A Phase II Study of Continuous Hepatic Arterial Infusion With Floxuridine (FUDR) and Dexamethasone (DEX) in Patients With Unresectable Primary Hepatic Malignancy

This phase II study aims to evaluate regional chemotherapy in patients with unresectable
primary hepatic malignancy. Specifically, eligible patients with hepatocellular carcinoma
and peripheral cholangiocarcinoma, considered unresectable after review by the Hepatobiliary
Surgery service, will undergo hepatic artery pump placement and continuous infusion of FUDR.
The protocol includes radiological and biological correlative studies.

The primary objectives of the study are 1.) to assess the efficacy of continuous hepatic
arterial infusion (HAI) of FUDR and dexamethasone (DEX) in patients with unresectable
hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and 2.)to assess
patient tolerability of this therapy stratified by degree of underlying hepatic parenchymal
disease, as determined on liver biopsy. Secondary objectives are 1.) to use dynamic MRI to
evaluate changes in tumor perfusion during treatment and to correlate these findings with
radiographic tumor response and 2.) to investigate molecular genetic changes associated with
these tumors using comparative genomic hybridization and cDNA array from tumor and liver
biopsy specimens obtained at the time of operation. All patients enrolled in the study will
begin HAI FUDR at 0.16 mg/kg/day. An initial cohort of 12 patients will be enrolled and
treated. Dose limiting toxicity (DLT) related to FUDR is defined by changes in liver
function blood tests that are unrelated to disease progression or mechanical biliary
obstruction. Modifications in the FUDR dose may be required. A patient will be considered
intolerant of therapy if treatment must be stopped due to DLT at least once during the first
3 months. Treatment will continue as long as there is at least stable disease and acceptable
toxicity.

If, in the initial cohort, 4 or more patients (> 30%) are intolerant of therapy or if there
are not at least 2 responders, then the study will be terminated. Otherwise, accrual will
continue to a maximum of 35 patients.

Inclusion Criteria:

- Patients with a liver mass that is radiographically consistent with HCC and a serum
alpha fetoprotein (AFP) > 500 ng/dl do not require biopsy confirmation of the
diagnosis.

- Patients with HCC or ICC undergoing exploration for a possible curative resection but
found to have unresectable disease confined to the liver will be eligible, provided
that no intraoperative findings would exclude them and prior informed consent has
been obtained (see below).

- There must be <70% liver involvement by cancer, and the disease must be considered
unresectable.

- Patients who have failed ablative therapy will be eligible.

- Patients must have a KPS > 60% and be considered candidates for general anesthesia
and hepatic artery pump placement.

- Patients with chronic hepatitis and/or cirrhosis are eligible

- Serum albumin must be >2.5 g/dl and total serum bilirubin must be <1.8 mg/dl based on
preoperative laboratory values within 14 days of registration.

- WBC must be >3500 cells/mm3 and platelet count must be >100,000/mm3 based on
preoperative laboratory values within 14 days of registration.

- The international normalized ratio (INR) must be less than 1.5 in patients not on
coumadin therapy, based on preoperative laboratory values within 14 days of
registration.

- Age >_ 18 years.

- Female patients cannot be pregnant or lactating.

- Patients must be able to understand and sign informed consent.

Exclusion Criteria:

- Patients who have received prior treatment with FUDR

- Patients who have had prior external beam radiation therapy to the liver.

- Patients who have a diagnosis of sclerosing cholangitis.

- Patients who have a diagnosis of Gilbert's disease.

- Patients who have clinical ascites

- Patients with hepatic encephalopathy

- Patients who have radiographic evidence of esophageal varices or history of variceal
hemorrhage.

- Patients with occlusion of the main portal vein nor of the right and left portal
branches Patients that have concurrent malignancies (except localized basal cell or
squamous cell skin cancers). Patient with active infection. Female patients who are
pregnant or lactating.