1.0 
INTRODUCTION 
1.1 Background 
Colorectal cancer (CRC) strikes 150,000 patients per year in the United States, with neater 
than 40% of these pauents destined to die of the disease despite current medical 
management. Death is commonly due to liver metastases with sequelae including 
progressive liver dysfuncdon. Greater than 70% of all padents with recurrent colorectal 
cancer develop liver metastases, and autopsy studies indicate that in at least half of these 
cases, liver involvement is the sole metastadc site(l). Metastases at other sites typically 
occur later in the natural history of the disease. For padents with metastadc liver tumors, 
systemic chemotherapy provides only modest benefit, mainly in disease palliadon. 
Regional chemotherapy by hepadc artery infusion may offer addidonal benefit in certain 
groups of padents, but is also ultimately limi ted as all padents will eventually fail this 
therapy (see below). Median survival after diagnosis of unresectable liver metastases is 
approximately 6 months, with the extent of liver involvement being the best predictor of 
survival dme(2). 
Hepatocellular cancer (hepatoma, HCC) strikes only about 15,000 padents per year in the 
United States, but about 1,250,000 padents worldwide, making it one of the most common 
malignant tumors in the world(3). Most padents present with tumors which are 
unresectable, and local recurrence is common even when resecdon is performed. Distant 
metastases are infrequendy of clinical significance, yet prognosis is generally dismal for 
this disease because of its inexorable progression with concomitant Liver dysfuncdon. 
Current therapies are largely ineffectual(4). Median survival is less than 6 months. 
1 .2 Regional Therapy of Liver Tumors Via Hepadc Artery Infusion 
Regional therapy of malignant liver tumors may be achieved by a number of methods, of 
which hepadc artery infusion is the most commonly employed in current clinical pracdce. 
The liver has a dual blood supply, with the portal vein supplying 75% and the hepadc 
artery 25% of hepadc blood flow. In contrast, malignant liver tumors derive nearly 100% 
of their blood supply from the hepadc artery(5). Regional therapy of liver tumors can thus 
be obtained via hepadc artery infusion, either following percutaneous catheterizadon of the 
hepadc artery or after surgical placement of a hepadc artery catheter attached to a 
subcutaneously implanted pumping device. The latter can be used to deliver chemotherapy 
via either bolus administradon or continuous infusion. 
Hepadc artery infusion therapy of malignant liver tumors offers potendal advantages over 
systemic therapy, depending on the agent to be administered. Agents with high total body 
clearance will achieve increased concentradons in the liver tumor if given by hepadc artery 
infusion. Agents which are efficiendy extracted by the hepadc parenchyma will achieve 
reduced systemic exposure, and therefore reduced systemic toxicity, if given by hepadc 
artery infusion. 
Currendy, liver metastases of colorectal cancer are frequendy treated by hepadc artery 
infusion, using fluoropyrimidine-based cytotoxic chemotherapy such as floxuridine 
(FUDR) administered by surgically implanted pump. This approach may be superior to 
systemic fluoropyrimidine chemotherapy for some padents(6, 7). Hepatocellular cancers 
are also frequendy treated with hepadc artery infusion, by surgically implanted pump or by 
chemoembolizadon. 
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Recombinant DNA Research, Volume 20 
