Fase I/II trial with melphalan for percutaneous chemosaturation (CS-PHP-Mephalan) in treating irresectable liver metastases

Malignancies of the liver are the third most important cause of cancer-related
deaths in the world. This kind of cancer can be primary (origin in the liver)
of secondary (metastases from another part of the body). The most common form
of primary liver cancer is the hepatocellular carcinoma (HCC) en the most
common form of secondary liver cancer are metastases of colorectal carcinoma
(CRCLM). About 30-50% of all patients with colorectal cancer, develop liver
metastases synchronous: 14.5-25%, metachronous: 14.5-25%).
Patients with liver metastases of colorectal carcinoma often have a bad
prognosis, and for these patients surgical resection is the only curative
option, despite the constant innovations in chemotherapy. The surgical
treatment offers an acceptable morbidity, mortality and the 5-year survival is
around 40-50%. Unfortunately only 20-25% of the patients with CRCLM qualify for
surgery. The other patients can only be treated with chemotherapy. A part of
the patients treated with chemotherapy and with initially irresectable
metastases, become operable because of the response to chemotherapy. The
disadvantage of systemic administration of chemotherapy in the treatment of
liver metastases is that, because of systemic toxicity, the maximum tolerated
dose is reached earlier than the minimum effective dose. To accomplish better
results with patients with irresectable metastases confined to the liver,
isolated hepatic perfusion ( IHP) has been developed. The principle of IHP is
to shut the liver off of the systemic circulation by performing an operation.
Subsequently the liver is flushed for an hour with a very high dose of
chemotherapy, which would be toxic and lead to fatal complications when
administered systemic. Then the liver is connected to the systemic circulation
again. Because this procedure is associated with considerable morbidity (20%)
and mortality (7%), a new procedure was developed by Delcath in which the
hepatic perfusion can be performed percutaneous. Expected is that both
morbidity and mortality will decrease significantly. In addition, this
procedure can be performed several times.

Primary objective
* To determine the overall response rate of two PHP with an interval of at
least 6 weeks and 3 mg/kg melphalan in irresectable liver metastases patients.
* To determine the percentage of patients qualifying for resection.
Secondary Objective
* To assess safety of PHP using the Generation 2nd Delcath system in patients
with irresectable liver metastases.
* To determine the overall survival and overall progression free survival
* To determine the duration of response and duration of stable disease
* To determine the quality of life after two percutaneous liver perfusions.

When all inclusion and exclusion criteria are met, a percutaneous hepatic
perfusion will be performed twice, with a at least 6 week interval between the
first and the second procedure.

When all inclusion and exclusion criteria are met, a percutaneous hepatic
perfusion will be performed twice, with an at least 6 week interval between the
first and the second procedure. The perfusion procedure is extensively
described in the protocol.

Instead of systemic chemotherapeutics, the patients receives isolated hepatic
perfusion twice, and one angiography.
This treamtent constists of less day admited in hospital, and no systemic
effect of chemotherapeutics.