Name: percutaneous hepatic perfusion (php) with melphalan as a treatment for unresectable metastases confined to the liver
Uploaded: 2016-07-31T14:00:00
Description: Watch this Scientific Journal Video about Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver at JoVE.com

The authors have no acknowledgements. 
The phase II study is financially supported by Delcath Systems.

Note: After a patient met all inclusion criteria and was carefully evaluated by a medical oncologist, surgeon and anaesthesiologist, a patient was included in the study. All patients provided written informed consent. Both clinical studies were approved by the Local Medical Ethics Committee of the Leiden University Medical Centre and are performed in accordance with the ethical standards of the Helsinki Declaration.
1. Pre-procedural Angiography by Interventional Radiologist
<ol>
	<li>In pre...

<ol>
	<li>Jovanovic, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ocular+melanoma:+an+overview+of+the+current+status.">Ocular melanoma: an overview of the current status.</a> Int J Clin Exp Pathol. 6 (7), 1230-1244 (2013).</li><li>Taylor, I., Bennett, R., Sherriff, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+blood+supply+of+colorectal+liver+metastases.">The blood supply of colorectal liver metastases.</a> Br J Cancer. 38 (6), 749-756 (1978).</li><li>van de Velde, C. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+successful+technique+of+in+vivo+isolated+liver+perfusion+in+pigs.">A successful technique of in vivo isolated liver perfusion in pigs.</a> J Surg Res. 41 (6), 593-599 (1986).</li><li>Vahrmeijer, A. L., Der Eb, M. M. V. a. n., Van Dierendonck, J. H., Kuppen, P. J., Van De Velde, C. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Delivery+of+anticancer+drugs+via+isolated+hepatic+perfusion:+a+promising+strategy+in+the+treatment+of+irresectable+liver+metastases?.">Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy in the treatment of irresectable liver metastases?.</a> Semin Surg Oncol. 14 (3), 262-268 (1998).</li><li>Vahrmeijer, A. L., van de Velde, C. J., Hartgrink, H. H., Tollenaar, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+melanoma+metastases+confined+to+the+liver+and+future+perspectives.">Treatment of melanoma metastases confined to the liver and future perspectives.</a> Dig Surg. 25 (6), 467-472 (2008).</li><li>Ben-Shabat, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+as+a+treatment+for+liver+metastases+of+uveal+melanoma.">Isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma.</a> J Vis Exp. (95), e52490 (2015).</li><li>Vahrmeijer, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increased+local+cytostatic+drug+exposure+by+isolated+hepatic+perfusion:+a+phase+I+clinical+and+pharmacologic+evaluation+of+treatment+with+high+dose+melphalan+in+patients+with+colorectal+cancer+confined+to+the+liver.">Increased local cytostatic drug exposure by isolated hepatic perfusion: a phase I clinical and pharmacologic evaluation of treatment with high dose melphalan in patients with colorectal cancer confined to the liver.</a> Br J Cancer. 82 (9), 1539-1546 (2000).</li><li>Rothbarth, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+high-dose+melphalan+for+the+treatment+of+colorectal+metastasis+confined+to+the+liver.">Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver.</a> Br J Surg. 90 (11), 1391-1397 (2003).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+200+mg+melphalan+for+advanced+noncolorectal+liver+metastases.">Isolated hepatic perfusion with 200 mg melphalan for advanced noncolorectal liver metastases.</a> Ann Surg Oncol. 15 (7), 1891-1898 (2008).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+melphalan+perfusion+of+colorectal+liver+metastases:+outcome+and+prognostic+factors+in+154+patients.">Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients.</a> Ann Oncol. 19 (6), 1127-1134 (2008).</li><li>Alexander, H. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+I-II+study+of+isolated+hepatic+perfusion+using+melphalan+with+or+without+tumor+necrosis+factor+for+patients+with+ocular+melanoma+metastatic+to+liver.">A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver.</a> Clin Cancer Res. 6 (8), 3062-3070 (2000).</li><li>Olofsson, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+for+ocular+melanoma+metastasis:+registry+data+suggests+a+survival+benefit.">Isolated hepatic perfusion for ocular melanoma metastasis: registry data suggests a survival benefit.</a> Ann Surg Oncol. 21 (2), 466-472 (2014).</li><li>Curley, S. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increased+doxorubicin+levels+in+hepatic+tumors+with+reduced+systemic+drug+exposure+achieved+with+complete+hepatic+venous+isolation+and+extracorporeal+chemofiltration.">Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration.</a> Cancer Chemother Pharmacol. 33 (3), 251-257 (1993).</li><li>Ravikumar, T. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+hepatic+vein+isolation+and+high-dose+hepatic+arterial+infusion+chemotherapy+for+unresectable+liver+tumors.">Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors.</a> J Clin Oncol. 12 (12), 2723-2736 (1994).</li><li>Lillemoe, H. A., Alexander, H. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Current+Status+of+Percutaneous+Hepatic+Perfusion+as+Regional+Treatment+for+Patients+with+Unresectable+Hepatic+Metastases:+A+Review.">Current Status of Percutaneous Hepatic Perfusion as Regional Treatment for Patients with Unresectable Hepatic Metastases: A Review.</a> Am Oncology and Hematology Rev. (15-23), (2014).</li><li>Pingpank, J. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Phase+I+study+of+hepatic+arterial+melphalan+infusion+and+hepatic+venous+hemofiltration+using+percutaneously+placed+catheters+in+patients+with+unresectable+hepatic+malignancies.">Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.</a> J Clin Oncol. 23 (15), 3465-3474 (2005).</li><li>Fitzpatrick, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Use+of+partial+venovenous+cardiopulmonary+bypass+in+percutaneous+hepatic+perfusion+for+patients+with+diffuse,+isolated+liver+metastases:+a+case+series.">Use of partial venovenous cardiopulmonary bypass in percutaneous hepatic perfusion for patients with diffuse, isolated liver metastases: a case series.</a> J Cardiothorac Vasc Anesth. 28 (3), 647-651 (2014).</li><li>Forster, M. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusion+for+unresectable+metastatic+melanoma+or+sarcoma+to+the+liver:+a+single+institution+experience.">Chemosaturation with percutaneous hepatic perfusion for unresectable metastatic melanoma or sarcoma to the liver: a single institution experience.</a> J Surg Oncol. 109 (5), 434-439 (2014).</li><li>Deneve, J. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusion+for+unresectable+isolated+hepatic+metastases+from+sarcoma.">Chemosaturation with percutaneous hepatic perfusion for unresectable isolated hepatic metastases from sarcoma.</a> Cardiovasc Intervent Radiol. 35 (6), 1480-1487 (2012).</li><li>Kandarpa, K., Machan, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Handbook of Interventional Radiologic Procedures. , 269-270 (2011).</li><li>Hofmann, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Unresectable+isolated+hepatic+metastases+from+solid+pseudopapillary+neoplasm+of+the+pancreas:+a+case+report+of+chemosaturation+with+high-dose+melphalan.">Unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas: a case report of chemosaturation with high-dose melphalan.</a> Pancreatology. 14 (6), 546-549 (2014).</li><li>Miao, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+hepatic+perfusion+in+patients+with+metastatic+liver+cancer:+anesthetic,+hemodynamic,+and+metabolic+considerations.">Percutaneous hepatic perfusion in patients with metastatic liver cancer: anesthetic, hemodynamic, and metabolic considerations.</a> Ann Surg Oncol. 15 (3), 815-823 (2008).</li><li>Vogl, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemosaturation+with+percutaneous+hepatic+perfusions+of+melphalan+for+hepatic+metastases:+experience+from+two+European+centers.">Chemosaturation with percutaneous hepatic perfusions of melphalan for hepatic metastases: experience from two European centers.</a> Rofo. 186 (10), 937-944 (2014).</li><li>Pingpank, J. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+III+random+assignment+trial+comparing+percutaneous+hepatic+perfusion+with+melphalan+(PHP-mel)+to+standard+of+care+for+patients+with+hepatic+metastases+from+metastatic+ocular+or+cutaneous+melanoma.">A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma.</a> J Clin Oncol. 28, 18s (2010).</li><li>Rothbarth, J., Vahrmeijer, A. L., Mulder, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modulation+of+cytostatic+efficacy+of+melphalan+by+glutathione:+mechanisms+and+efficacy.">Modulation of cytostatic efficacy of melphalan by glutathione: mechanisms and efficacy.</a> Chem Biol Interact. 140 (2), 93-107 (2002).</li><li>Bartlett, D. L., Libutti, S. K., Figg, W. D., Fraker, D. L., Alexander, H. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+for+unresectable+hepatic+metastases+from+colorectal+cancer.">Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer.</a> Surgery. 129 (2), 176-187 (2001).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hepatic+perfusion+with+oxaliplatin+combined+with+100+mg+melphalan+in+patients+with+metastases+confined+to+the+liver:+A+phase+I+study.">Isolated hepatic perfusion with oxaliplatin combined with 100 mg melphalan in patients with metastases confined to the liver: A phase I study.</a> Eur J Surg Oncol. , (2014).</li><li>Rothbarth, J., Tollenaar, R. A., van de Velde, C. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+trends+and+future+perspectives+in+isolated+hepatic+perfusion+in+the+treatment+of+liver+tumors.">Recent trends and future perspectives in isolated hepatic perfusion in the treatment of liver tumors.</a> Expert Rev Anticancer Ther. 6 (4), 553-565 (2006).</li><li>van Etten, B., de Wilt, J. H., Brunstein, F., Eggermont, A. M., Verhoef, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isolated+hypoxic+hepatic+perfusion+with+melphalan+in+patients+with+irresectable+ocular+melanoma+metastases.">Isolated hypoxic hepatic perfusion with melphalan in patients with irresectable ocular melanoma metastases.</a> Eur J Surg Oncol. 35 (5), 539-545 (2009).</li><li>van Iersel, L. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+isolated+nonresectable+liver+metastases+in+colorectal+cancer+patients:+a+case-control+study+of+isolated+hepatic+perfusion+with+melphalan+versus+systemic+chemotherapy.">Management of isolated nonresectable liver metastases in colorectal cancer patients: a case-control study of isolated hepatic perfusion with melphalan versus systemic chemotherapy.</a> Ann Oncol. 21 (8), 1662-1667 (2010).</li></ol>

Patients with unresectable liver metastases can be treated with systemic therapy. However, for patients with metastatic uveal melanoma, no standard systemic therapy is available and immunotherapy or targeted therapy have not yet been able to show improved survival. Isolated hepatic perfusion has been shown to be an effective treatment for patients with unresectable uveal melanoma metastases confined to the liver.9,28 For colorectal cancer metastases more therapeutic systemic options are available, but some pat...

Resection of malignant liver tumors is the first choice of treatment for both primary and secondary hepatic malignancies. However, a large proportion of patients are not candidates for surgery because of extended disease or location of the metastases. For patients with unresectable metastases from colorectal carcinoma, systemic therapy is often the preferred treatment. Hepatic metastases from uveal melanoma are often small and diffusely spread throughout the liver. No standard systemic therapy is available for this group of patients. Local therapy can be an alternative to systemic treatment, in case the metastases are confined to the liver.
Because of the specific vascular anatomy of the liver, this organ can be isolated from the systemic circulation. This allows perfusion of the liver with high dose chemotherapy (IHP, isolated hepatic perfusion). Besides, liver malignancies have a dominant or exclusive vascular supply from the hepatic artery, whereas 70-80% of the supply of the non-tumorous liver parenchyma is derived from the portal vein.1,2 This technique was developed over twenty years ago, to treat patients with unresectable metastases from various primary origins.3,4 Especially, uveal melanoma patients with metastases in the liver may be candidates for IHP because the metastases are often small and spread throughout the entire liver, and at present no standard systemic therapy is available.5,6
The principle of IHP is to temporarily isolate the liver from the systemic circulation and perfuse the organ with a high dose of chemotherapy, leading to high local drug exposure with limited systemic side effects.7 This high dose of chemotherapy would be toxic and lead to complications when administered systemically. The majority of IHP studies were performed with melphalan, and have investigated treatment of hepatic metastasis from colorectal cancer patients, as well as patients with uveal melanoma metastases.8,9 Several studies of IHP during open surgery suggest that this treatment might be effective: 50-59% tumor response rates (partial and complete response) for the treatment of colorectal cancer and a 68% tumor response rate for patients with metastatic uveal melanoma have been reported.8,10,11,12 Despite these treatment results, this procedure never gained wide acceptance, because of the complexity of the procedure, the duration of hospital stay and the associated morbidity and mortality.
Percutaneous hepatic perfusion (PHP) offers a minimal invasive alternative to IHP and was first demonstrated in a porcine model in 1993 using doxorubicin13 and the first in human trial was performed by Ravikumar et al. in 1994.14 Due to lack of evidence of efficacy, the technique was largely abandoned until the early 2000&#39;s when it was re-evaluated in the National Cancer Institute (NCI) in the United States.15 During PHP, a catheter is placed percutaneous into the proper hepatic artery via the femoral artery to infuse the chemotherapeutic agent. A second catheter is placed in the inferior caval vein via the femoral vein to aspirate the hepatic chemosaturated outflow (see the PHP circuit in Figure 1). The isolation aspiration catheter placed in the caval vein is a double balloon catheter, prohibiting leakage into the systemic circulation. The aspirated chemosaturated blood is filtered by a double charcoal filter and returned to the patient by a third catheter placed in the internal jugular vein. The patient is admitted in the hospital with a length of stay of ~3 days. The PHP procedure is performed in an angiography room under general anaesthesia by a well-trained multidisciplinary team consisting of a dedicated interventional radiologist, anaesthesiologist and an extracorporeal perfusionist. A surgical oncologist and medical oncologist are also members of this multidisciplinary team, and especially focus on informing the patient, patient selection and post-operative care.
<img alt="Figure 1" src="/files/ftp_upload/53795/53795fig1.jpg" /> 
Figure 1. Schematic image of the PHP circuit. This figure displays the set-up of the PHP circuit. It shows an isolated hepatic perfusion circuit with extra-corporeal bypass line. <a href="https://www.jove.com/files/ftp_upload/53795/53795fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
This minimal invasive procedure is associated with less operative morbidity and can be repeated several times (at least up to 4 times). Besides, it only takes approximately 3 to 4 hr&#160;and patient recovery is fast. The advantage of PHP is the fact that all sizes of metastases can be treated, and micro metastases are being treated as well. Also the location of the metastases, close to vascular structures and bile ducts, is not a contraindication for PHP. Initial studies were performed with the 1st generation filter, with a 77% (mean) filter extraction efficiency.16 Recently, the results of a phase III trial were published by Hughes et al. showing a significant improvement of hepatic progression free survival in uveal melanoma patients with hepatic metastases treated with PHP compared to best alternative care.17
Since April 2012 a 2nd generation filter is available. In pre-clinical studies the 2nd generation filter is extracting 98% of melphalan. Several studies and case series investigating PHP for multiple indications have been published, but apart from the recent publishing phase III trial, survival has not extensively been analysed.16,18,19,20 In the present investigation, we focus on the interventional radiology procedure, as well as the anaesthetic management and the extra corporeal circulation that is used during this procedure in order to facilitate the use of this treatment in other medical centers.

<table border="0" cellpadding="0" cellspacing="0" width="1115">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:411px;">Delcath 2nd Generation Hepatic CHEMOSAT Delivery System&#160;</td>
			<td style="width:357px;">Delcath Systems Inc., New York, New York, USA</td>
			<td style="width:180px;">602001 and 602002</td>
			<td style="width:167px;">Item no. 1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Isofuse Isolation Aspiration Catheter (Double Balloon Catheter)</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
			<td rowspan="2">Item no. 1a</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">10F Venous Return Catheter</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Hemofiltration Cartridges</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
			<td rowspan="2">Item no. 1b</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Circuit components</td>
			<td>Delcath Systems Inc., New York, New York, USA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Level-1 rapid fluid management system</td>
			<td style="width:357px;">Smiths Medical</td>
			<td style="width:180px;"></td>
			<td>Item no. 2</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;">22G arterial line&#160;</td>
			<td style="width:357px;">Arrow International Inc. /&#160; Teleflex Inc.,Dublin, Ireland</td>
			<td style="width:180px;"></td>
			<td>Item no. 3</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Vigileo, Monitor</td>
			<td>Edwards Lifesciences Corp, Irvine, California, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 4</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">7.5F Triple lumen intravenous catheter, 20 cm&#160;</td>
			<td>Vygon, Valkenswaard, Nederland</td>
			<td></td>
			<td>Item no. 5</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">5F sheath&#160;</td>
			<td style="width:357px;"></td>
			<td style="width:180px;"></td>
			<td>Item no. 6</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">2.7 Progreat microcatheter&#160;</td>
			<td>Terumo, Tokyo, Japan</td>
			<td>MC-PP27131</td>
			<td>Item no. 7</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">18F sheath&#160;</td>
			<td style="width:357px;"></td>
			<td style="width:180px;"></td>
			<td>Item no. 8</td>
		</tr>
		<tr height="84">
			<td height="84" style="height:84px;">Auto-injector Medrad Mark V ProVis</td>
			<td>Bayer, Indianola, Pennsylvania, USA</td>
			<td style="width:180px;">Not available anymore, replaced by&#160;Medrad&#160;Mark 7 Arterion&#160;Injection System</td>
			<td>Item no. 9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Melphalan</td>
			<td>Alkeran, Aspen Pharmacare, Dublin, Ireland</td>
			<td style="width:180px;"></td>
			<td>Item no. 10</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Heparin LEO, 5000 IE/ml</td>
			<td style="width:357px;">LEO Pharma AB, Denmark</td>
			<td style="width:180px;"></td>
			<td>Item no. 11</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Centrifugal pump</td>
			<td style="width:357px;">Medtronic, Minneapolis, Minnesota, VS</td>
			<td style="width:180px;"></td>
			<td>Item no. 12</td>
		</tr>
		<tr height="21">
			<td colspan="2" height="21" style="height:21px;">Voluven colloid solution (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection)</td>
			<td style="width:180px;"></td>
			<td>Item no. 13</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Iopromide 300, Ultravist</td>
			<td style="width:357px;">Bayer, Indianola, Pennsylvania, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 14</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Detachable coil, Interlock</td>
			<td style="width:357px;">Boston Scientific, Marlborough, Massachusetts, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 15</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:411px;">Vascular plug, Amplatzer 4</td>
			<td style="width:357px;">St. Jude Medical, St Paul,Minnesota, USA</td>
			<td style="width:180px;"></td>
			<td>Item no. 16</td>
		</tr>
	</tbody>
</table>

percutaneous hepatic perfusion (php) with melphalan as a treatment for unresectable metastases confined to the liver

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Knowledge about PHP is based on small phase I and II trials and case series and a recent larger phase trial III; an overview of published results is shown in Table 1. One paper discusses the anaesthesiology procedure, hemodynamic and metabolic aspects of the treatment. However, no survival data were reported.22 Three larger trials that were reported, included metastatic liver disease from different primary tumors and the results are therefore difficult to inter...

Watch this Scientific Journal Video about Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver at JoVE.com

Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

In this manuscript, we describe percutaneous isolated hepatic perfusion with simultaneous chemofiltration as treatment for unresectable liver metastases. This procedure is performed under general anaesthesia in the angiosuite by an experienced team, consisting of an interventional radiologist, a clinical perfusionist and anaesthesiologist.

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn ...

The overall goal of this procedure is to carry out Percutaneous Hepatic Perfusion to treat unresectable metastases confined to the liver. The main advantage of this technique is that it allows delivery of a high dose of chemotherapeutic agents to the liver with limited systemic exposure. It is minimally invasive, and therefore associated with low mobility and mortality rates.And finally, an advantage is that it can be repeated. Demonstrating the procedure will be Christian Martini, the anesthesiologist, and Fred Tijl, the perfusionist. In preparation for the PHP procedure, perform a pre-procedural angiography several days prior to PHP, according to the text protocol.On the day of the PHP procedure, have the extracorporeal profusionist, or ECP, collect the chemo saturation tubing pack, chemo filters, and the centrifugal pump as provided by the manufacturer. With carbon dioxide gas, flush the complete extracorporeal circuit. Then, use 0.9%sodium chloride and heparin to prime the circuit, including the filters.Allow six liters of heparinized 0.9%sodium chloride to rinse the extracorporeal system initially through the force of gravity. Then after the carbon filters are fully hydrated, use the centrifugal pump to apply more pressure to the filter to remove the remaining gas bubbles. After the anesthesiologist prepares the patient according to the text protocol, have the interventional radiologist or IR, use ultrasound to place a 7.5F triple lumen, 27 centimeter intravenous catheter in the left internal jugular vein, or IJV.Next, place a 10F venous return catheter in the right IJV, and insert a 5F sheathe into the left common femoral artery, or CFA. Using eight to 10F and 12 to 14F dilaters, perform a serial dilation of the right common femoral vein, or CFV, using the dilaters to adjust the insertion opening to the correct size. Then insert an 18F sheathe that will be used to introduce the double balloon catheter.Check the blood pressure of the patient. Following the administration of heparin and after starting norepinephrine and phenylephrine according to the text protocol, through the 5F sheathe in the left CFA, introduce the 2.7F micro catheter coaxially, and with angiography monitoring, insert it into the proper hepatic artery or lobar arteries. Attach filters and pump to the sheathe in the jugular vein BIJECP.Through the 18F sheathe and the right CFV, introduce the 16F double balloon catheter or isolation aspiration catheter, and via the angiography monitor, place it with the tip in the right atrium. Attach the extracorporeal filter system to the balloon catheter. Fill the extracorporeal system with the patient's blood.Next, start the centrifugal pump per the manufacturer's instructions. And after intravenous infusion of 0.5 liters of colloid solution, use a 50%saline, 50%contrast medium mixture to inflate the cranial balloon. Monitor the blood pressure by anesthesiologist and radiologist, for a decrease in blood pressure is likely after inflation of the cranial balloon.Then with the coddled balloon still deflated, slowly retract the double balloon catheter until the cranial balloon is at the junction of the right atrium and the inferior caval vein or ICV, just above the right hepatic vein. The balloon will now be wedge shaped. Using a solution of 90%saline and 10%contrast medium, inflate the coddled balloon until the lateral edges start to become effaced by the ICV.To use phonography to check the position of the balloons and to check for leaks, by hand, inject 20 milliliters of contrast through the fenestration port of the venous double balloon catheter. Check the position of the balloons by retrograde injection of contrasts through the fenetrated double balloon catheter. When sufficient flows and pressures have been reached according to the text protocol, open the filters one by one.Then, when a systolic blood pressure between 140 and 160 milliliters of mercury has been reached, close the bypass line. Attach the melphalan into the injector and load the pump. Be aware of a drop in blood pressure.After performing another venography to check positioning of the double balloon, perform an angiogram by injecting contrast through the micro catheter in the hepatic artery to rule out arterial spasm. When a steady flow rate is established, no leakage is present, and the patient's blood pressure is stable, use an auto-injector to administer 100 milliliters of three milligrams per kilogram of melphalan into the proper hepatic artery or sequentially into both lobar arteries at a rate of 0.4 ccs per second. Following the 30 minutes of chemotherapeutic infusion, continue hemofiltration for an additional 30 minute washout period.After complete infusion, a 30 minute washout time follows. After the washout period, slowly deflate the double cava balloons. Then empty the extracorporeal circuit as much as possible before stopping the extracorporeal perfusion.Remove the double balloon catheter and the infusion micro catheter, but leave the access sheathes in place until coagulation is normalized. Place a vascular closure device in the common femoral artery if desired, to achieve hemostasis. Finally, close and remove the bypass circuit, stabilize the patient, and carry out post-operative care according to the text protocol.Shown here is an overview of small case one and two trials, and a case series for PHP. The first manuscript was published in 1994 and 5-FU and doxorubin were used. Published overall response rates varied between 30 and 90%and survival data were not reported.A recent phase three trial comparing PHP to best alternative care, or BAC, for patients with hepatic metastases of uveal melanoma reports significant improved hepatic progression-free survival of seven months, compared to 1.6 months for the group that received BAC. Once mastered, this procedure can be performed in three to four hours if performed properly. When attempting percutaneous hepatic perfusion, patient selection is very important.Patients should be fit to undergo treatment and they should have liver-dominant or liver-only disease. Patients that are most likely to be the best candidates for percutaneous hepatic perfusion are patients with metastases from ocular melanoma. After watching this video, you should be able to understand how percutaneous hepatic perfusion is performed in a patient with liver tumors.Bare in mind that the procedure is best performed by a well trained and dedicated team of interventional radiologists, anesthesiologists, perfusionists, and technicians. Don't forget that significant hemodynamic perturbations may occur during the procedure and may require administration of high doses of sympathomimetics. Bone marrow depression is not uncommon and may be anticipated by administration of granulocyte colony-stimulating factor one to two days after the procedure.

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