

Patients taking immunosuppressive drugs or on chronic anticoagulation will not be eligible.

Patients with active infections will not be eligible.

Patients with biopsy proven cirrhosis or evidence of significant portal hypertension manifested by ascites, esophageal varices on endoscopy, or radiologic studies showing significant collateral vessels around the organs drained by the portal venous system will be excluded.

Patients with ischemic cardiac disease or history of congestive heart failure with an LVEF less than 40% will be excluded.

Patients with COPD or other chronic pulmonary disease with PFT's less than 50% predicted for age will be excluded.

Patients with a history of VOD are ineligible.

Patients with chronic active hepatitis based on a positive serology test for surface antigen B or C will be excluded if there is evidence of cirrhosis on pathology. If no pathology specimen exists then evidence for cirrhosis will be determined based radiological studies and physical examination. If there are no indications of it then the patient will be registered on study and a biopsy will be obtained at the time of laparotomy for IHP with the expectation that occult clinically significant cirrhosis is very unlikely. If cirrhosis is pathologically confirmed the patient will not undergo treatment and be taken off study. Patients with radiographic or other signs of cirrhosis will undergo percutaneous biopsy prior to registration.

Special Instructions: Currently Not Provided

Keywords:

HAI Therapy

IHP

Randomization

Systemic Chemotherapy

Survival

Recruitment Keywords:

Metastatic Colorectal Cancer

Chemotherapy

HAI Therapy

Conditions:

Colorectal Cancer

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma

Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma

Update on hepatic intra-arterial chemotherapy

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