Name: Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma (Video) | JoVE Journal
Uploaded: 2015-01-25T14:00:00.000+00:00
Duration: 9 min 52 s
Description: Learn isolated hepatic perfusion with melphalan for treating liver metastases of uveal melanoma. This surgical technique delivers high-dose chemotherapy directly to the liver while minimizing systemic toxicity.

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5 minutes

Lennart Wiman (photographer) is acknowledged for excellent video recording.

Patients provided&#160;written&#160;informed consent and the study was approved by the Regional Ethical Review Board at the University of Gothenburg.
1. Anesthesia
<ol>
	<li>Set up all the monitoring (ECG, blood pressure cuff) 17.</li>
	<li>Insert an epidural catheter in the lower to mid thoracic level 17.</li>
	<li>Induce anesthesia with Propofol 2 mg/kg, 150 &#181;g of Fentanyl, and Rocuronium 0.6 mg/kg through a previously inserted peripheral venous catheter.</li>
	<li>Preoxygenate and intubate the patient. Maintain anesthesia with Sevoflurane, oxygen and air 17.</li>
	<li>Insert a double lumen central venous catheter and an arterial catheter. Monitor CVP and arterial pressure 17.</li>
</ol>
2. Isolation of the Liver and Cannulation of Vessels
<ol>
	<li>Administer 100 IE/kg of heparin and give antibiotic prophylaxis (e.g., 160 mg of Trimethoprim and 800 mg of Sulfamethoxazole).</li>
	<li>Using the percutaneous Seldinger technique, place a 17 Fr catheter in the femoral vein and a 15 Fr catheter in the external jugular vein 18. Verify the positions of the catheters by fluoroscopy.</li>
	<li>Perform a laparotomy by an L-shaped incision from the xiphoid process down the midline and then extended to a right subcostal incision 19.</li>
	<li>Verify that no extra-hepatic metastases exist in the abdomen by a complete inspection and palpation.
	<ol>
		<li>If any suspicious lesions are found, verify malignancy by frozen section.</li>
		<li>Terminate the procedure if there is evidence of extrahepatic manifestation (periaortal adenopathy, abdominal metastases). Lymphadenopathy in the porta hepatis is not considered a contraindication.&#160;</li>
	</ol>
	</li>
	<li>Mobilize the liver by dividing the falciform ligament, the left and right triangular ligament and the coronary ligament 19.</li>
	<li>Dissect the caval vein beginning from the renal veins up to the diaphragm with ligation of retroperitoneal tributary veins.</li>
	<li>Identify the right adrenal vein and place a vessel loop around it.</li>
	<li>Identify the right gonadal vein. Dissect it for 5-10 cm. Place a purse-string suture around the entrance to the caval vein.
	<ol>
		<li>Place a ligature distally on the gonadal vein. Using scissors, open the gonadal vein 3-5 cm from the caval vein.</li>
		<li>Insert an 18 Fr wire-reinforced catheter through the right gonadal vein and place the tip retrohepatically above the renal veins.</li>
		<li>Place a ligature around the gonadal vein to secure the position of the catheter.</li>
		<li>Verify the return of blood through the catheter. Heparinize the catheter 18.&#160;</li>
	</ol>
	</li>
	<li>Dissect the hepatoduodenal ligament and visualize the common hepatic artery, the gastroduodenal artery and the proper hepatic artery.
	<ol>
		<li>Place vessel loops around the common hepatic artery and the gastrodoudenal artery.</li>
		<li>Dissect the portal vein and place a vessel loop around it.</li>
		<li>Isolate the rest of the ligament containing the common bile duct and include all of this in a vessel loop.&#160;</li>
	</ol>
	</li>
	<li>Lift the gastroduodenal artery with the vessel loop. After interrupting the arterial inflow, make an incision using scissors.
	<ol>
		<li>Insert an 8-12 Fr catheter with its tip into the proper hepatic artery. Secure the position with a ligature around the gastroduodenal artery.</li>
		<li>Verify blood return in the catheter and then heparinize it 18.</li>
	</ol>
	</li>
	<li>Prime the perfusion system with one unit of packed erythrocytes, 100 ml of albumin (50 g/L), 100 ml of Tribonat (sodium bicarbonate), 2500 units of heparin (5,000 IE/ml) and 250 ml of crystalloids.</li>
	<li>Connect the arterial and the caval vein catheters to the perfusion system consisting of a heart lung machine equipped with a roller pump and a heater together with a venous reservoir, oxygenator and tubing systems of disposable type.</li>
	<li>Connect the femoral and external jugular catheters to the venovenous bypass pump consisting of a centrifugal pump, along with a heater unit and start bypass.</li>
	<li>Complete the isolation of the liver by tightening a Rumel tourniquet around the caval vein infrahepatically above the renal veins and clamping the caval vein suprahepatically using a Klintmalm vascular clamp.
	<ol>
		<li>Tighten a Rumel tourniquet around the common bile duct, the portal vein and the right adrenal vein and finally clamp the hepatic artery using a vascular clamp.</li>
	</ol>
	</li>
</ol>
3. The Perfusion
<ol>
	<li>Start the perfusion and manually monitor the blood level in the venous reservoir. Adjust the flow rate until a steady-state level is reached, usually a flow rate between 500-1,200 ml/min.</li>
	<li>Place thermistor probes into the right and left liver lobes and one directly into the arterial catheter.</li>
	<li>Heat the perfusate aiming at a target liver temperature of 40 oC. Keep this temperature throughout the perfusion.</li>
	<li>Place a scintillation probe over the venovenous bypass pump head.</li>
	<li>Calibrate the leakage monitoring system, by injecting a small dose of 10 MBq 99mTc-albumin (1 ml) into the systemic circulation and register the baseline activity.
	<ol>
		<li>Inject a ten-fold higher dose, 100 MBq 99mTc-albumin (1 ml), into the hepatic perfusion unit.</li>
		<li>Record any leakage from the perfusion system to the systemic circulation as an increase in activity measured by the scintillation probe.</li>
		<li>Record any leakage from the systemic circulation to the perfusion system as an increase in volume in the venous reservoir.&#160;</li>
	</ol>
	</li>
	<li>When steady-state of the flow rate is established, no leakage is present and the liver temperature has reached 40 &#176;C, inject melphalan at a dose of 1 mg/kg bodyweight into the perfusion system divided into two doses given 30 min apart.</li>
</ol>
4. End the Perfusion and Remove Catheters
<ol>
	<li>After 60 min of perfusion, empty the perfusate from the system and irrigate the liver with 1,000 ml of crystalloid.</li>
	<li>Add one unit of packed erythrocytes to the perfusion unit, infuse into the liver and then stop the perfusion.</li>
	<li>Release the Klintmalm clamp and the Rumel tourniquet from the caval vein.</li>
	<li>Release the Rumel tourniquet from the hepatoduodenal ligament.</li>
	<li>Remove the ligature from the gastroduodenal artery. Remove the catheter and ligate the vessel.</li>
	<li>Release the clamp from the hepatic artery.</li>
	<li>Remove the catheter from the gonadal vein and ligate the vessel.</li>
	<li>Stop the veno-venous bypass pump and disconnect the tubes.</li>
	<li>Close the abdomen with an uninterrupted fascial suture and then an intracutaneous skin suture.</li>
	<li>Remove the catheters in the femoral and external jugular veins and apply local pressure for 5 min.</li>
</ol>
5. Postoperative Care
<ol>
	<li>Extubate the patient and transfer to postoperative care unit for 24 hr. Keep monitoring central venous pressure and arterial blood pressure.</li>
	<li>Transfer the patient to a surgical department for a typical of 3-7 days of post-operative care.</li>
	<li>Continue with low-molecular weight heparin (LMWH) at a dose of 5,000 IE/day for a total of 4 weeks.</li>
</ol>

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<li>Ausman, R. K., Aust, J. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Isolated+perfusion+of+the+liver+with+HN2%5BTitle%5D)+AND+%22Surgical+Forum%22%5BJournal%5D)">Isolated perfusion of the liver with HN2.</a> Surgical Forum. 10, 77-79 (1960).</li>
<li>Dahl, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Interaction+of+hyperthermia+and+chemotherapy%5BTitle%5D)+AND+%22Recent+results+in+cancer+research.+Fortschritte+der+Krebsforschung.+Progres+Dans+Les+Recherches+Sur+Le+Cancer%22%5BJournal%5D)">Interaction of hyperthermia and chemotherapy.</a> Recent results in cancer research. Fortschritte der Krebsforschung. Progres Dans Les Recherches Sur Le Cancer. 107, 157-169 (1988).</li>
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<li>Rizell, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Isolated+hepatic+perfusion+for+liver+metastases+of+malignant+melanoma%5BTitle%5D)+AND+%22Melanoma+research%22%5BJournal%5D)">Isolated hepatic perfusion for liver metastases of malignant melanoma.</a> Melanoma research. 18 (2), 120-126 (2008).</li>
<li>Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Isolated+hepatic+perfusion+with+200+mg+melphalan+for+advanced+noncolorectal+liver+metastases%5BTitle%5D)+AND+%22Annals+of+Surgical+Oncology%22%5BJournal%5D)">Isolated hepatic perfusion with 200 mg melphalan for advanced noncolorectal liver metastases.</a> Annals of Surgical Oncology. 15 (7), 1891-1898 (2008).</li>
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<li>Sharma, K. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hepatic+arterial+chemoembolization+for+management+of+metastatic+melanoma%5BTitle%5D)+AND+%22AJR.+American+Journal+Of+Roentgenology%22%5BJournal%5D)">Hepatic arterial chemoembolization for management of metastatic melanoma.</a> AJR. American Journal Of Roentgenology. 190 (1), 99-104 (2008).</li>
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<li>Ku, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Extracorporeal+adriamycin-removal+following+hepatic+artery+infusion%3A+use+of+direct+hemoperfusion+combined+with+veno-venous+bypass%5BTitle%5D)+AND+%22Nihon+Geka+Gakkai+Zasshi%22%5BJournal%5D)">Extracorporeal adriamycin-removal following hepatic artery infusion: use of direct hemoperfusion combined with veno-venous bypass.</a> Nihon Geka Gakkai Zasshi. 90 (10), 1758-1764 (1989).</li>
<li>Curley, S. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hepatic+arterial+infusion+chemotherapy+with+complete+hepatic+venous+isolation+and+extracorporeal+chemofiltration%3A+a+feasibility+study+of+a+novel+system%5BTitle%5D)+AND+%22Anti-Cancer+Drugs%22%5BJournal%5D)">Hepatic arterial infusion chemotherapy with complete hepatic venous isolation and extracorporeal chemofiltration: a feasibility study of a novel system.</a> Anti-Cancer Drugs. 2 (2), 175-183 (1991).</li>
<li>Beheshti, M. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Percutaneous+isolated+liver+perfusion+for+treatment+of+hepatic+malignancy%3A+preliminary+report%5BTitle%5D)+AND+%22Journal+of+Vascular+And+Interventional+Radiology+%3A+JVIR%22%5BJournal%5D)">Percutaneous isolated liver perfusion for treatment of hepatic malignancy: preliminary report.</a> Journal of Vascular And Interventional Radiology : JVIR. 3 (3), 453-458 (1992).</li>
</ol>

The authors have nothing to disclose.

Patients with metastatic uveal melanoma have few therapeutic options. Chemotherapy 6, immunotherapy 23 and targeted therapy 24 have not been able to show improved OS. For patients with few liver metastases, liver resection is an option 12. Other treatments include hepatic intra-arterial chemotherapy (HIA) 9, transarterial chemoembolization (TACE) 25 and selective internal radiation therapy (SIRT) 26.
IHP is a major an...

Uveal melanoma is the most common primary intraocular malignancy in adults, with the incidence being highest in Caucasian populations 1. Local treatment consists of enucleation or local plaque radiation therapy 2,3. Irrespective of local treatment, metastatic disease will ultimately develop in about 35-50% of the patients 4,5. The liver is the most common site of metastases and approximately 50% of the patients present with isolated liver metastases. The median overall survival (OS) for patients with liver metastases is 6-12 months 4. Several different systemic and regional treatment strategies have been explored, but survival rates have not improved 2.
Treatment with systemic chemotherapy, both single substance (Dacarbazine or Temozolomide6) or combination treatments (BOLD regimen7, gemcitabine with treosulfan 8), shows response rates of less then 10 %. Hepatic intra-arterial chemotherapy (HIA) has shown a slightly higher overall response rate compared to systemic chemotherapy, but no increase in overall survival 9. Transarterial chemoembolization (TACE) with cisplatin and carboplatin showed a partial response in 57% of patients with a median survival of 9 months10. Selective internal radiation therapy (SIRT) has shown a partial response in 62% of patients with a median survival of 7 months 11. In a study on liver resection, including 255 patients, an overall survival of 14 months was reported; in 76 of the patients where a microscopically complete resection was possible, the survival was 27 months 12.
Isolated hepatic perfusion (IHP) is a regional treatment option, originally developed by Ryan and Ausman. The rationale behind the technique is to surgically isolate and perfuse the liver with a high dose of a chemotherapeutic agent while avoiding systemic toxicity 13. In addition, concurrent hyperthermia mediates an increased uptake of the chemotherapeutic agent by changes in tumor blood flow and cellular membrane permeability 14. Complete vascular isolation is confirmed with a radioactive tracer technique using Tc-99 labeled human serum albumin 15. A retrospective phase II study has shown a potential survival benefit of 14 months (26 vs. 12 months) for patients that underwent IHP compared to the longest survivors with uveal melanoma liver metastases in Sweden 16.
Here we present the technique of IHP with a short review of current results and future perspectives.

<table><tbody><tr><td>Wire re-inforced catethers</td><td>Medtronic Inc, Minnesota, USA</td><td></td><td>12-18Fr</td></tr><tr><td>St&amp;ouml;ckert S5</td><td>Sorin Group, Mirandola, Italy</td><td></td><td>Heart-lung machine</td></tr><tr><td>Rotaflow</td><td>Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany</td><td></td><td>Centrifugal pump</td></tr><tr><td>HU 35</td><td>Maquet cardiopulmonary AG, Hirrlingen, Germany</td><td></td><td>Heater unit</td></tr><tr><td>Flexbumin 200 g/l</td><td>Baxter Medical AB, Kista, Sweden</td><td></td><td></td></tr><tr><td>Tribonat</td><td>Fresenius Kabi AB, Uppsala, Sweden</td><td></td><td></td></tr><tr><td>Heparin LEO, 5000 IE/ml</td><td>LEO Pharma AB, Sweden</td><td></td><td></td></tr><tr><td>Ringer Acetate</td><td>Baxter Medical AB, Kista, Sweden</td><td></td><td></td></tr><tr><td>Vasculosis</td><td>Cis-Bio International, Gif-Sur-Yvette, France</td><td></td><td>99mTc-albumin</td></tr><tr><td>MedicView</td><td>SystemData AB, Gothenburg, Sweden</td><td></td><td>Leakage monitoring system</td></tr><tr><td>Alkeran</td><td>Aspen Europe GmbH, Bad Oldesloe, Germany</td><td></td><td>melphalan</td></tr></tbody></table>

isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma

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

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

An initial report included 22 patients treated with melphalan with or without TNF-alpha. The results showed an overall response rate of 62%, including two patients with CR (10%), and a median overall survival of 11 months 20. A subsequent study reported on the outcome of 29 consecutive patients treated using melphalan alone. The outcome was very similar with a 62% overall response including 10% complete response and a median survival of 12 months 21.
In a study by Rizell ...

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.

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

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.

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