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10.1245/ASO.2004.09.021
Annals of Surgical Oncology 11:598-605 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Isolated Hypoxic Hepatic Perfusion With Orthograde or Retrograde Flow in Patients With Irresectable Liver Metastases Using Percutaneous Balloon Catheter Techniques: A Phase I and II Study

Boudewijn van Etten, MD, Flavia Brunstein, MD, Marc G. A. van IJken, MD, Andreas W. K. S. Marinelli, MD, PhD, Cornelis Verhoef, MD, Joost R. M. van der Sijp, MD, PhD, Gunther Guetens, PhD, Gert de Boeck, PhD, Ernst A. de Bruijn, PhD, Johannes H. W. de Wilt, MD, PhD and Alexander M. M. Eggermont, MD, PhD

From the Department of Surgical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands (BvE, FB, MGAvI, CV, JHWdW, AMME); Department of Surgery, Haaglanden Medical Centre, The Hague, The Netherlands (AWKSM); Department of Surgery, VU Medical Center, Amsterdam, The Netherlands (JRMvdS); Laboratory of Experimental Oncology, University of Leuven-Hospital Gasthuisberg, Leuven, Belgium (GG, GdB, EAdB); and Department of Chemistry, University of Antwerpe, Wilrijk, Belgium (GG).

Correspondence: Address correspondence and reprint requests to: Alexander M. M. Eggermont, MD, PhD, Department of Surgical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands; Fax: 31-10-439-1011; E-mail: a.m.m.eggermont{at}erasmusmc.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Isolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter–mediated isolated hypoxic hepatic perfusion (IHHP) technique.

Methods: In this phase I and II study, 18 consecutive patients with irresectable colorectal or ocular melanoma hepatic metastases were included. Two different perfusion methods were used, both with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight patients, the portal vein was occluded, and outflow was via the hepatic veins into an intracaval double-balloon catheter. This orthograde IHHP had on average 56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a triple balloon blocking outflow into the caval vein and allowing outflow via the portal vein. The retrograde IHHP still had 35% leakage on average.

Results: Although local drug concentrations were high with retrograde IHHP, systemic toxicity was still moderate to severe. Partial responses were seen in 12% and stable disease in 81% of patients. The median time to local progression was 4.8 months.

Conclusions: We have abandoned occlusion balloon methodology for IHHP because it failed to obtain leakage control. We are presently conducting a study using a simplified surgical retrograde IHHP method, in which leakage is fully controlled, which translates into high response rates.

Key Words: Liver metastases • Isolated hepatic perfusion • Melphalan • Balloon catheter • Phase I and II study • Percutaneous


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Approximately 50% to 60% of colorectal cancer patients will develop liver metastases during follow-up. In nearly a quarter of these patients, the liver is the only site of disease.1 If hepatic metastases of colorectal cancer are resectable, 5-year survival rates are reported between 25% and 45%, depending on several prognostic factors.2 Patients with irresectable hepatic metastases have a 0% to 2% 5-year survival rate. Therefore, aggressive, selective treatment of the liver seems justified because control of hepatic metastases translates into improved overall survival. There is no standard treatment for unresectable hepatic metastases confined to the liver, so novel treatment modalities have to be developed.

Although response rates with novel systemic chemotherapeutic agents such as oxaliplatin and irinotecan in combination with 5-fluorouracil are promising, overall survival remains poor.3–5 To improve responses and survival, locoregional chemotherapeutic regimens have been developed, such as hepatic artery infusion (HAI), chemoembolization, and isolated hepatic perfusion (IHP). For most chemotherapeutic agents, a steep dose-response curve can be demonstrated, and exposure of the liver metastases to higher drug concentrations by means of locoregional treatment might result in improved control of hepatic metastases. HAI exploits the first-pass effect of the liver, resulting in high local, but low systemic, drug exposure. Several repeated HAI regimens produced higher response rates compared with systemic chemotherapy, with a 2-year survival of 50% to 60%.6–11

In animal studies, Marinelli et al.12,13 demonstrated that significantly higher intrahepatic concentrations can be reached by IHP compared with HAI. In a leakage-free perfusion setting, IHP shields the systemic compartment to drug exposure, and in combination with a washout procedure, it protects against systemic toxicity. Classic surgical IHP (SIHP) with melphalan or mitomycin C has been studied in animal models and has resulted in high response rates.14–16 Clinical studies using melphalan with or without tumor necrosis factor (TNF)-{alpha} have shown promising results.17–24 The phase II trial performed by the National Cancer Institute of SIHP with melphalan and TNF demonstrated an overall response rate of 75%.18

SIHP is a major, complex, expensive, and time-consuming operation. These features in combination with potential toxicity are major drawbacks toward wide clinical application. Moreover, this procedure can be performed only once. To address these problems, we developed a leakage-free isolated hypoxic hepatic perfusion (IHHP) technique with balloon catheters in pigs.25 With melphalan and TNF, it was demonstrated that isolated perfusion with balloon catheters was feasible and showed minimal systemic leakage. On the basis of these favorable pharmacokinetic results, a phase I and II study with melphalan was developed for patients with irresectable liver metastases. In this report, we present the results of the first 18 patients who underwent IHHP with balloon catheter techniques with orthograde or retrograde flow through the liver.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection Criteria
In all patients, a radical resection of the primary tumor was performed before the patient entered the study protocol. The liver metastases were considered irresectable on the basis of multiple lesions in multiple segments of the liver or location near vascular structures. Tumor involvement had to be <50% of the total liver volume to prevent massive necrosis in case of a response. Absence of extrahepatic tumor growth was evaluated by computed tomographic (CT) scan of the thorax and abdomen. All patients had a Karnofsky performance score of at least 90, liver enzymes (ALT, AST, and AF) not higher than five times the normal values, and bilirubin not higher than two times the normal values. Exclusion criteria included age younger than 18 or older than 75 years; portal hypertension; significant central nervous system disease; significant cardiovascular, pulmonary, or renal disease; uncontrolled infections; presence of organ grafts; and chemotherapy or radiotherapy within 4 weeks before the IHHP. Angiography was routinely performed to exclude aberrant hepatic arteries or to visualize other anatomical anomalies. Patients with severe arteriosclerosis of the aortic-iliac-femoral vessels that made placement of balloon catheters impossible were also excluded. All IHHPs were performed at the Daniel den Hoed Cancer Center. The study protocol was approved by the Medical Ethical Committee of the Erasmus University Medical Centre, and written, informed consent was obtained from all patients.

Perfusion Circuit
Perfusion sets (PfM, GmbH, Cologne, Germany) consisted of a double-balloon catheter (12F; balloon capacity, 25 mL; distance between balloons, 4–5 cm) for venous isolation of the liver. An aortic occlusion balloon catheter (12F; balloon capacity, 25 mL) for compensating for the decrease of cardiac preload during the procedure and a tubing set with a volume of 220 mL containing a bubble trap were used. All IHHPs were performed with inflow via the hepatic artery. In the first eight patients, a predominantly open technique was used to cannulate the proper hepatic artery via the gastroduodenal artery with a 8F catheter (Fig. 1). From patient 9 to 18, we used a percutaneous 5F stopflow occlusion catheter (PfM) introduced before surgery via the groin by using the Seldinger technique (Table 1; Fig. 2). Except for patient 12 and patient 15, who had a double hepatic artery, the balloon was positioned in the proper hepatic artery.



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  		FIG. 1. Schematic representation of isolated hypoxic hepatic perfusion with a percutaneous catheter in the hepatic artery (inflow) and double-balloon catheter in the caval vein (outflow). Orthograde flow method.

 

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  		TABLE 1. Characteristics of 18 patients with irresectable liver metastases treated by IHHP with melphalan
 


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  		FIG. 2. Schematic representation of isolated hypoxic hepatic perfusion with a percutaneous catheter in the hepatic artery (inflow), a triple-balloon occlusion catheter in the caval vein, and an outflow catheter in the portal vein. Retrograde flow method.

 
The first eight patients were perfused with a double-balloon catheter in the caval vein, with occlusion of the portal vein and outflow via the side holes in the caval vein catheter (Fig. 1). To improve leakage control, a triple-balloon occlusion catheter was developed (PfM), and the outflow was diverted to the portal vein, creating a retrograde flow. This triple balloon was used from patients 9 to 18. It occludes the retrohepatic caval vein in a section of 18 cm, versus 12 cm with the double-balloon catheter (Fig. 2). In the perfusion circuit, flow was maintained by a roller pump, and pressure was measured via a side-line.

Drugs
Melphalan 1 mg/kg (Alkeran; Wellcome Ltd., London, UK) was used in all patients and infused through a side-line into the perfusion circuit.

Surgical Procedure of the Orthograde Flow IHHP
A small right subcostal incision was made, and cannulation of the gastroduodenal or hepatic artery was established. A cholecystectomy was routinely performed in only the first five patients. When percutaneous techniques were used before surgery, palpation confirmed the position of the balloon in the proper hepatic artery. Surgical exposure of the femoral artery and vein in the groin was made, and cannulation of the artery was performed with an aortic occlusion catheter positioned under radiographic control just above the celiac axis. Patients were subsequently heparinized with heparin 2 mg/kg. Cannulation of the femoral vein was then performed with the caval double-balloon catheter positioned under radiographic control. The proximal balloon was placed at the level of the diaphragm, and the distal balloon was placed just below the liver; this was confirmed by palpation. Between the two caval balloons, 20 mL of contrast solution was rapidly injected to visualize the hepatic veins at their confluence into the retrohepatic caval vein. After clamping of the portal vein and connecting the hepatic artery catheter and the caval balloon catheter to the perfusion circuit primed with 220 mL of Hemaccel (Behring Pharma, Amsterdam, The Netherlands), the orthograde isolated perfusion was performed (Fig. 1; Table 1; patients 1–8).

Surgical Procedure of the Retrograde Flow IHHP
Before the operation, the hepatic artery was cannulated via the groin as described previously. Via the abdominal incision, the portal vein was dissected. The femoral artery and vein were cannulated, and the occlusion balloons were positioned both in the vena cava and the aorta. The portal vein was then cannulated with a 14F catheter for outflow (Table 1; patients 9–18). Patients were subsequently heparinized with heparin 2 mg/kg. After connection to the perfusion circuit, a retrograde perfusion was commenced through the portal veins. The retrograde perfusion setup is depicted in Fig. 2.

The perfusate was circulated by a constant flow (Table 1). Stable perfusion was monitored by pressure measurement and the perfusate level in the bubble trap. Methylene blue was injected into the arterial catheter to check homogeneous distribution over both lobes of the liver. Then melphalan was infused into the circuit, and the perfusion was conducted for 20 minutes. After 20 minutes, a washout procedure was performed by using 1 L of Hemaccel to collect the venous effluent. Total liver ischemia time never exceeded 60 minutes. The isolation was terminated by deflating the caval balloon followed by the aortic balloon and releasing the ligature of the portal vein (orthograde IHHP), or by decannulation and closing the venotomy of the portal vein (retrograde IHHP).

Leakage Monitoring
During IHHP, potential drug leakage was monitored by using a radioactive tracer. A small calibration dose of human serum albumin radiolabeled with iodine-131 was injected into the systemic circulation before the perfusion, and a 10-fold higher dose of the same isotope was injected into the IHP circuit. Continuous monitoring was performed with a precordial scintillation probe. Systemic leakage is expressed quantitatively as a percentage (100% leakage represents a homogeneous distribution of the isotope in the body).21

Blood Sampling
Before, during, and after the perfusion, blood samples were taken and collected to study the pharmacokinetics of melphalan and the hematological, renal, hepatic, and gastrointestinal toxic side effects. Toxicity was graded according to the standard World Health Organization (WHO) common toxicity criteria.26

Measurement of Melphalan Concentrations
Melphalan was measured in plasma by gas chromatography-mass spectrometry. P-[Bis(2-chloroethyl)-amino]-phenylacetic acid methyl ester was used as an internal standard. Samples were extracted over trifunctional C18 silica columns. After elution with methanol and evaporation, the compounds were derivatized with trifluoroacetic anhydride and diazomethane in ether. The stable derivates were separated on a methyl phenyl siloxane gas chromatography capillary column and measured selectively by single ion monitoring gas chromatography-mass spectrometry in the positive EI mode described previously by Tjaden and de Bruijn.27

Assessment of Tumor Response
Tumor response was assessed by comparing preperfusion CT and magnetic resonance imaging scans of the liver with scans made at 6 to 8 weeks after IHHP. The tumor marker carcinoembryonic antigen (CEA) was monitored (when indicated) before surgery and 6 to 8 weeks after perfusion but was not used for response assessment. Clinical responses were assessed by standardized WHO criteria26: complete remission, regression of all measurable disease in the liver for >4 weeks; partial remission (PR), regression of the tumor size by >50% for >4 weeks; stable disease, regression <50% of the tumor in the liver or progression <25% for >4 weeks; and progressive disease, progression >25%.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
In total, 18 patients were included in the protocol: 7 women and 11 men with a mean age of 63.2 years (range, 39–71 years). Seventeen patients had irresectable colorectal liver metastases, and one patient had ocular melanoma hepatic metastases.

Leakage Control
In the first eight IHHPs with a double-balloon intracaval catheter, a mean leakage of 56% (range, 20%–100%) was measured. Repeated adaptations to the catheter design in terms of balloon size and interballoon distance were performed. This led to a change of concept and the design of a triple-balloon caval vein occlusion catheter with outflow via the portal cannula and a retrograde flow direction (patients 9–18). Leakage then decreased to an average of 35% (range, 5%–85%).

Toxicity Study
Regional toxicity consisted mainly of a transient increase of liver enzymes during the first week after IHHP: 83% of the patients had WHO grade 2 or 3 toxicity (Table 1). No coagulopathy was observed. In one patient we were confronted with severe hepatic toxicity (grade 4). Unfortunately, this patient died within 30 days of the operation (discussed in detail in Complications).

Because of the leakage of melphalan during the perfusion, most patients were treated with granulocyte colony-stimulating factor (Neupogen; Amgen B.V., Breda, The Netherlands) in an attempt to prevent severe leucopenia. Systemic toxicity consisted mainly of leucopenia (WHO grade 1–3 in 44% and severe grade 4 leucopenia in 27%) for 10 to 20 days after perfusion. In most patients with relatively less leakage, no or only mild leucopenia was observed. No renal or gastrointestinal toxicity was observed.

Melphalan Pharmacokinetics
Figure 3 shows a drug concentration-versus-time curve in the isolated circuit and in the systemic circulation. It shows melphalan concentrations during a retrograde IHHP (patient 9). Very high regional and negligibly low systemic melphalan concentrations were observed. After surgery, this patient had only mild hepatic toxicity and no signs of systemic toxicity. The area under the concentrations-versus-time curve calculation showed a regional concentration advantage, with an area under the curve regional/systemic ratio of 28.2.



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  		FIG. 3. Pharmacokinetics of melphalan during isolated hypoxic hepatic perfusion (patient 9, with 15% leakage during perfusion). The area under the concentration-versus-time curve (AUC) was calculated between 5 and 20 minutes: regional 335,500 ng x min/mL versus systemic 11,870 ng x min/mL. The AUC ratio (regional/systemic) was 28.2.

 
Complications
Patient 3 developed paralysis of both legs a few days after the procedure. During the clinical observation period, the symptoms decreased, and after approximately 3 months, the paralysis had disappeared completely. This temporary neurological feature was probably caused by perioperative ischemia of spinal marrow by occlusion of the Adamkiewicz artery. This arteria radicularis magna supplies part of the spinal marrow and was probably occluded by the aortic balloon catheter.

One patient (patient 20) developed liver abscesses 2 weeks after IHHP. He underwent the perfusion with 65% leakage and developed grade 3 hematological and hepatic toxicity. Then a period with fever occurred, and CT scan demonstrated multiple abscesses in the liver. These abscesses were located at the former sites of the colorectal metastases. Moreover, an abscess was apparent at the blind end of the rectum as a result of the Hartmann procedure performed for his primary tumor several months before. This was the possible focus for the bacteremia causing the infected necrotic masses in the liver. After 2 months with multiple percutaneous draining periods of the liver abscesses and antibiotic treatment, he finally developed aspiration pneumonia and died of respiratory failure.

One patient died within 30 days of the operation, resulting in a mortality during this phase I and II study of 5%. This patient (patient 12) presented with ocular melanoma metastases and had an uneventful IHHP with only 5% leakage. After surgery, she developed severe dyspnea and grade 4 hepatic toxicity. Mechanical ventilation was indicated because of respiratory failure. Hepatic dysfunction increased rapidly, and 8 days after surgery, the patient died. Autopsy results showed pneumonia. There were no signs of pulmonary (thrombus or tumor) embolism. An ischemic liver was found with almost total necrosis of the melanoma metastases. Surprisingly, almost 70% of the liver was replaced by tumor, although a CT scan 4 weeks before perfusion showed an estimated tumor involvement of <40%. We assume that the metastases must have grown very rapidly in the last weeks before IHHP and the remnant of normal liver tissue was not enough to survive the hepatic toxicity caused by the IHHP.

Tumor Response and Patient Survival
Stable disease was demonstrated in 81% (13 of 16) of assessable patients after 6 to 8 weeks (Table 1). Patients 12 and 16 were not assessable with respect to tumor response. In 12% of patients (2 of 16), a PR was seen. Two patients (12%) developed progressive disease after IHPP. In both patients who had a PR, CEA levels decreased to normal (<5 µg/mL) levels. CEA levels decreased in at least eight of the stable disease patients, but none had reached normal levels. Progressive disease at the liver occurred with a mean interval after IHHP of 4.8 months (range, 3–13 months). Seven patients developed systemic metastases. Five developed pulmonary metastases 3 to 7 months after IHHP. One patient had metastatic lesions in the sacral bone at the same time of liver metastasis progression at 4 months after perfusion. In one patient, peritoneal carcinomatosis was detected 5 months after IHHP. In one patient, a local recurrence at the rectum was detected. Median patient survival was 11.1 months (range, 0–32 months).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the last decade, isolated liver perfusions have been performed by a few centers worldwide, and the antitumor effect showed promising response rates (up to 75%) and a potentially prolonged mean survival of 16 to 24 months.17,20 The major drawbacks of the technique are the magnitude, the costs, and the nonrepeatability of the surgical procedure. In the open procedure, the entire liver has to be mobilized, and all lumbar veins have to be ligated to guarantee a leakage-free perfusion. Classic SIHP also uses a venovenous bypass and a heart-lung machine, which is a time-consuming procedure that necessitates a specialized perfusion team. The mean SIHP operation time is 8.6 hours, with a mean packed RBC transfusion of 5.7 units. The main goal of our study was to develop a less invasive, less costly, and potentially repeatable percutaneous technique that would allow safe perfusion in a much shorter time and that could be repeated and performed without a heart-lung machine or venovenous bypass. Moreover, IHHP makes use of hypoxia, which renders tumor cells more sensitive to cytostatic agents in general and which particularly enhances the antitumor effects of drugs such as melphalan.28,29 In pigs we previously demonstrated a leakage-free IHHP technique with an open double-balloon catheter in the caval vein.25 The same technique in patients resulted in major leakage in this study. This occurred despite positioning the two balloons directly above and below the orifices of the hepatic veins and trying to occlude the lumbar veins. By replacing the open double-balloon catheter by a triple-balloon occlusion catheter, which should occlude the adrenal vein and all lumbar veins, but also the hepatic veins, more successful hepatic perfusion could be performed with inflow via the hepatic artery and outflow via the portal vein. The mean operating room time was reduced to 3 hours, and the mean transfusion was one RBC unit.

The mean leakage decreased from 56% in the orthograde IHHP to 35% in the retrograde setting. We anticipated a decrease in leakage along the learning curve, but unless increasing experience and technical modifications occur with IHHP, it is still not possible to perform it leakage free in this setting. We assume that diaphragmatic, lumbar, and adrenal veins are the main cause for the type of leakage we observed. Veins around the common bile duct in the hepatic ligament could also be a potential cause, but temporary ligation of the ligament during perfusion was performed routinely, because we started with the retrograde perfusion, and leakage remained. Leakage started directly after the start of the perfusion and remained at a constant level during the procedure. Because of this persisting leakage problem and subsequent dose-limiting systemic toxicity, we were not able to escalate to higher melphalan dosages. Higher local melphalan concentrations seem to be a prerequisite for improving tumor responses. Vahrmeijer et al.20 reported a correlation between high-dose melphalan SIHP (3 mg/kg) for colorectal liver metastases and patient survival.

Leakage-free perfusion is of major importance for the potential application of TNF-{alpha}, a cytokine with significant antitumor effects at high concentrations. The adequate concentration for TNF to induce its synergistic antitumor effect is too high for intravenous administration. The use of TNF has led to excellent clinical responses after isolated limb perfusion with melphalan and TNF for irresectable soft tissue sarcomas and melanomas.30,31 In isolated limb perfusion, TNF proved to be very effective and safe. These perfusions are performed with minimal systemic leakage of 0% to 10%.30,31 Whether TNF contributes to therapeutic efficacy in IHP remains unclear. We recently demonstrated in a preclinical rat liver metastasis model that increased intratumoral melphalan uptake is strongly correlated with the microvessel density of the tumor.32 Only hypervascularized tumors showed improved melphalan uptake in tumor tissue and synergistic antitumor effects after IHP with melphalan and TNF. Because colon carcinoma metastases are hypovascular, IHP with melphalan alone might be just as effective as it is combined with TNF. This was demonstrated in our colorectal liver metastasis model, which showed no increased intratumoral melphalan concentrations and a lack of therapeutic efficacy compared with IHP with melphalan alone. Results from the National Cancer Institute showed the same duration of response after SIHP for colorectal metastases with or without TNF.18,33,34 However, in patients with highly vascularized ocular melanoma metastases, the addition of TNF in SIHP yielded to a prolonged response compared with SIHP with melphalan alone: 14 vs. 6 months, respectively.35 These clinical results seem to confirm the hypothesis about the indication for the utility of TNF in IHP. Because the minimally invasive IHHP methodology we report here is not without leakage, the addition of TNF in this setting seems impossible.

Savier et al.36 recently reported a phase I study with four patients repeatedly treated by 10 courses of melphalan-based SIHP and percutaneous IHP. At percutaneous IHP, the hepatic artery was used for inflow of the perfusate, and an open double-caval balloon catheter was used for outflow. The portal vein was occluded by a percutaneous balloon catheter to complete isolation. This group was also confronted with major leakage starting as soon as the perfusion commenced. This was measured after surgery by systemic melphalan levels. Severe (grade 3–4) systemic toxicity (hematological) was observed after perfusion in this study. Because of lower melphalan doses varying from 15 to 45 mg, no severe hepatic toxicity was observed. Others have used percutaneous IHP techniques combined with extracorporal charcoal hemoperfusion filters for the venous effluent, predominantly in patients with hepatocellular carcinoma.37–39 This technique is completely different from the balloon catheter technique described in our study, but results look promising, although toxicity is also significant. Systemic toxicity not only might be related to the surgical technique or catheter, but also might be influenced by the drug used. Our study with 18 consecutive patients in this phase I and II study showed advantages compared with SIHP regarding magnitude and operating time, although morbidity and mortality were still significant. Despite technical modifications and increasing experience, leakage was still observed, and regional and systemic toxicity remained.

With respect to regional toxicity, we emphasize that at least 50% of functional liver tissue should be present. Especially in fast-growing melanoma metastases, liver imaging and laboratory investigation should be performed shortly before the operation. The only fatal complication occurred after a technically uncomplicated IHHP with less leakage but was due to hepatic failure, on the basis of massive liver replacement by fast-growing metastases.

Systemic toxicity is directly correlated with leakage of cytostatic agents during perfusion and an effective washout procedure. Vahrmeijer et al.20 could escalate up to 3 mg/kg of melphalan safely provided that leakage was minimal. In our series, leakage <20% prevented leucopenia almost completely. In a leakage-free perfusion setting, hepatic toxicity will be the dose-limiting factor.

In conclusion, balloon catheter–mediated IHHP failed because no good leakage control was achieved by either the orthograde or the retrograde method. We therefore have abandoned this program. Instead we have used the experience to develop a surgically much simplified method to perform a retrograde IHHP with fully controlled leakage and, thus, improved local drug concentrations; improved washout at the end of the perfusion; and much improved toxicity and response rates. Finally, we emphasize that systemic or locoregional maintenance therapy after IHHP also has to be considered to control the liver metastases. Continuing locoregional treatment by HAI after an IHP procedure is technically feasible and seems to prolong the duration of the response and survival.18


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the full text version at www.annalssurgicaloncology.org. They are not available in the PDF version.

Supported by a grant of the Dutch Cancer Society/Queen Wilhelmina Foundation.


   FOOTNOTES
 
Isolated hypoxic hepatic perfusion with balloon catheters resulted in high local drug concentrations but failed to obtain leakage control by either an orthograde or a retrograde flow method.

Received for publication September 30, 2003. Accepted for publication March 3, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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