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The Oncologist, Vol. 5, No. 5, 416-424, October 2000
© 2000 AlphaMed Press

NCI All Ireland Cancer Conference Proceedings

Current Status of Isolated Hepatic Perfusion With or Without Tumor Necrosis Factor for the Treatment of Unresectable Cancers Confined to Liver

H. Richard Alexander, Jr., David L. Bartlett, Steven K. Libutti

Surgical Metabolism Section, Surgery Branch, Division of Clinical Sciences, National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA

Correspondence: H. Richard Alexander, Jr., M.D., Head, Surgical Metabolism Section, Surgery Branch, NCI, NIH, Building 10, Room 2B07, Bethesda, Maryland 20892, USA. Telephone: 301-496-2195; Fax: 301-402-1788.

ABSTRACT

Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors or primary colangio- or hepatocellular carcinomas. A number of regional treatment strategies including infusional chemotherapy and local ablative therapy are under clinical development and attest to the difficulty in adequately treating this condition. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not gained widespread application. In light of the remarkable antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers confined to the liver and, with additional clinical development, will most likely be a more routinely considered option for patients with this condition.

Key Words. Isolation perfusion • Tumor necrosis factor • Metastatic cancer of the liver • Melphalan • Unresectable cancers

INTRODUCTION

Metastatic or primary unresectable cancers confined to the liver present a significant clinical problem. Of the 140,000 new patients diagnosed with colorectal cancer annually in the United States, approximately 20%-30% of patients will die of progressive metastatic disease confined to the liver [1-3]. In 70%-90% of patients with ocular melanoma, the liver is the initial or major site of progressive metastatic disease [4, 5]. Even with aggressive treatment, the median survival after liver metastases are diagnosed is less than 12 months for patients with ocular melanoma [4-6] and between 12-24 months for patients with colorectal cancer [7-9]. Stage IVA hepatocellular cancer patients typically survive fewer than 12 months [10].

A number of regional treatment strategies are under clinical development for metastatic or primary unresectable cancers of the liver, and provide an opportunity to dose intensify therapy while limiting systemic toxicity. Because established metastatic deposits in the liver derive their blood supply primarily from the hepatic artery [11, 12] and normal hepatic parenchyma derives the majority of its blood flow from the portal system, hepatic arterial infusion of chemotherapeutics, using either percutaneously placed catheters or implantable pumps, has been used for patients with a variety of histologies [7-9, 13-15]. In addition, local ablative techniques including cryotherapy, radiofrequency ablation, or local ethanol injection have been used for metastatic or primary deposits in the liver. However, none of these therapies have sufficient efficacy to be considered standard therapy [16-18].

Isolated hepatic perfusion (IHP) was first clinically applied almost 40 years ago [19], and over the subsequent 20 years a limited number of institutions reported relatively small series of patients treated with IHP using various chemotherapeutics [20-23] or hyperthermia alone [24]. The results of these initial reports indicated that IHP is associated with significant morbidity and a treatment-related mortality in the range of 10%-25%. In addition, it was not clear based on relatively small numbers of patients whether the antitumor effects were significant enough to justify such an aggressive approach (Table 1Go).


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  		Table 1. Summary of previous IHP chemotherapy trials [39]
 
In 1992 Dr. Lienard and Dr. Lejeune reported the initial results of isolated limb perfusion using tumor necrosis factor (TNF), interferon gamma and melphalan for patients with in transit melanoma or unresectable extremity sarcoma [25]. In that initial report the authors observed a 90% complete response rate and an overall response rate of 100%, which was considerably better than what had been observed previously using melphalan alone [26]. Subsequently, a number of institutions have verified the significant antitumor activity of TNF and melphalan when administered via isolated limb perfusion for extremity sarcoma and melanoma [26-28]. In addition, a number of institutions initiated clinical trials of IHP using TNF alone or in combination with melphalan [29-32] (Table 1Go).

MATERIALS AND METHODS

Between April of 1993 and December of 1999, 147 patients underwent IHP on various approved institutional protocols in the Surgery Branch of the United States National Cancer Institute using TNF alone, melphalan alone, or a combination of melphalan and TNF. All patients had histologically proven unresectable metastatic or primary cancers confined to the liver, and a performance status adequate to safely undergo a major operative procedure. Patients were required to have normal hepatic synthetic function as evidenced by a normal serum bilirubin and coagulation profile. Elevations in hepatic transaminases were allowed if they were thought to be secondary to the presence of metastatic disease in the liver. On an infrequent basis, treatment was administered to a few patients with limited, easily resectable, extrahepatic disease in whom the liver disease represented the major life-threatening component of their illness.

IHP is administered via a laparotomy incision. Initially the abdomen is inspected to exclude the presence of occult extrahepatic disease, particularly peritoneal carcinomatosis. Limited periportal lymphadenopathy is resected in the course of the preparation of the liver for IHP and does not exclude one for treatment. The liver is extensively mobilized in preparation for IHP to insure that there is no leak of perfusate in the systemic circulation. The right and left lobes of the liver are released from their diaphragmatic attachments and the retrohepatic vena cava is extensively dissected out of the retroperitoneum from the level of the renal veins to the diaphragm, which includes systematic identification and ligation of retroperitoneal venous tributaries and the right adrenal vein. This maneuver insures that there will be no leak of perfusate from the isolated segment of retrohepatic inferior vena cava (IVC). A prophylactic cholecystectomy is performed and the fibrofatty connective tissue around the periportal structures is extensively dissected and divided in order to prepare the vessels for perfusion and prevent any leak of perfusate. A saphenous vein and axillary vein cutdown are performed and then the patient is systemically anticoagulated with intravenous heparin.

The hepatic perfusion circuit is shown schematically in Figure 1Go. An external veno-venous bypass circuit is established by placing a cannula in the saphenous vein, which is advanced into the infrarenal IVC and a second cannula advanced through the axillary vein to the superior vena cava. This allows active shunting of IVC blood during treatment. Next, the portal venous blood flow is shunted by placing a venous cannula through a portal venotomy into the superior mesenteric vein which is incorporated into the veno-venous bypass circuit and eliminates portal venous flow to the liver during treatment. The inflow cannula for perfusion is positioned in the gastroduodenal artery and once this is secured, a cross clamp is placed across the common hepatic artery and on the suprahepatic IVC. Once this has been accomplished, complete vascular isolation of the liver is complete and perfusion is initiated. Stable perfusion parameters are usually achieved almost immediately (Fig. 2Go). A Swan-Ganz catheter is used as a thermistor probe and advanced into the portal vein into the liver parenchyma for reading of central hepatic temperatures, and two other transhepatic temperature probes are placed in the left and right lobes. The perfusion parameters typically used during IHP are shown in Table 2Go. The 1-l perfusate contains a unit of crossmatched packed red blood cells, and the sodium bicarbonate is added as necessary to maintain a perfusate pH greater than 7.2. The flush is used to remove residual perfusate containing chemotherapeutics or biological agents from the liver vasculature and results in minimal detectable circulating levels of melphalan or TNF after treatment. In fact, toxicities related to the procedure when complete vascular isolation is achieved are largely related to the effects of the perfusate agents in the liver.



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  		Figure 1. Schematic representation of the IHP circuit. Arterial inflow is via a cannula in the GDA and outflow is via a cannula positioned in an isolated segment of the IVC. The closed recirculating perfusion circuit containing one l of solution consists of a reservoir/bubble oxygenator, a roller pump and a heat exchanger. The veno-venous bypass circuit shunts blood from the infrahepatic IVC and the portal vein to the systemic circulation during IHP.

 


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  		Figure 2. Photo of the porta hepatis following cannulation for IHP. A cannula is present in the GDA for inflow and a larger bypass cannula is secured in the portal vein positioned in the superior mesenteric vein. A Swan-Ganz catheter with a thermistor tip is positioned in the intrahepatic portal vein to monitor central hepatic temperature during IHP. Note the vascular cross clamp on the proximal hepatic artery to prevent inflow on blood.

 

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  		Table 2. Treatment and perfusion parameters used during IHP
 
A list of the various protocols conducted in the Surgery Branch using IHP is shown in Table 3Go. Initially, 16 patients were treated with an escalating dose of TNF alone combined with a fixed dose of interferon gamma. Subsequently, an alternating dose-escalation IHP trial of TNF and melphalan was conducted in 14 patients to determine the maximum safe tolerated dose of these agents when used in combination in a 1-h hyperthermic hepatic perfusion. Fifty patients were then treated on a phase II trial of TNF and melphalan in combination to determine response rates and duration of response for various histologies. Because clinical grade TNF is not currently available for clinical trials in the United States, more recent experience with IHP has been conducted without TNF. A phase I melphalan-alone dose escalation trial has enrolled 45 patients. In this trial 23 patients with noncolorectal histologies were treated in cohorts of three to six with escalating-dose melphalan administered using a modification of the inflow circuit to include both the gastroduodenal artery (GDA) and portal vein. Twenty-two patients with colorectal cancer confined to liver were treated identically except that perfusate inflow was via the GDA alone. Dose-limiting hepatic veno-occlusive disease (VOD) was observed at doses of 2.5 and 2.0 mg/kg of melphalan, respectively. In addition, cannulation and inflow via the portal vein resulted in one partial portal vein thrombosis and was not used in subsequent trials.


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  		Table 3. Summary of surgery branch IHP protocols for unresectable hepatic malignancies
 
Currently two IHP trials are open, one using 1.5 mg/kg melphalan administered via a 1-h IHP for patients with metastatic ocular melanoma, primary cholangiocarcinoma, or metastatic neuroendocrine tumors confined to liver. For patients with colorectal cancer, the melphalan IHP is combined with hepatic arterial infusional therapy (HAI) using floxuridine (FUDR) and leucovorin (LV) administered for 14 days each month starting six weeks after IHP. Nineteen patients have been treated using this combined therapy.

Toxicity, response rates, duration of response, survival and pharmacokinetic responses have been conducted on the majority of patients treated. In addition, because of the known procoagulant vascular effects of TNF on tumor-associated endothelium, tumor and liver biopsies were obtained in a cohort of patients before and after IHP and analyzed for in vivo capillary permeability to determine if TNF is causing specific and significant capillary leak during hepatic perfusion [33].

RESULTS

The general results of the various trials conducted in the Surgery Branch are shown in Table 3Go. In the initial dose-escalation trial of TNF, dose-limiting coagulopathy was encountered at 2 mg of TNF and therefore, the maximum safe tolerated dose of TNF when administered as a 60-min hyperthermic hepatic perfusion was determined to be 1.5 mg. This is considerably less than the dose that is tolerated in isolated limb perfusion and highlights the highly variable tissue tolerance to the cytokine. In the subsequent trial of 14 patients treated with an alternating dose escalation of melphalan and TNF, hepatic VOD was encountered in one patient at a dose of 2 mg/kg of melphalan and dose-limiting coagulopathy was encountered in another patient treated with 1.5 mg TNF. Therefore, the maximum and safe tolerated doses of these agents used in combination was determined to be 1 mg of TNF and 1.5 mg/kg of melphalan.

In the phase II trial, the response rates have been calculated for the entire cohort, and outcomes of the first 34 patients on study have been analyzed in detail. The hemodynamic and treatment parameters observed during IHP are shown in Table 4Go. The overall response rate in the 50 patients was 74% and was observed across virtually all types of histologies treated. The response rates were maintained even in patients who had numerous metastases, large metastases or who had a significant percentage of liver replaced by tumor (Table 5Go). Although the median duration of response was nine months, the range of response duration was considerable and in some circumstances extended beyond three years (Figs. 3 and 4GoGo). These data clearly show the capacity of IHP with TNF and melphalan to result in substantial regression of refractory advanced metastatic cancers of the liver in the majority of patients treated.


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  		Table 4. Treatment parameters observed during IHP
 

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  		Table 5. Response to IHP based upon number of lesions, diameter of largest tumor, or percent hepatic replacement in 33 evaluable patients
 


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  		Figure 3. Gadolinium enhances T1-weighted magnetic resonance imaging (MRI) scans through the liver of a patient with metastatic ocular melanoma to liver. She had been explored at another institution for potential resection but found to have multiple bilobar sites of disease in addition to the large right-sided lesion. Scans show the significant and durable partial response following a 1-h IHP with melphalan and TNF which remained stable for over 36 months. The patients subsequently developed regional and systemic recurrence.

 


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  		Figure 4. Gadolinium enhanced T1-weighted MRI of a patient with metastatic colorectal cancer to the liver. The patient was treated with a 1-h IHP using melphalan alone and received post-IHP HAI with FUDR and LV. The patient has had an ongoing response for over 14 months.

 
Toxicity associated with IHP using TNF and melphalan occurs frequently but is almost always reversible. In over 140 patients treated on various clinical protocols, the overall mortality rate is 6%, and the majority of these treatment-related deaths is a result of toxicities encountered in the phase I trials. In the phase II trial using the maximum safe tolerated doses of agents, the treatment-related mortality rate was 4%. Almost all patients have transient and significant elevations in hepatic function tests that return towards baseline within seven days of treatment. Because the liver is a metabolically active organ that is the site of proinflammatory cytokine production, significant elevations in interleukin 6 (IL-6) and IL-8 are observed in the perfusate during treatment. Peak systemic levels after treatment are observed within 4-6 h and are comparable to those levels that have been detected in patients with life-threatening septic shock [34].

There is no leak of perfusate during IHP as determined by intraoperative I-131-radiolabeled human serum albumin in the vast majority of patients treated. There have been only two patients who had any measurable leak of perfusate during treatment and in both circumstances, the leak was recognized early on and corrected by repositioning of a vascular occluding clamp. Because of the complete vascular isolation that is routinely achieved, there is no measurable TNF in the systemic circulation during or after treatment. The perfusate levels are shown in Figure 5Go. As can be seen, the initial concentration of 0.6 mg/l is predicted based upon a dose of 1 mg of TNF administered into a one l perfusion circuit and a hepatic blood volume of approximately 300 ml. The concentrations of TNF over time stay constant consistent with those observed during isolated limb perfusion and reflect minimal degradation or tissue uptake. Tumor biopsies were obtained in patients before and after treatment and counts of I-131 albumin were quantitated and corrected per 100 mg of tissue. Because the vascular bed of the liver is flushed with saline at the completion of treatment, any counts of I-131 present in tissue reflect interstitial albumin which is a direct reflection of capillary leak. As can be seen in Figure 6Go, there was a significant increase in capillary leak observed specifically in tumor compared to liver after IHP. However, when the degree of capillary leak was determined in patients treated with TNF (n = 20) or without TNF (n = 7), there was no difference in capillary permeability in tumor after IHP, indicating that the augmented capillary leak that occurs in tumor must occur secondary to factors independent of TNF [33].



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  		Figure 5. Perfusate TNF levels over time during IHP. The initial value obtained 15 min after commencing treatment is consistent with the dilutional effect of 1 mg in a total volume of 1.3 l (1 l perfusate and 300 ml blood volume in liver). The levels stay fairly constant indicating minimal tissue absorption or degradation of TNF during IHP.

 


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  		Figure 6. Assessment of vascular permeability in liver and tumor before and immediately after IHP with (n = 20) or without TNF (n = 7). All patients underwent IHP with melphalan and received I-131-radiolabeled albumin immediately prior to IHP. Patients were treated identically except for the use of TNF in seven. Tissue samples were harvested, weighed, and I-131-radiolabeled albumin per 100 mg of tissue was quantified. Top panel shows the significant increase in vascular permeability in tumor after IHP compared to liver after IHP and pre-IHP tumor (*p < 0.01). However, there was no difference in the increase in vascular permeability in tumor after IHP in those who received TNF compared to those who did not (bottom panel).

 
The exact contribution of TNF in IHP with melphalan is not known. In 34 patients with metastatic colorectal cancer confined to liver, the overall radiographic partial response rate was 77% with a median duration of nine months following IHP with melphalan and TNF. In a subsequent cohort of patients that were not necessarily matched for all potential prognostic parameters that could affect outcome, IHP with melphalan alone at the same dose was administered but the patients also received post-IHP HAI. The overall radiographic response rate in this group was 74% with a significantly longer median duration of response of 14.5 months. It is important to appreciate that these latter results were obtained in a group of patients with largely refractory and advanced disease; 50% had failed one or more previous chemotherapy regimens for their established hepatic metastases, and the median percent hepatic replacement was greater than 20%.

CONCLUSIONS

There are several issues that remain with respect to the use of IHP for unresectable malignancies confined to the liver. The data from our institution and others show that IHP with TNF and melphalan can result in substantial regression of advanced cancers in most patients. Furthermore, the treatment can be done safely and with minimal long-term morbidity. Without TNF, IHP with melphalan alone may have significant antitumor efficacy and, when used with HAI for patients with refractory and advanced colorectal cancer metastatic to liver, produces a high and durable response rate. Further refinements in technique will be necessary in order to optimize patient outcome. Critical evaluation of TNF in IHP must be continued in order to determine what role, if any, it has in the antitumor effects observed following treatment. Current studies are under way to determine the utility of combining IHP with other regional treatment strategies such as postperfusion HAI with FUDR and LV in order to prolong and improve the response and duration of response in patients with metastatic colorectal cancers of the liver. A similar strategy using fotemustine in patients with metastatic ocular melanoma to liver may be justified because of the reasonable efficacy of HAI with fotemustine alone in this setting [15].



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  		Giant's Causeway; Rocks and Irish Sea©Davi Ellen Chabner

 
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Received June 20, 2000; accepted for publication June 21, 2000.




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