| Title | Isolated hepatic perfusion for treatment of liver metastases: optimization and efficacy-testing of a novel, percutaneously applicable perfusion technique (PIHP) |
|---|---|
| Period | 2000 - 12 / 2004 |
| Status | Completed |
| Research number | OND1275144 |
| Background: Isolated hepatic perfusion (IHP) is an experimental surgical technique to treat patients with non-resectable metastases from colorectal cancers (and other tumor types) confined to the liver. Data obtained from phase I/II studies with the alkylating drug melphalan, performed at the Leiden University Medical Center (LUMC), show that this procedure can lead to a significant anti-tumor response and to a median life expectancy of 28 months (being approximately 11 months in case of systemic treatment) with relatively high quality of life. However, IHP is an invasive and technically difficult, not repeatable operation that cannot be performed on a routine basis. As the results are encouraging, interest exists to develop percutaneously applicable IHP procedures. Recently, a minimally invasive procedure has been proposed in which the liver is perfused under hypoxic conditions. An entirely different strategy is being developed in a collaborative effort of the University of Malmö (Sweden), the LUMC and the Netherlands Cancer Institute/Antonie van Leeuwenhoek Hospital (NKI/AvL). In this approach the vena cava is occluded at the level of the hepatic veins. Instead of using the hepatic veins as outflow tract for the perfusion, the flow is diverted through arteria-portal/ arteria-venous collaterals to the vena portae. By placing a suction catheter transhepatically in the vena portae it is possible to use the porta as the outflow channel. Preclinical pilot studies performed in pigs and rats in Malmö and Leiden show that: 1) it is technically feasible to perfuse the liver parenchyma with adequate flow rates by occluding the inferior vena cava and using the vena porta as outflow channel; 2) this zone 1-restricted perfusion does not lead to reduced melphalan uptake in experimental liver metastases, but improves the tumor/liver ratio; 3) this IHP can be performed percutaneously. Objectives: The primary objective of our research, performed in close collaboration with the Malmö group, is the further development and efficacy-testing of this potentially more versatile, percutaneously applicable IHP procedure (PIHP). IHP can be used both for drug delivery and to achieve a selective increase in temperature of the perfused tissues. A secondary objective is therefore to investigate whether the application of hyperthermia (HT) increases tumor responses of melphalan. Plan of investigation: Experiments in pigs and rats will be performed in preparation for a phase I clinical study. 1. The pig model: (i) Two different catheter perfusion systems will be tested, one with and one without portal decompression, in order to gain experience with flow rates and pump settings. The basis for testing will be the catheter system that has already been developed by the Malmö group. For each of the flow settings/catheter configurations perfusate leakage into the systemic circulation will be monitored. (ii) PIHP with melphalan will be performed to determine the extent of post-PIHP melphalan leakage into the systemic circulation and, if necessary, to test a strategy aimed at reducing this leakage. (iii) The pig model will be used as a training model for the team of perfusionist/radiologist and surgeon in preparation for the clinical studies. 2. The rat model (liver metastases induced by subcapsular grafting of CC531 colorectal cancer cells): This will be used to evaluate toxicity parameters and anti-tumor effects comparing (i) the old and the new perfusion scheme; (ii) in the new perfusion scheme: (a) normothermic with hyperthermic and (b) hypoxic with oxygenized IHP. (iii) If hepatotoxicity proves to be a problem: to investigate the extent of HT-induced oxidative stress and the capacity of desferrioxamine, allopurinol, glutathione (GSH) and L-2-oxothiazolidine-4-carboxylate (OTC) to reduce these toxicities without compromising tumor cell kill. 3.The clinical studies: Based on data from the rat model we will choose (i) either oxygenized or hypoxic conditions and (ii) whether or not to pursue with HT. After a phase I dose-escalating PIHP study we may continue with a phase I temperature-escalating study with reduced melphalan doses or directly with a phase II study with the MTD melphalan. If hyperthermic PIHP with melphalan proves to be an interesting option, and having established an optimal melphalan dose/temperature combination based on tumor response (serum CEA, liver CT scans), we will start a phase II study on the efficacy of hyperthermic PIHP with melphalan. In the phase II study, the PIHP procedure will be repeated in the same patient in case of recurrence. Survival data will be compared with data from the current study on surgical IHP. Possible results: PIHP will be considerably less invasive than the surgical IHP procedure, with the advantage of repeatability in the same patient, higher cost-effectiveness, and applicability in a broader group of patients (other primaries than colorectal cancer) and in different treatment modalities (including those based on gene transfer). |
| Secretariat | Leiden University Medical Center - LUMC (UL) |
|---|---|
| Financier | Dutch Cancer Society |
| Project leader | Dr. J.H. van Dierendonck |
|---|---|
| Project leader | Prof.dr. G.J. Mulder |
| Project leader | Prof.dr. L.J. Schultze Kool |
| A70000 | Public health and health care |
|---|---|
| D21200 | Biophysics, clinical physics |
| D23120 | Oncology |
| D23220 | Internal medicine |
| D23340 | Biopharmacology, toxicology |
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