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The Oncologist, Vol. 9, No. 6, 653-664, November 2004; doi:10.1634/theoncologist.9-6-653
© 2004 AlphaMed Press

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 The Past Decade of Experience With Isolated Hepatic Perfusion
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The Past Decade of Experience With Isolated Hepatic Perfusion

Amelia Grover, H. Richard Alexander, Jr.

Surgical Metabolism Section, Surgery Branch, Center for Cancer Research National Cancer Institute, Bethesda, Maryland, USA

Correspondence: H. Richard Alexander, Jr., M.D., Head, Surgical Metabolism Section, National Cancer Institute/NIH, 10 Center Drive, Building 10, Room 2B07, Bethesda, Maryland 20892-1502, USA. Telephone: 301-496-2195; Fax: 301-402-1788; e-mail: Richard_Alexander{at}nih.gov


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the principles of regional therapy for unresectable primary or metastatic cancer confined to the liver.
  2. Explain the principles of isolated perfusion of the liver.
  3. Describe the efficacy and toxicity of isolated perfusion of the liver.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
 References
 
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. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. 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 enjoyed consistent or widespread evaluation. In light of the 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 patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers.

Key Words. Liver metastases • Primary hepatic neoplasms • Colorectal cancer • Ocular melanoma • Isolation perfusion • Regional chemotherapy • Hyperthermia


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
 References
 
Patients with isolated unresectable hepatic tumors present a significant clinical challenge. Metastases can result from both primary and metastatic cancers and encompass a variety of histologies, including hepatocellular carcinoma (HCC), cholangiocarcinoma, colorectal carcinoma, ocular melanoma, breast cancer, renal cell cancer, and neuroendocrine tumors. Sequelae from progressive tumor growth in the liver, or in the case of neuroendocrine tumors from uncontrolled peptide hormone production, can be debilitating. Of more than 140,000 new cases of colorectal cancer diagnosed annually in the United States, it has been estimated that 20%–30% of patients will die of progressive metastatic disease mainly or entirely confined to the liver [1, 2]. In a recent large prospective, randomized study of patients with stage IV colorectal cancer, 85% had metastatic disease that involved liver and 41% had disease confined to the liver [3]. In patients with ocular melanoma, the liver is the initial or sole site of metastatic disease in 70%–90% of patients who recur [4, 5]. Despite aggressive treatment, median survival for patients with unresectable hepatocellular cancer (stage IVa), colorectal cancer, or ocular melanoma is between 9–18 months, 12–24 months, and 2–14 months, respectively [4, 6–10].

Systemic chemotherapy has had only limited success in the treatment of these patients although newer agents have shown promise for those with colorectal cancer. In patients with metastatic colorectal cancer, a trial of irinotecan, 5-fluorouracil (5-FU), and leucovorin as first-line chemotherapy resulted in a 39% overall response rate and a median time to disease progression of 6–7 months [11]. Oxaliplatin with 5-FU given as first-line therapy has an objective response rate of 50% [3, 12]. However, for patients who fail first-line therapy, these agents may have limited utility. For example, treatment with 5-FU, leucovorin, and oxaliplatin had only a 9.9% response rate in patients who had tumor progression after irinotecan-based treatment [13]. Recently, bevacizumab, an anti-vascular endothelial growth factor inhibitor, and cetuximab, an epidermal growth factor receptor inhibitor, have been approved for use with chemotherapy in patients with advanced colorectal cancer [14, 15]. On the other hand, metastatic ocular melanoma to the liver is generally refractory to systemic chemotherapy, which produces short-term responses in less than 10% of patients [4, 10, 16].

In some circumstances regional treatment to control disease in the liver is appropriate. To improve response rates and patient outcome, many treatment efforts have been focused on using regional therapies for patients with unresectable liver metastases. This includes both infusional and local ablative therapies. Hepatic arterial infusional (HAI) therapy, isolated hepatic perfusion (IHP), chemoembolization, cryotherapy, radiofrequency ablation, and ethanol ablation are all examples.

Local ablative therapies are attractive because they target and obliterate established tumor deposits with limited damage to the surrounding normal hepatic parenchyma. In addition, they have minimal systemic side effects. However, they are restricted by both the size and number of lesions to which they can be applied. In a review of the treatment of patients with HCC, percutaneous local ablative therapy is effective only for tumors less than 5 cm in diameter and less than three in number [17]. In addition, physical proximity of lesions to vascular or biliary structures can make the metastatic deposits unamenable to this therapy. Lastly, local ablative techniques do not address small occult or microscopic metastases.

Regional chemotherapy to the liver takes advantage of directed intensive chemotherapy that has minimal systemic toxicity. It treats the entire organ at risk, including small undetected or microscopic metastases that local ablative therapies may miss. IHP and HAI are two examples of regional chemotherapy. HAI delivers chemotherapy usually via a subcutaneously implanted port or pump. By using chemotherapies with high first-pass extraction through the liver, the systemic toxicity can be minimized and higher doses of the chemotherapy can be used. In addition, established hepatic metastases derive their blood supply predominantly from the hepatic arterial circulation [18], therefore providing an opportunity to maximize delivery of chemotherapy to established hepatic metastases by infusion through the hepatic artery [19, 20]. However, many prospective random assignment trials have failed to consistently demonstrate a survival advantage compared with systemic chemotherapy in patients with metastatic colorectal cancer to the liver [7–9, 21, 22]. Vascular isolation and perfusion of a cancer-bearing region or organ of the body have been used clinically for over 50 years [23]. The use of vascular isolation and perfusion can be applied to any cancer-bearing organ or region to which the arterial and venous supply can be isolated and diverted from the systemic circulation. Isolated perfusion of the lung [24–26], the kidney [27], and the extremities [28] has been performed.

IHP was first performed more than 40 years ago by Ausman [29]. During IHP the liver is completely isolated from the systemic circulation, allowing a high concentration of the agent to be infused with minimal exposure to the systemic circulation. The treatment dose is only limited by the toxicity of the drug to the liver and not the patient as a whole. High-dose biological therapy using tumor necrosis factor (TNF) that is not tolerated systemically can also be used. In contrast to HAI, various chemotherapies with a lower first-pass extraction can be used since the liver is perfused using a recirculating system without exposure to systemic circulation over time. Finally, hyperthermia can be a component of treatment. Hyperthermia may have direct tumoricidal activity and has established synergistic effects with chemotherapeutic or biologic agents in experimental models [30–34].


   OPERATIVE TECHNIQUE
Top
 Learning Objectives
 Abstract
 Introduction
 Operative Technique
Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
 References
 
The current technique of IHP has been described in detail and is summarized here [35]. The pretreatment evaluation includes computed tomography scans of the chest, abdomen, and pelvis along with magnetic resonance imaging of the liver to evaluate the extent of hepatic disease and to define hepatic vascular anatomy. In addition, if the patient has undergone previous chemoembolization or HAI, they undergo angiography to assess hepatic vascular anatomy. In rare cases of aberrant arterial anatomy, multiple inflow catheters can be used.

A limited incision is made initially to allow exploration and determination of the actual extent of disease and to evaluate the mobility of the liver. The degree of lymphadenopathy is assessed and, if limited to the porta hepatis, it is resected and the procedure progresses forward. Peritoneal implants or more extensive adenopathy preclude perfusion, and the dissection would be terminated at this point.

If no contraindication to perfusion is identified, the incision is extended. The liver is fully mobilized and the inferior vena cava (IVC) is exposed. All of the retroperitoneal venous tributaries to the IVC, including the right adrenal vein and the suprahepatic phrenic veins, are ligated. Structures of the porta hepatis are skeletonized and mobilized. A segment of the gastroduodenal artery is dissected to serve as the arterial cannulation site for the isolated hepatic perfusion. The gall bladder is removed to prevent postoperative chemical cholecystitis. Finally, a saphenous and axillary vein cutdown are performed.

A veno-venous bypass circuit is then set up with IVC and portal blood flow incorporated into this circuit. Once this is complete, the IVC can be occluded supra- and infrahepatically with vascular cross clamps and the infrahepatic caval blood flow and portal flow are shunted to the axillary vein.

A venous return cannula is positioned in the retrohepatic portion of the IVC just below the hepatic veins to collect the venous effluent. This cannula is connected to the venous outflow line of the extracorporeal bypass circuit for isolated perfusion. The arterial inflow catheter is introduced into the gastroduodenal artery and positioned at the confluence of the common hepatic artery and the gastroduodenal artery. Some centers have used a dual inflow system to both the hepatic artery and the portal vein; however, there is no clear-cut advantage over hepatic arterial perfusion alone. Supra- and infrahepatic caval cross clamps are then applied and the perfusion is initiated using a roller pump, heat exchanger, and a bubble oxygenator (Fig. 1Go). Hepatic temperature is monitored to ensure adequate hyperthermia and to ensure uniform delivery of perfusate to both hepatic lobes.



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  		Figure 1. Illustration of the IHP circuit. The perfusion circuit is shown on the patient’s right. Arterial inflow through the hepatic artery is via a cannula in the gastroduodenal artery. Venous outflow from the hepatic veins is collected via a cannula placed in an isolated segment of the retrohepatic IVC. Vascular occluding clamps are shown on the IVC above and below the liver and on the hepatic artery to isolate the vascular inflow and outflow of the liver. On the patient’s left is the veno-venous bypass circuit that shunts blood from the portal vein and infrahepatic IVC to the systemic circulation (via the axillary vein) using a centrifugal pump.

 
Table 1Go lists typical perfusion parameters. Stable perfusion parameters are achieved almost immediately with rapid and uniform heating of the liver parenchyma. Initially, monitoring for intraoperative perfusate leak was routinely used. However, after numerous leak-free procedures were performed, this monitoring was thought to be unnecessary and is no longer performed [35]. After perfusion is complete, the liver is flushed to remove residual chemotherapy or biological agents. Circulating levels of therapeutic agents are minimal or not detectable after treatment. After the flush the vessels are decannulated and vascular repairs are made.


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  		Table 1. Typical IHP treatment parameters
 
Because this technique requires extensive manipulation of the tumor-burdened liver, we initially had concerns regarding microembolization of tumor cells during treatment. This was evaluated by Wu et al. by performing reverse transcriptase/polymerase chain reaction with primers for tyrosinase or carcinoembryonic antigen from patients with ocular melanoma or colon carcinoma who underwent IHP [36]. No circulating tumor cells were detected in the systemic circulation.

More recently, investigations into the use of a percutaneous method of IHP with melphalan have been started. The circuit for percutaneous hepatic perfusion is shown in Figure 2Go. HAI of melphalan is via a percutaneously placed catheter in the femoral artery, and hepatic venous outflow is collected by a second cannula placed percutaneously through the femoral vein using fluoroscopy. This catheter also possesses two balloons that are localized to inflated in the supra- and infrahepatic vena cava to isolate the hepatic circulation from the systemic circulation. Hepatic venous effluent is melphalan extracted via in-line activated charcoal filters before blood is returned to the systemic circulation. Results of a phase I feasibility study with escalating dose melphalan have been reported [37]. Extraction efficiency of the filters was over 80% and antitumor activity was observed in 5 of 12 evaluable patients after four planned treatments given every 3 weeks. With this approach the patient is spared a laparotomy and extensive dissection required for the open method, and the duration of the procedure is shortened.



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  		Figure 2. Illustration of the percutaneous HP circuit. The perfusion circuit is shown on the patient’s right (Panel A). Arterial inflow through the hepatic artery is via a percutaneously placed catheter in the femoral artery. Venous outflow from the hepatic veins is collected via a cannula placed in an isolated segment of the retrohepatic IVC with balloons that sit above and below the liver and isolate the hepatic. Panel B demonstrates the catheter within the IVC and the holes within the catheter that collect the hepatic effluent and shunts it toward the perfusion circuit. Panel C shows angiographic confirmation of the placement of the IVC balloons and the lack of leak around the balloons.

 

   RECENT CLINICAL RESULTS WITH IHP
Top
 Learning Objectives
 Abstract
 Introduction
 Operative Technique
 Recent Clinical Results With...
Results of IHP Related...
 Conclusions
 References
 
Over the past decade IHP has been investigated at several centers including the National Cancer Institute (Table 2Go). Interpretation and comparison of the results from these different studies are difficult because of the use of nonstandard response criteria at some centers and differences in treatment regimens. Regimens have included doxorubicin, cisplatin, mitomycin C, and melphalan with or without TNF. In addition, multiple tumor types, often in small numbers of patients, make it difficult to draw conclusions regarding efficacy. Some studies have reported the use of IHP as an adjuvant treatment at the time of hepatic resection [38, 39]; however, the majority of studies have used IHP as primary treatment for unresectable hepatic tumors (Table 2Go).


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  		Table 2. Summary of IHP trials reported after 1993
 
The majority of studies over the past 10 years have evaluated treatment with melphalan with or without TNF. Interest in the use of melphalan and TNF for IHP stemmed from a report by Lienard et al. in which patients with in-transit melanoma or unresectable sarcoma underwent isolated limb perfusion with hyperthermia, melphalan, and TNF [40]. The trial, largely confirmed by others, showed a complete response rate of greater than 75% for patients with in-transit melanoma and limb salvage of greater than 80% for patients with initially unresectable extremity sarcoma. TNF is a good agent for use in IHP since it has been shown to have antitumor efficacy with a single dose in murine models, has significant dose-limiting toxicity following systemic administration, and has synergy with chemotherapy and hyperthermia in experimental models [41].

We have shown melphalan and TNF can be effectively contained within the perfusion circuit (Fig. 3Go). The cardiovascular effects, hepatic toxicities, and cytokine production after treatment with TNF in the perfusion circuit have been evaluated. The use of TNF is associated with tachycardia and mild hypotension for 12–24 hours after treatment, which is likely secondary to the release of inflammatory cytokines, such as interleukin-6 and interleukin-8 [42–45]. However, in most circumstances these are not clinically significant toxicities. Transient hepatic toxicity is manifested by elevations in transaminases and serum bilirubin level that peak within 24–48 hours after treatment and return to baseline by 30 days after perfusion [23].



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  		Figure 3. The plots represent the mean (± standard deviation) of TNF concentrations over time in the systemic circulation and perfusate in 32 individuals undergoing isolated IHP [66].

 

   RESULTS OF IHP RELATED TO HISTOLOGY
Top
 Learning Objectives
 Abstract
 Introduction
 Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
Conclusions
 References
 
Colorectal Carcinoma
Results of series of patients with colorectal cancer undergoing IHP have been reported. In one study, 51 patients underwent a 60-minute hyperthermic IHP with melphalan and TNF (32 patients) or melphalan alone followed by postoperative hepatic intra-arterial infusional 5-fluoro-2'-deoxyuridine (FUDR) and leucovorin (19 patients) (Table 3Go) [46]. The HAI was given for 14 days monthly for up to 12 months starting 6 weeks after surgery. The median operative time for this study was 8.5–9 hours with a median blood loss of 2.2 l and a range of 1–5 l. This reflects the considerable time necessary to mobilize and prepare the liver for perfusion, which did not decrease substantially with additional experience in performing the procedure. Morbidity associated with IHP is not inconsequential; the grade 3/4 treatment toxicities are listed in Table 4Go. Hypotension and hyperbilirubinemia were more common in the group receiving TNF but were generally mild and not of significant clinical consequence [42]. The overall high frequency of hepatic toxicity reflects the effects of high-dose hyperthermic chemotherapy being delivered to the entire hepatic parenchyma and in almost every case was transient in nature and required no intervention. The perioperative morbidity included one reoperation for bleeding. Five patients needed reintubation postoperatively secondary to poor ventilation, pulmonary edema, or adult respiratory distress syndrome. There was one perioperative death (2%). The overall objective radiographic response rate (all partial) was 76% (38 of 50 assessable patients), with a median duration of 10.5 months (range, 2–21 months). Twenty-four of 31 patients who had IHP alone (77%) had a partial response and 14 of 19 patients (74%) had a response after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI. Median survival was 16 and 27 months, respectively. There was a 69% response rate in those who failed prior therapy and a 67% response rate in those with partial hepatic replacement of 25% or greater. Post-IHP HAI appeared to prolong the duration of response and was associated with a longer survival. IHP was performed with acceptably low morbidity, and significant antitumor activity was seen in patients with unresectable hepatic metastases from colorectal cancer, including those with refractory disease or high disease burden.


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  		Table 3. Results of IHP ± HAI for patients with colorectal cancer
 

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  		Table 4. Grade 3/4 toxicities after IHP/TNF/melphalan or IHP/melphalan followed by HAI in 51 patients with metastatic colorectal cancer
 
IHP alone has good activity in patients with metastatic colorectal cancer metastases that are refractory to both previous systemic and regional chemotherapy [47]. Seven patients who had failed previous systemic and regional HAI therapy were treated with IHP using TNF alone (n = 2), melphalan with TNF (n = 3), or melphalan alone (n = 2). In this study the median operative time was 9.5 hours (range, 6.25–10.6 hours), with a median blood loss of 2,557 ml (range, 800–4,000 ml), consistent with the experience in the larger cohort of colorectal cancer patients treated with IHP. At a median potential follow-up of 16 months, the overall objective radiographic response rate (all partial responses) was 71% (5 of 7 assessable patients) (Fig. 4Go). The two patients who did not experience a response were treated with TNF alone. IHP with melphalan also has good activity in patients who have been previously treated with irinotecan, 5-FU, and leucovorin (IFL). In 25 patients with progressive colorectal cancer after IFL or irinotecan alone, IHP with melphalan resulted in an overall response rate of 64% (1 complete response; 15 partial response). The median duration of response was 11 months (range, 3–16 months). The median survival for the patients was 11 months (range, 1–27 months) and a 2-year survival of 28%. The results demonstrate that IHP has significant antitumor effects in patients who have already shown resistance to other therapies.



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  		Figure 4. T1-weighted magnetic resonance imaging studies in a patient with unresectable colorectal metastases confined to the liver. Previous systemic and intra-arterial chemotherapy failed and the patient underwent a 60-minute hyperthermic IHP with melphalan alone. The top panels show the pretreatment images through the liver and the bottom panels show the corresponding images post-treatment demonstrating a stable partial response at 13 months [67].

 
IHP has been shown to have efficacy when administered in patients who have experienced tumor progression after irinotecan-based systemic therapy. Of 25 patients who underwent IHP with melphalan at our institution as a second-line treatment after irinotecan, the overall radiographic response rate was 60% and the 2-year survival was 28% (Fig. 5Go). These data suggest that IHP may have benefit in patients with colorectal cancer liver metastases after tumor progression with newly available treatment agents such as oxaliplatin or irinotecan.



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  		Figure 5. Kaplan-Meier actuarial overall survival curve of 25 patients undergoing IHP for metastatic colorectal cancer that progressed on treatment with irinotecan-based therapy.

 
Ocular Melanoma
The liver is the sole or initial site of metastases in 70%–90% of individuals who recur with ocular melanoma [4, 5]. Once liver metastases are diagnosed, median survival is only 2–7 months [4]. Chemoembolization and intra-arterial chemotherapy have only modest activity but are the most efficacious therapies reported. Mavligit et al. [48] reported a 46% overall radiographic response rate and a median survival of 11 months in 30 patients with this condition treated with chemoembolization, and Leyvraz et al. [49] reported a 40% response rate and median survival of 14 months in 30 patients treated with HAI using fotemustine.

We have reported previously our treatment of 22 patients with metastatic ocular melanoma with IHP using melphalan and TNF (n = 11) or melphalan alone (n = 11) [49]. As is consistent with our previous studies, the mean operative time was 8.4 hours overall with a mean blood loss of 1,919 ml. The toxicities are listed in Table 5Go. There was one treatment-related death (5%). Of the 21 evaluable patients there was an overall response rate of 62%, including two radiographic complete responses (9.5%) and 11 partial responses (52%). The overall median duration of response was 9 months (range, 5–50 months), which was significantly longer in those treated with TNF than without (14 versus 6 months, respectively; p = 0.04). Overall median survival in 22 patients was 11 months.


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  		Table 5. Toxicity and morbidity in patients with metastatic ocular melanoma treated with IHP
 
More recently, results of 29 patients treated with a 60-minute hyperthermic IHP using melphalan alone have been reported [50]. There was no treatment-related mortality and a transient hepatic toxicity was observed in 19 patients (65%). There were 3 (10%) complete responses (duration: 12, 14+, and 15 months) and 15 (52%) partial responses (mean duration: 10 months) (Table 6Go, Fig. 6Go). The initial site of disease progression included the liver in 17 of 25 patients (68%) who recurred. At a median follow-up of 30.7 months, the median actuarial progression-free and overall survivals were 8 and 12.1 months, respectively. In addition, exploratory univariate survival analysis identified several factors that were associated with survival, including baseline lactate dehydrogenase (LDH) (100–160 versus 161+ U/l), number of metastases (1–20 versus 21–60), size of largest metastases (1.5–7 versus 7.5+ cm), and percent hepatic replacement. These factors were then evaluated in a Cox model, which indicated that the only factor that was significantly independently associated with response and survival was baseline LDH (Fig. 7Go). Treatment with IHP can result in significant regression of metastatic deposits in the liver in the majority of ocular melanoma patients. However, the duration of the response is variable and too often very brief. Further evaluation for patients with this condition is warranted, perhaps with additional agents used in the perfusate to meaningfully improve their outcome.


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  		Table 6. Results of treatment in patients undergoing IHP for liver metastases from ocular melanoma
 


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  		Figure 6. T2-weighted magnetic resonance imaging studies demonstrating a complete response in a patient with ocular melanoma metastatic to the liver before (top panels) and 1 year after IHP (bottom panels) [68].

 


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  		Figure 7. Kaplan-Meier actuarial survival curves of 29 patients(*) undergoing IHP for metastatic ocular melanoma to the liver based on baseline LDH levels. Survival was significantly improved for 10 patients with baseline LDH <160 (upper normal limit = 226 U/l)(O) compared with 17 patients with baseline LDH >160 U/l (X) [68].

 
Primary Hepatic Neoplasms
Primary hepatic neoplasms occur commonly throughout the world. Although preferably treated with surgical resection or hepatic transplantation, many patients are not candidates because of tumor size, location, or number. Many patients with primary hepatic malignancies can have associated hepatic cirrhosis and are not suitable candidates for regional therapy such as IHP. In our clinical trials, patients with biopsy-proven cirrhosis or evidence of significant portal hypertension by history, endoscopy, or radiologic studies are excluded from treatment with IHP. Patients must also have adequate hepatic function as evidenced by bilirubin <2.0 mg/dl and a prothrombin time within 2 seconds of the upper normal limit.

We have reported our results in treating seven patients with unresectable primary hepatic neoplasms with IHP with melphalan and TNF (n = 3) or melphalan alone (n = 4) [51]. Four patients had hepatocellular carcinoma and three had cholangiocarcinoma or adenocarcinoma of unknown primary origin that was presumed to have arisen from hepatobiliary elements. Five of seven patients (71%) had a partial response to IHP. Three patients were alive with disease at a median follow-up of 10 months. Four patients died 6, 11, 15, and 27 months after perfusion.

There are few other reports of IHP for primary hepatic lesions. Four patients with hepatocellular cancer were treated by IHP with melphalan with or without cisplatin by a Swedish group [52]. One patient had a partial response and there were no complete responses. Although there are only limited data, we feel that for those patients who have been evaluated for and do not qualify for other standard treatment options, further evaluation is necessary to evaluate whether IHP should be used in the treatment of unresectable primary hepatic malignancies.

Other Histologies
Few patients with other histologies have been treated in significant numbers. Small numbers of patients with breast cancer, renal cancer, tracheal cancer, and leiomyosarcoma have been treated with IHP and a few responses have been reported. Because many cancers spread to numerous organs and not only to the liver, it is less common for those to be referred for and treated with IHP.

Neuroendocrine tumors are a relatively uncommon tumor that can exhibit isolated hepatic metastases. Seven patients with liver metastases at our last review had been treated at the National Cancer Institute for liver metastases from neuroendocrine tumors. Patients were treated with melphalan alone (4 patients), melphalan with TNF (2 patients), and TNF alone (1 patient). Four of the patients had a partial response (57%). Three died of disease at 7, 13, and 36 months after IHP. We are currently re-evaluating our experience with this histology.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
References
 
Unresectable liver tumors from various tumor histologies are a significant cause of morbidity and mortality for cancer patients. Numerous treatment modalities are available to these patients, and the number of possible treatment options reflects the lack of any one being sufficiently efficacious to be considered conventional therapy. Regional chemotherapeutic strategies have the advantage over local ablative therapies of delivering chemotherapy to the whole liver rather than to isolated locations within the liver. IHP can deliver higher doses of chemotherapy that would not be tolerated through systemic administration or with HAI since there is complete vascular isolation of the liver. Currently, work is being done to evaluate if hepatic perfusion can be performed percutaneously. This would simplify the procedure, making it more widely available. In addition, the patient would not have to undergo a major laparotomy. In the future the efficacy of other agents in this setting will be evaluated, in addition to the possible incorporation of liver perfusion as an adjunct to systemic treatment.

IHP is a therapy that can cause significant physiological changes within its recipient but clearly can be performed safely with the proper patient selection and experience with the procedure. Its efficacy has been demonstrated in multiple histologies, and further studies are ongoing.

The clinical setting in which IHP should be considered deserves comment. As newer and more efficacious systemic treatments have become available for patients with metastatic colorectal cancer, there is understandable enthusiasm for using these systemic regimens as first-line therapy. Response rates with irinotecan- or oxaliplatin-based regimens have response rates and duration of responses on par with what has been reported using HAI with FUDR [3, 53, 54]. However, almost all responses using these regimens are partial in character, and efficacy with these agents as second-line therapy is very modest. For example, oxaliplatin has less than a 10% response rate in patients whose tumors have progressed on irinotecan [13]. Initial data suggesting that IHP has good efficacy in this setting would support its continued evaluation as a second-line treatment modality for patients with metastases confined to liver. In patients with tumor histologies other than colorectal cancer and who have progressive multifocal liver metastases, earlier application of IHP appears justified. All patients enrolled on our approved protocols are counseled regarding other treatment options available to them, the advantages and disadvantages of these treatments, and the experimental nature of this procedure. Current clinical trials to clarify the appropriate clinical setting for IHP are continuing at multiple centers.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Operative Technique
 Recent Clinical Results With...
 Results of IHP Related...
 Conclusions
 References
 

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Received February 12, 2004; accepted for publication June 28, 2004.




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