Liver involvement by cancer occurs frequently and is a major source of morbidity and mortality. Preliminary observations in patients with liver cancers suggest that the proliferating peripheral rim of many tumor nodules is hypervascular relative to the normal liver. When microspheres of appropriate size (20-40 Mum) are injected to form a homogenous suspension in the hepatic artery, microspheres will lodge in the microcirculation (precapillary arterioles and capillaries) in direct proportion to the capillary cross-sectional area with more going to hypervascular regions. The objective of this study is to examine, in patients with liver tumors, potentially selective differences between the microcirculation of hepatic tumors and normal liver and, to exploit those differences therapeutically to deliver more chemotherapy and radiotherapy specifically to the tumor with the use of starch microspheres and yttrium 90 microspheres. A totally implanted drug delivery system will be used to reliably introduce agents so as to infuse the entire liver. Tumor and normal liver microvasculature will be examined using hepatic arterial injection of Tc99m-macroaggregated albumin (Tc-MAA) combined with nuclear tomographic scanning. The ability of hepatic arterial infusion of vasoactive agents (epinephrine, norepinephrine, vasopressin) to shift flow from normal to the tumor microcirculation will be defined. Concurrent hepatic arterial injection of biodegradable starch microspheres in a drug solution (mitomycin or bischlorethylnitrosourea) will be used to increase drug delivery to the tumor microcirculation with decreased exposure systemically. Hepatic arterial administration of yttrium 90 microspheres will be studied as a means to deliver internal radiotherapy to hepatic tumors. After a preclinical study in dogs, prolonged continuous hepatic arterial infusion of bromodeoxyuridine will be examined as a means to selectively radiosensitize tumor to yttrium 90 microspheres. The use of vasoactive agents combined with microspheres may further improve therapeutic selectivity and will be examined concurrently. These studies, designed to examine and exploit the tumor microcirculation in the liver, may provide a basis for new therapeutic approaches in other regionally-confined tumors.
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