Arteriovenous shunting in patients with colorectal liver metastases

Abstract

SummaryThe outlook for patients with colorectal liver metastases is poor. Microspheres have been combined with cytotoxics and administered via the hepatic artery in an attempt to improve tumour drug exposure within the liver. However, it has been suggested that arteriovenous connections might occur in association with intrahepatic tumours causing loss of regional advantage, and that the administration of microspheres further exacerbates arteriovenous shunting. In seven patients with colorectal liver metastases, base-line shunting was measured using a tracer quantity of radio-labelled albumin microspheres. The shunted fraction of a 'therapeutic quantity' of microspheres was subsequently measured in the same group of patients using albumin microspheres carrying a different radio-label. Base-line shunt for 0.5 x 106 microspheres was found to be 2.2 ± 1.8% (mean ± s.d.); the percentage shunt of a therapeutic quantity (40 -80 x 106) of microspheres was 3.0±0.8%. We conclude that arteriovenous shunting in patients with colorectal liver metastases is minimal, and is not significantly increased by the administration of therapeutic quantity of microspheres during regional chemotherapy.Conventional treatment of colorectal liver metastases has yielded disappointing results, and attention has turned to hepatic arterial chemotherapy. The potential advantages of regional therapy over systemic drug administration are that high drug levels can be achieved in the tumour-bearing organ and that systemic drug concentrations fall when the drug is retained within the organ, thereby minimising toxicity.Particle-bound regional chemotherapy has been used in an attempt to improve drug uptake by the target organ. There are two mechanisms of value. Firstly, cytotoxic drugs have been co-administered with biodegradable microspheres which temporarily slow hepatic arterial blood-flow in the tumourbearing liver and increase uptake of drug by the cells (Dakhil et al., 1982;Thom et al., 1989). Secondly, anti-cancer agents, including Adriamycin, mitomycin C, 5 fluorouracil, cis-platin and cytocidal radio-nuclides have been loaded into particles which act as controlled release vehicles in the target tissue Fujimoto et al., 1985;Okamoto et al., 1986;Herba et al., 1988).If, however, arteriovenous shunting were associated with liver metastases (Zeissman et al., 1983), a proportion of arterially administered drug would bypass vascular beds in the tumour-bearing liver and be carried to the lungs. The effect would be to reduce tumour drug exposure, increase systemic side-effects and in the case of some particle-bound cytotoxics, increase pulmonary toxicity.With both approaches for enhancing regional therapy, relatively large numbers of particles may be required, either because of the relatively low drug pay-loads associated with some cytotoxic-loaded microspheres, or in order to optimise the arrest of arterial blood-flow. Unfortunately, there have been reports that very high levels of shunting occur when large numbers of microspheres are injected into th...

Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases

“…However, we have recently shown that base-line shunting in patients with colorectal liver metastases is low and not significantly increased following the regional administration of a 'therapeutic' dose of microspheres (Goldberg et al, 1990b). In clinical practice therefore, we have not found arteriovenous shunting to be a problem.…”

Characterisation of tumour blood flow using a 'tissue-isolated' preparation

“…Wheeler et al (1986), in their study of human head and neck cancer, also suggested that some of the shunting they observed (on average 23% of the total blood flow) may have been in normal tissue rather than in the tumour itself. Goldberg et al (1991) have discussed the problems associated with using microspheres for measurement of shunted fraction and concluded that once errors such as leaching of radioactivity from the spheres and heterogeneity in sphere size were minimised the shunted fraction within human liver metastases could be reduced to less than 6%. Gullino and Grantham (1961b), who developed the original method for growing 'tissueisolated' tumours in the ovarian site, used uptake of 42KC1 or 86RbCl and Sapirstein's principles (Sapirstein, 1958) to determine blood flow to rat tumours growing in the ovary for comparison with the total venous outlfow.…”

Microvascular Architecture of Hepatic Metastases in a Mouse Model

“…The majority of treatment modalities are based on the concept that the metastases receive a predominant hepatic arterial supply1'2. However, some tumours obtain a portal vein supply or establish arterioportal anastomoses [3][4][5][6] in order to compensate for arterial loss in treatment targeting the hepatic artery. These observations growth is dependant on angiogenesis, the process by which new capillary blood vessels are generated from preexisting capillaries and venules, induced by growth factors released by the tumour and from those present in the host milieu8-1.…”