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femoral artery and vein are obtained, and an angiogram is active against both resting and rapidly dividing tumor cells.
performed via the celiac and superior mesenteric arteries The maximum level of melphalan-induced DNA crosslinks
to define the arterial anatomy. The gastroduodenal artery is is reached within 4 h of regional perfusion and declines
usually embolized to minimize any extrahepatic perfusion thereafter. Side effects and toxicities observed from a Phase
[11]
and a catheter is positioned in the hepatic artery proper I trial are described in detail below.
under fluoroscopic visualization. A double balloon catheter
is then introduced percutaneously via the right common PHP vs. IHP
femoral vein. The cephalad balloon is inflated with contrast There are some advantages to PHP when compared with IHP.
until it is maximally inflated while in the right atrium and Multiple infusions can be administered via PHP, which may
then withdrawn until indentation of the diaphragmatic hiatus improve the duration of responses compared to a single
is visualized under fluoroscopy. The caudal balloon is then infusion using IHP. A percutaneous approach also avoids
inflated until the balloon wall is deformed indicating a seal. the morbidity of an open surgical procedure. However, the
Hepatic venous isolation is obtained both superiorly and complications resulting from this type of procedure are those
inferiorly to the hepatic veins. Given the IVC will be blocked commonly associated with vascular procedures, including,
by the balloon, a bypass circuit is needed. The bypass circuit but not limited to, hepatic artery dissection, hematoma,
is composed of a venous Delcath 16F polyethylene catheter pseudoaneurysm, pneumothorax from line placement, and
with one large fenestrated lumen and 3 accessory lumens, possible device failure. Specifically, deep venous thrombosis,
flushed bypass tubing, 2 filters, and the internal jugular central heparin induced thrombocytopenia, anaphylaxis to
venous return line. Contrast is injected via the fenestrated protamine have been observed. In comparison to PHP, IHP
[8]
lumen to confirm that the hepatic outflow is sealed and there has the advantage of the ability to administer hyperthermic
is no leakage of hepatic outflow into the systemic circulation. chemotherapy up to a temperature of 40 °C, which would
All of this is critical to be accomplished prior to administration otherwise be fatal if systemically administered; this can be
of any chemotherapeutic agents. Since venous return from accomplished in IHP due to the complete surgical isolation of
the lower extremities is blocked at this time, veno-venous hepatic blood flow in a closed circuit. [2]
bypass is initiated. Just prior to initiation of this bypass
circuit and filter activation, some patients can experience a One must have experience with PHP as it can result in
transient drop in blood pressure requiring additional fluid transient hemodynamic changes, such as decreased mean
and infrequent vasopressor support.
arterial blood pressure and venous return secondary
to initiation of extracorporeal filtration and mechanical
After confirmation of vascular outflow isolation, chemotherapy
is given for a 30 min continuous infusion via the proper occlusion of the inferior vena cava. Acidosis has also been
hepatic artery catheter. Occasionally due to anatomy, the observed requiring the administration of intravenous sodium
[12]
chemotherapy infusion must be split between the right and bicarbonate. Therefore, PHP must be done with a well-
the left hepatic artery to avoid any chemotherapy infusion to trained, experienced, and coordinated multidisciplinary team
organs other than the liver. The filtration circuit is continued consisting of a vascular surgeon or interventional radiologist,
for an additional 30 min after the chemotherapy is infused anesthesiologist, and physicians that can safely manage the
to ensure adequate removal of the agent. Reversal of effects from the procedure and chemotherapy in a closely
anticoagulation after the procedure is achieved via protamine monitored setting.
administration, along with fresh frozen plasma, as necessary
for safe catheter removal. After the start of reversal, the DATA AND OUTCOMES OF TRIALS
balloons are deflated and the IVC and hepatic artery catheters
are removed. However, the venous and arterial sheaths and Phase I dose escalation trial
internal jugular catheter are not removed until coagulation The initial study evaluating the feasibility of hepatic arterial
normalizes. The patient is placed in a monitored setting melphalan infusion using PHP for unresectable hepatic
[8]
for a minimum of 12 h and is maintained on bedrest for 4 h malignancies was completed by Pingpank et al. The phase
post-procedure. Postoperative laboratory studies are usually I study treated an initial cohort of 12 patients at 2.0 mg/kg,
assessed daily while the patient is in the hospital, and once followed by an additional 16 patients treated with escalating
a patient’s liver function tests and complete blood count doses to the maximum tolerated dose (MTD) of 3.0 mg/kg. A
[8]
stabilize, they are discharged. Labs are repeated within 5-7 total of 78 treatments were administered to 28 patients. The
days after discharge and weekly due to delayed hematologic histologies of patients with metastatic liver disease included:
changes secondary to melphalan exposure, which generally ocular melanoma, neuroendocrine neoplasms, colorectal
has a nadir of 7-10 days post-procedure [Figure 2]. cancer, cutaneous melanoma, adrenocortical carcinoma,
pancreatic adenocarcinoma, retroperitoneal sarcoma, breast
What is melphalan adenocarcinoma, and renal cell carcinoma. Three patients
L-phenylalanine mustard (melphalan) is an alkylating agent. It with unresectable primary hepatobiliary tumors also
has been attractive for use in PHP because as an agent used received treatment. At 3.5 mg/kg, a dose limiting toxicity of
for regional therapy, its peak perfusate concentrations are neutropenia and/or thrombocytopenia was observed in 2
10- to 100-fold higher than maximally tolerated peak levels of 6 patients. Many patients who were treated experienced
[10]
with systemic intravenous administration. Melphalan is transient hepatic and systemic toxicities.
200 Hepatoma Research | Volume 2 | July 13, 2016