DELIVERY OF ANTICANCER DRUGS VIA ISOLATED HEPATIC PERFUSION - A PROMISING STRATEGY IN THE TREATMENT OF IRRESECTABLE LIVER METASTASES

The prognosis of patients with irresectable liver metastases derived f rom colorectal cancer is invariably poor; unfortunately, these tumours show only minor responses to conventional anticancer agents. The best responses have been obtained by fluoropyrimidines delivered as contin uous infusion into the hepatic artery (HAI): their rapid uptake and de toxification by liver cells results in relatively low systemic drugs l evels. This approach increases mean survival duration from 17 to 26 mo nths and, in few patients, causes ''down-staging'' that may result in resectability. To improve opportunities for chemotherapy, the techniqu e of 1-hour recirculating perfusion of the vascularly isolated liver ( isolated hepatic perfusion, IHP) was developed. If leakage to the syst emic circulation is negligible-and the compounds used do not readily c ause hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered systemically. Because alkylating agents generally have s teep dose-response curves, mitomycin C (MMC) and melphalan (L-PAM) ent ered phase I/II studies on IHP. Using these drugs, IHP was performed i n principle as a single procedure in 60 otherwise untreated patients a t our institution. However, despite preliminary data that indicate imp ressive clinical responses are obtained, improvement over HAI will pro bably be minor. Because IHP is a complicated way of drug delivery, one could argue that its use is justified only when it has the potential to kill all tumour cells in the liver. We critically discuss the possi bilities of IHP and/or the use of gene therapy in an IHP setting. (C) 1998 Wiley-Liss, Inc.