Hepatic arterial chemotherapy for metastatic colorectal carcinoma

Abstract

Summary 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.The conventional notion of chemotherapy is of a truly systemic treatment designed to combat widely disseminated malignant disease. Colorectal carcinoma is relatively unresponsive to chemotherapy (Mayer, 1992), despite an increasing understanding of drug mechanisms of action at the molecular level. To date, systemic 5-FU plus folinic acid is considered the optimum treatment for metastatic colorectal cancer, yielding response rates of around 25% and median survival of around 12 months (Piedbois et al., 1992). These disappointing results reflect, in part, the narrow therapeutic ratio of 5-FU and the presence of associated severe systemic side-effects limiting dose escalation. Regional chemotherapy affords an alternative method of cytotoxic drug administration which circumvents the constraints of systemic administration, while introducing the concept of targeted drug delivery to metastatic disease localised to specific components of the body.Three levels of tumour targeting have been described (Widder et al., 1979): (1) selective drug delivery to the tumourbearing organ, (2) drug delivery biased to tumour rather than to normal tissue within that organ and (3) enhancement of uptake of cytotoxic drug by malignant cells. In this context, regional chemotherapy constitutes first-order targeting. Currently, the value of this method of drug delivery is being assessed in a number of different malignancies, but experience is greatest in the treatment of hepatic metastases from colorectal carcinoma.Colorectal carcinoma is the second most common malignancy in the UK and the cause of over 19,000 deaths per year. Epidemiological studies show that the incidence of colorectal carcinoma is increasing, with approximately 28,000 new cases now being diagnosed annually. Up to 50% of patients with colorectal carcinoma develop liver metastases, from which as many as 70% of patients will subsequen...

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

“…This might enhance anti-tumour efficacy as steep dose-response curves have been described for most chemotherapeutic agents (Frei, 1980;Canellos, 1987). Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994). Although HAI has been shown to improve short-term tumour response rates over systemic chemotherapy, it only slightly affects survival, while significant dose-limiting toxicity has been encountered (Kemeny, 1987;Pentecost, 1993;De Takats, 1994;Chang, 1987).…”

“…Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994). Although HAI has been shown to improve short-term tumour response rates over systemic chemotherapy, it only slightly affects survival, while significant dose-limiting toxicity has been encountered (Kemeny, 1987;Pentecost, 1993;De Takats, 1994;Chang, 1987). Alternatively, isolated hepatic perfusion (IHP), including total vascular isolation of the liver, has been reported to significantly increase intrahepatic drug concentrations when compared with HAI, while maintaining sufficiently low systemic drug levels (Aigner, 1982;Skibba, 1983;De Brauw, 1988;Marinelli, 1991;Radnell, 1990).…”

Minimally Invasive Management of Hepatic Metastases

“…Median survival for each of these chemotherapy regimes results in a 12-month median survival. 4,5 Hepatic resection for metastatic colorectal cancer to the liver results in the best opportunity for longterm survival.6 Of the 15,000 cases in the United…”

Perkutane Implantation von Portsystemen in der Arteria hepatica

“…Patienten und Methode: Bei 50 Patienten mit Metastasen oder malignen Primärtumoren der Leber wurden 52 Portsysteme interventionell über die Femoralarterie implantiert.Über einen femoralen Zugang wurde ein handelsüblicher Angiographiekatheter in der Leberarterie plaziert und an ein Portsystem angeschlossen, das in der Leiste in einer subkutanen Tasche Di e lokoregionäre Chemotherapie zeigt im Vergleich zur systemischen Chemotherapie deutlich bessere Erfolgsraten, insbesondere bei Lebermetastasen kolorektaler Tumoren [13]. Patienten und Methode: Bei 50 Patienten mit Metastasen oder malignen Primärtumoren der Leber wurden 52 Portsysteme interventionell über die Femoralarterie implantiert.Über einen femoralen Zugang wurde ein handelsüblicher Angiographiekatheter in der Leberarterie plaziert und an ein Portsystem angeschlossen, das in der Leiste in einer subkutanen Tasche Di e lokoregionäre Chemotherapie zeigt im Vergleich zur systemischen Chemotherapie deutlich bessere Erfolgsraten, insbesondere bei Lebermetastasen kolorektaler Tumoren [13].…”