NIH Clinical Research Studies

Protocol Number: 04-C-0229

Active Accrual, Protocols Recruiting New Patients

Title:
A Phase II Trial of Isolated Hepatic Perfusion (IHP) with Melphalan for Subjects with Metastatic Unresectable Colorectal Cancers of the Liver with Disease Refractory to First Line Systemic Chemotherapy
Number:
04-C-0229
Summary:
This study will determine whether infusing a drug called melphalan directly into the liver (isolated hepatic perfusion) can shrink tumors in patients with colorectal cancers of the liver. Similar perfusion studies with melphalan have been done in patients with liver cancer and in patients with a serious type of skin cancer called melanoma. In both studies tumors shrank, some up to less than half the original size. IHP has been used with melphalan, with melphalan and another drug called tumor necrosis factor, and with melphalan followed by chemotherapy given directly into the liver blood vessels after IHP.

Patients 18 years of age and older with colorectal cancer that has spread to the liver may be eligible for this 2-year study. Patients whose tumor has spread to limited sites beyond the liver may also be considered eligible if the tumors outside the liver can be treated with surgery or radiation therapy. Patients must weigh at least 30 kilograms (66 pounds). Candidates are screened with a physical examination, chest x-ray, blood tests, electrocardiogram (EKG), CT scan of the chest, abdomen and pelvis, and MRI scan of the liver.

Participants undergo laparotomy and isolated hepatic perfusion (IHP), as follows:

- Laparotomy is a type of surgery done under general anesthesia through a small incision in the abdomen. It allows the surgeon to look at the amount and location of tumor in the abdomen. Sometimes tumors are found at laparotomy that were not detected by imaging tests such as CT and MRI. Patients who are found at laparotomy to have tumors that cannot be treated may not continue in the study. Patients who remain in the study proceed with IHP.

- IHP is a major operation, done under general anesthesia. In this procedure, catheters (plastic tubes) are placed into the large blood vessels that deliver blood to and remove blood from the liver, creating a circulation to the liver separate from the rest of the body. During the operation, the liver receives oxygen from an external pump similar to the heart-lung machine used in open-heart surgery. For one hour, melphalan is administered through the pump in large doses that would not be safe if it reached all parts of the body in the normal blood circulation. The entire operation lasts between six and eight hours. If the patient's gallbladder has not been removed previously, it may be removed during the IHP. Other tumors found in the abdomen are also removed if they can easily be resected. Patients usually can be discharged from the hospital about 11-14 days after the surgery.

Patients return to NIH 6 weeks after discharge for a checkup, x-rays, and blood tests and are then followed at the clinic every 3 to 4 months for x-rays and blood tests. Patients are also asked to complete quality of life questionnaires before surgery and at each clinic visit after surgery to evaluate the effect of the treatment on overall well being.

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. Patients with limited sites of extra-hepatic disease and who have dominant life-limiting disease in liver will be considered eligible if the extra-hepatic sites can be treated with local ablative measures such as resection or external beam radiation therapy.

Subjects must have progressed while receiving or after completing therapy with an irinotecan or oxaliplatin containing systemic chemotherapy regimen for treatment of established hepatic metastases. Chemotherapy treatment failure is defined as disease progression evidenced by tumor growth or new lesions on imaging modalities or increasing serum CEA.

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 at time of registration to be put in on study and at 24 hours prior to surgery.

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/microL, and a creatinine of lessthan or equal to 1.5 mg/dL unless the measured creatinine clearance is greater than 60mL/min/1.73m(2). 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.

Pathology will be confirmed by N.I.H. pathologists in the Laboratory of Pathology.

EXCLUSION CRITERIA

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

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

Patients with active infections are not 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 significant 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:
Melphalan
Progression-Free Survival
Clinical Response
Duration of Response
Quality of Life
Recruitment Keywords:
Colorectal Cancer
Conditions:
Investigational Drug(s):
None
Investigational Device(s):
None

Contacts:
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:
Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH.

Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999 Sep;230(3):309-18; discussion 318-21.

PMID: 10493478

Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M, Steinberg SM.

A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases.

Ann Surg. 1987 Dec;206(6):685-93.

PMID: 2961314

Hohn DC, Stagg RJ, Friedman MA, Hannigan JF Jr, Rayner A, Ignoffo RJ, Acord P, Lewis BJ.

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial. J Clin Oncol. 1989 Nov;7(11):1646-54.

PMID: 2530317

Active Accrual, Protocols Recruiting New Patients

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