Abstract
In this review, the rationale of regional chemotherapy for treatment of hepatic metastases in advanced colorectal carcinoma is discussed. Pharmacokinetic principles and early clinical experience of hepatic arterial drug administration are summarised. The regional advantage of fluoropyrimidine compounds in this setting is well established, and recent evidence suggests that 5-fluorouracil (5-FU) is more efficacious than the analogue 5-fluoro-2'-deoxyuridine (FUDR). However, while significantly higher clinical response rates can be achieved with hepatic arterial infusion (HAI) chemotherapy compared with conventional intravenous drug administration, patient survival benefit is not significantly different. Several novel approaches to overcome the limitations of HAI therapy are currently being explored. These include concomitant use of biodegradable microspheres, which both slow tumour blood flow and enhance tumour drug uptake, and use of vasoactive agents to redistribute arterial blood flow towards tumours. In addition, novel chemotherapeutic agents which exploit unique biological characteristics of hepatic tumours are entering clinical trial.
Highlights
Pharmacological rationale for regional chemotherapyThe rationale for regional drug therapy in the management of hepatic metastases is the finding that established malignant lesions (greater than 1 cm diameter) derive most of their blood supply from the hepatic artery, in contrast to normal hepatocytes, which have a dual supply via the portal venous circulation (Stagg et al, 1984)
The median survival of patients with multiple metastases is 3-5 months in most series (Fortner et al, 1984)
There is sufficient clinical trial data available on regional chemotherapy to enable the definition of clinical parameters which may predict both response to treatment and survival, in order to select patients most likely to benefit from regional chemotherapy (Kemeny et al, 1989a; Rougier et al, 1991)
Summary
The rationale for regional drug therapy in the management of hepatic metastases is the finding that established malignant lesions (greater than 1 cm diameter) derive most of their blood supply from the hepatic artery, in contrast to normal hepatocytes, which have a dual supply via the portal venous circulation (Stagg et al, 1984). The concept of delivering chemotherapy to the liver via hepatic arterial infusion dates as far back as 1959 (Sullivan et al, 1959), and over the following 20 years the pharmacological principles governing regional drug delivery were established. The principal advantage of regional chemotherapy over conventional systemic therapy is the possibility of achieving higher drug concentrations at the tumour site while reducing systemic exposure and toxicity (Dedrick et al, 1978). Where CITB is the total body clearance obtained during intravenous infusion, Q is the blood flow through the treated organ and E is the extraction ratio (the fraction of drug that is extracted during a single pass through the treated organ). The ideal drug for hepatic arterial infusion would have a high total body clearance and a high extraction rate by the target organ (Table I). Hepatic arterial infusion of the anti-metabolite 5-FU or its analogue, FUDR, would theoretically maximise drug exposure to the tumour capillary bed, but result in low systemic levels and minimal subsequent toxicity to the patient (Ensminger et al, 1978)
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