Amifostine (ethyol) as modulator of hepatic and biliary toxicity from intraarterial hepatic chemoembolization: Results of a phase I study

Background/Aims: Hepatic and biliary toxicity are still significant problem s after intraarterial hepatic chemoembolization for liver metastases from l arge bowel cancers. In about 30-60% of the patients hepatic and biliary tox icity are the limiting aspects of intraarterial hepatic chemoembolization a nd exclude a lot of patients from a repeated beneficial treatment. Amifosti ne (Ethyol) is a prodrug that must be dephosphorylated to the free thiol in which form it can detoxify free oxygen radicals generated by radiation, hy poxia and by drugs such anthracydines, platinum analogues and alkylating ag ents. Amifostine as inactive prodrug is primarily metabolized at the tissue site by membrane alkaline phosphatase, which is highly active in the cell membranes of normal endothelial cells and biliary tree cells but not in the cell membranes and neovascular capillaries of tumor. When dephosphorylated to WR-1065, amifostine is rapidly taken up into normal liver cells by a ca rrier-mediated facilitated diffusion transport process. The resulting high thiol content in normal liver tissue (biliary cells and hepatocytes) compar ed with the negligible concentration in liver metastases from large bowel c ancers probably provides for selective drug resistance to intraarterial hep atic chemoembolization protecting normal tissue and allowing full therapeut ic effect on tumor. Methodology: From May 1997 we planned a phase I study in patients receiving intraarterial hepatic chemoembolization for liver metastases from large bo wel cancers. We started at 200mg/m(2) dissolved in 250cc of normal saline g iven in 15min in the intrahepatic artery 20min before an intraarterial hepa tic chemoembolization consisting of mitomycin 10mg/m(2), epirubicin-50, cis platin-60 diluted in 10 mt of contrast media, mixed in 15mL of lipiodol UF followed by a gelfoam powder solution until stagnation of the flow. The esc alating dose, every 3 patients, was: 200mg/m(2), 250mg/m(2), 300mg/m(2), 35 0mg/m(2). Results: Toxicity has been observed at 350mg/m(2): 1 patient reported trans ient hypotension (Blood pressure 70/50mm Hg), 1 patient had skin flushing a nd dyspnoea. 300mg/m(2) are well tolerated and seem to reduce the level of transaminases, lactic acid dehydrogenase, and gamma -glutamyl transferase. Also the duration of necrotic damage, always observed after intraarterial h epatic chemoembolization, seems shorter compared with historical controls. Conclusions: Amifostine can be certainly administered at 300mg/m(2) as intr aarterial infusion and could be a significant step to ameliorate the therap eutic ratio of intraarterial hepatic chemoembolization.