Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Uveal melanoma is the most common primary intraocular malignancy in adults. The incidence is highest in Caucasian populations in Europe. The incidence shows a gradient from north to south, decreasing from over eight to nine per million in Scandinavia to less than two per million in the southern European countries.

Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50%of the patients. With the liver being the most common site for metastasis, the median survival for patients with liver metastasis is about six to 12 months, and no treatment has in randomized trials ever been shown to prolong survival. One treatment option is isolated hepatic perfusion.

The principle idea behind this technique is the surgically isolated region of the body and then deliver a high concentration of a chemotherapeutic agent to the tumor while avoiding systemic toxicity. Briefly, the procedure starts with a placement of catheters into the femoral and external jugular veins. The catheters are then connected to an external venal venous bypass pump to allow for shunting of the blood.

When the caval vein is later clamped for the perfusion, a catheter is placed into the caval vein under the liver, and another catheter is placed into the proper hepatic artery. The arterial and caval catheters are then connected to a heart lung machine and the perfusion is started. The liver is heated, and the chemotherapeutic agent Melphalan is then perfused through the liver for 60 minutes.

The liver is rinsed and the procedure ends with the removal of the catheters. Experimental models of isolated hepatic perfusion was originally developed by Ryan and Osman in 1960. The outcome of the first five patients treated with isolated hepatic perfusion was reported.

IHP has been clinically evaluated in several studies, mainly for liver metastasis derived from colorectal cancer, melanoma and neuroendocrine tumors, but also for primary hepatic malignancies for patients with isolated liver metastasis from uveal melanoma. A phase two trial has suggested a 14 month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period, 26 versus 12 months, this patient with Uveal melanoma developed isolated liver metastasis after several years. A CAT scan shows limited disease burden, but it's evident at laparotomy that a patient has more extensive disease than showed by the radiology.

We will now describe the procedure in more detail. It begins with a placement of catheters into the femoral and external jugular veins to allow for venal venous shunting of the blood from the lower to the upper part of the body. When the caval vein is later clamped via the right gonadal vein, a catheter is inserted into the caval vein.

The tip of the catheter is placed retro hepatic above the renal veins, and all retroperitoneal veins from above the renal veins to the diaphragm are ligated, including the right adrenal vein. This patient had three branches of the hepatic artery to deliver via the gastroduodenal artery. A catheter is inserted with its tip into the proper hepatic artery.

The perfusion lines are handed over to the surgeon and the arterial and caval catheters are connected to a heart lung machine. The venal venous shunt is connected to the previously inserted catheters in the femoral and external jugular veins. The caval vein is now clamped, infra hepatic above the renal veins using a tourniquet and supra hepatically between the liver and the diaphragm.

Using a vascular clamp, a tourniquet is placed around the hepato duodenal ligament, including the portal vein and the bile duct, and finally, the hepatic artery is clamped. The temperature of the ingoing blood is measured by placing a thermistor probe directly into the arterial catheter. The temperature in the liver parenchyma is also continuously measured with thermistor probes placed directly into the liver.

The perfusion is started with a flow rate of about 500 to 1200 milliliters per minute. With a target liver temperature of 40 degrees Celsius, a scintillation probe is placed over the pump in the vino venous shunt. A small dose of 10 megal technetium labeled albumin is injected into the systemic circulation and registered by the computer system.

As baseline activity. A tenfold higher dose a hundred megal is then injected into the hepatic perfusion unit. Any leakage from the perfusion circuits will appear as an increase in radioactivity in the systemic circulation measured by the scintillation probe.

When steady state is established and the temperature has reached 40 degrees Celsius, melphalan at a dose of one milligram per kilogram, body weight is injected into the perfusion system, divided into two doses given 30 minutes apart. Temperature flow rate leakage and perfusion pressures are recorded continuously. After 60 minutes, the Perfu eight containing melphalan is emptied from the system and the liver is irrigated with 1000 milliliters of ringer acetate.

Finally, one unit of erythrocytes are added to the phys, eight infused into the liver, and then the perfusion is stopped. The shunts are disconnected and the temperature probes are removed. The catheters are removed, and the gastroduodenal artery and the gonadal vein are ligated.

The abdomen is closed, and finally, the catheters in the femoral and external jugular vein are removed. The outcome of isolated hepatic perfusion for isolated liver metastasis of UIL melanoma has been analyzed retrospectively in a number of series. The perfusion technique and inclusion criteria used in the different studies have varied taken together.

The overall response rate is 61%including a complete response rate of 8%The median survival differs between nine and 24 months with a mortality between zero and 22%The higher mortality reported is from a study analyzing improvements in the technique during several years and reports no mortality in the later years. In an attempt to answer the question as to whether IHP prolonged survival, a register study using the Swedish National Patient Register was carried out. All patients in Sweden with uveal melanoma, liver metastasis were identified and a comparison between patients treated with IHP and the longest surviving patients during the same time period was done.

There was a significant improved survival of 14 months for patients that underwent IHP compared to the control group. In 2013, a phase three study, the scandium trial was launched in Sweden where patients with liver metastasis of uveal melanoma are randomized to isolated hepatic perfusion or best alternative care. No crossover from the best alternative care to isolated hepatic perfusion group is allowed in the trial, whereas patients randomized to isolated hepatic perfusion and then progress can cross over to the best alternative care arm.

The primary endpoint is overall survival at 24 months, hepatic progression-free survival response, serious adverse events, and quality of life being secondary endpoints. The planned is 78 patients during five years. Inclusion criteria include biopsy verified liver metastasis of uveal melanoma, and no evidence of extra hepatic manifestations by PET ct.

No more than 50%of the liver volume should be replaced by two more, and no previous treatment is allowed for the metastatic disease. Isolated hepatic perfusion is a treatment option with a high response rate, acceptable surgical morbidity, and with a potential survival benefit of more than one year. However, there is a need for larger randomized trials to verify the promising results and to more clearly define the role for this treatment modality.