Liver involvement by cancer is a major source of morbidity and mortality. The development of a totally implanted drug delivery system has rekindled interest in hepatic arterial chemotherapy and generated a large patient population amenable to studies aimed at more effective regional therapy. Our recent studies in patients with liver cancer using tomographic nuclear medicine scans after hepatic arterial injection of tracer microspheres indicate that tumors are often hypervascular compared to normal liver. Our objective is to develop therapeutic approaches exploiting such potentially selective differences between the microcirculation of hepatic tumors and normal liver. The ability of hepatic arterial infusion of vasoactive agents (epinephrine, norepinephrine, angiotensin) to shunt blood flow and microsphere delivery from normal liver to hepatic tumor nodules will be examined. Hepatic arterial administration of yttrium 90 microspheres will be studied as a means to deliver internal radiotherapy and, the ability of hepatic arterial infusion of bromodeoxyuridine (BUDR) to selectively radiosensitize tumor to these microspheres will be explored. Extensive preclinical studies in rabbits bearing the VX2 tumor (intrahepatically implanted) and in dogs will be used to rationally support the development (and FDA approval) of invesstigational clinical protocols. The rabbit model will be used for vasoconstrictor regimen studies, to examine BUDR pharmacodynamics, and to investigate comparative response to combined therapies. The dog will serve as a large animal model for pharmacokinetic studies and to establish the relative toxicities of therapeutic regimens combining hepatic arterial yttrium 90 microspheres with regional radiosensitizer regimens. Clinical efforts will consist of an initial phase I study of yttrium 90 microspheres alone and then ultimately progress to phase I studies of rational combinatins as directed by studies in the preclinical models. It is anticipated that the results of these investigations will provide a basis for large scale randomized phase III trials (in cooperative groups) as well as for the application of regional radiosensitizer-radiotherapy regimens in the treatment of other regionally-confined tumors such as head and neck cancer, brain tumors, and tumors of the extremities.
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