Phase I/II study of oxaliplatin combined with melphalan in isolated hepatic perfusion for the treatment of liver metastases.

In the Netherlands 8400 patients are diagnosed with colorectal cancer each
year. Approximately 50% of these patients develop liver metastases. If these
metastases are confined to the liver, complete surgical resection is possible
in 25% of patients, resulting in a median survival of 32-46 months. In 75% of
the patients with metastases confined to the liver, resection is impossible due
to size or localization of metastases. For these patients systemic chemotherapy
remains the only treatment option. One of the major drawbacks of systemic
treatmentis that the maximum tolerable dose has been achieved before the
minimal active dose has been adminstered. To improve results in patients with
irresectable liver metastases, isolated hepatic perfusion (IHP) has been
developed. In the past years melphalan, a relatively old drug, has been the
only drug applied in IHP. In systemic chemotherapy, on the other hand, several
new agents, including oxaliplatin have been introduced succesfully. Oxaliplatin
is rapidly absorbed and transformed to its active form. In studies where
oxaliplatin is administered systemically hepatotoxicity is raley mentioned. In
vitro studies have shown a schedule dependent synergistic interaction between
melphalan and oxaliplatin.

Firstly, determination of the maximum tolerated dose (MTD) , dose limiting
toxicity (DLT) and farmacokinetics in IHP with sequential administration of
oxaliplatin and melphalan.
Secondly, evaluation of toxicity, tumor response and survival after IHP with
sequential administration of oxaliplatin and melphalan at the MTD previously
determined.

This is a singlecenter, combined phase I/I study. Patients who are eligable
for this study will be treated once with a escalating dose of oxaliplatin
combined with melpalan untill the maximum tolerated dose (MTD) and dose
limiting toxicity (DLT) have been achieved. After which another 40 patients
will be treated with the MTD. Treatment will be evaluated at a 3 month interval
(6 month interval after 1 year) thruogh CT-scans untill progression of liver
disease has occured.

Single isolated hepatic perfusion with an escalating dose of oxaliplatin
(initial dose 50mg, with 50mg incease each escalation) for 30 minutes, followed
by 30 minutes perfusion with 100mg melphalan.

Patients will undergo a full medical examination. Laboratory testing, CT scans
of thorax and abdomen will be performed as to establish extent of disease and
operability.
The risks of IHP are either associated to the surgical procedure (dissection,
bleeding, infection, etc), similar to the standard procedure, or are the risks
(both liver toxicity and systemic toxicity) associated to the administration of
oxaliplatin and melphalan (see also page 22-23 of the study protocol).
After perfusion patients will undergo laboratory testing en imaging (CT scan)
every three months untill liver progression occurs.