
<b>Isolated Liver Perfusion & Liver Metastasis 
Selected Medical Journal Annotated Citations</b> 
[For the full abstract, use the links provided, or search on Pubmed.  Ed.] 


1: Arch Surg. 2003 Mar;138(3):325-32.  
<b>Percutaneous isolated hepatic perfusion for chemotherapy: a phase 1 study. </b>
Savier E, Azoulay D, Huguet E, Lokiec F, Gil-Delgado M, Bismuth H. 
Centre Hepato-Biliaire, Hopital Paul Brousse, Villejuif, 94800 France. eric.savier@psl.ap-hop-paris.fr 

Increasing the drug concentration in tumors may produce massive tumoral response. By using a variety of hepatic vascular isolation techniques, high concentrations of chemotherapeutic drugs may be achieved in the hepatic vascular bed. 
...: Ten patients with irresectable and chemoresistant hepatic tumors were eligible for study participation; ...
Patients received 3 successive courses of chemotherapy by IHP. The first course was given at laparotomy, and the next 2 courses were given percutaneously. The interval between courses was 3 to 6 weeks. Each course involved IHP of the liver for 15 to 30 minutes, without oxygenation, with 1 to 3 boluses of melphalan (15 mg). 
...IHPs were performed (4 at laparotomy and 6 percutaneously). Concentrations of melphalan in the extracorporeal circulation were 10 times higher than those in the systemic circulation. Percutaneous IHPs had more leakage than those at laparotomy. However, hepatotoxicity was minimized. One patient experienced hepatic artery thrombosis, and 3 had severe neutropenia. Minor complications included ascites and pleural effusion. No deaths were observed 2 months after the last IHP. One partial response was observed (hepatic metastases of breast cancer). ...<b>Percutaneous IHP for intensive chemotherapy is less aggressive and less hepatotoxic than IHP at laparotomy and may be iterative [repeatable].</b> 
&&url PMID: 12611582 


2: Support Care Cancer. 2003 Jan;11(1):1-10. Epub 2002 Jun 08. 
<b>Curative and palliative aspects of regional chemotherapy in combination with surgery. </b>
Muller H, Hilger R. 
Department of Surgical Oncology, Carl von Hess Hospital, Hammelburg, Germany. h.mueller@klinik-hammelburg.de 

Many attempts have been made in the last two decades to improve the outcome of patients with advanced or metastasised solid tumours. In particular, combined-modality treatment strategies combining surgery with more localised therapies, e.g. radiotherapy, or systemic therapies such as chemotherapy have yielded promising data. The aim of regional chemotherapy is to improve locoregional cytostatic drug concentrations by achieving greater local efficacy and to diminish systemic side effects by reducing plasma drug levels. Highly qualified and experienced exponents of regional chemotherapy can complement surgical measures by applying multimodal strategies, because of their high efficacy in terms of tumour mass reduction without permanent tissue injuries, such as fibrosis or the damage to the vascular bed familiar from radiotherapeutic interventions. During the last 15 years, several new and very effective methods of administration, such as isolated pelvic perfusion or isolated thoracic perfusion, have extended the therapeutic arsenal of regional chemotherapy. The techniques needed for such transcutaneous and minimally invasive approaches as angiographically administered intra-arterial chemotherapy have been improved and side effects and the complication rate, dramatically reduced. <b>Pharmacokinetic evaluations have demonstrated the high efficacy of one of the new regional modes of administration, isolated abdominal perfusion. With this technique, it is possible to attain cytostatic drug concentrations twice as high as those attained with systemic high-dose therapy with the same drug (treosulfan), but with only a quarter of the dosage and without bone marrow transplantation. Such techniques are now also available for the pelvic area, the thoracic region, the chest wall, the liver and the limbs. Regional chemotherapy is a very effective tool for induction therapy when tumours are apparently inoperable, as it can lead to sufficient shrinkage to make such tumours resectable.</b> ...  
&&url PMID: 12527948 


3: Cancer J. 2002 May-Jun;8 Suppl 1:S68-81.  
<b>Surgical approaches to liver metastases. </b>
Alexander HR Jr. 
Surgical Metabolism Section, Surgery, Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland 20892, USA. 

Metastases confined to the liver from tumors arising in the gastrointestinal tract or other sites represent a significant clinical problem. Although the majority of patients present with disease that is not amenable to resection based on the size, number, or anatomic distribution of tumors, for selected patients with limited extent of disease surgical resection can result in long-term survival. ... For patients with unresectable metastases confined to liver, a number of regional therapies are in clinical development and share the advantages of intensifying therapy at the site of tumor while minimizing or eliminating unnecessary systemic exposure and toxicity. One such approach is vascular isolation and perfusion, also known as isolated hepatic perfusion or IHP, in which the liver is treated with high dose chemotherapy and/or biological agents under hyperthermic conditions. <b>Although only a limited number of centers have reported substantial experience with this procedure, it appears to have significant efficacy even in patients with advanced tumor burden orthose with tumors refractory to other types of therapy.</b> The status of IHP is presented. 
&&url PMID: 12075704 


4: Eur J Cancer. 2002 May;38(7):1023-33.  
<b>Treatment of liver metastases, an update on the possibilities and results. </b>
Ruers T, Bleichrodt RP. 
Department of Surgery, University Medical Centre Nijmegen, Nijmegen, The Netherlands. t.ruers@heel.azn.nl 

...only a limited number of patients appear to be candidates for [liver metastases] resection, far more patients prove to have unresectable disease. ... The variables most consistently associated with a poor prognosis and tumour recurrence are tumour-positive resection margins and the presence of extra-hepatic disease. Hence, patient selection and preoperative staging should concentrate on accurate imaging of the liver lesions and the detection of extrahepatic disease. For liver imaging, spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), supplemented by intra-operative ultrasound, are currently regarded as the best methods for evaluating the anatomy and resectability of colorectal liver metastases. Extrahepatic disease should be investigated by spiral CT of the chest and abdomen and when possible by ...positron emission tomography (FDG-PET). <b>Resection remains the gold standard ... In experienced centres, resection is a safe procedure and mortality rates are below 5%. The aim of resection should be to obtain tumour-negative resection margins. Edge cryosurgery should be considered in cases where very close resection margins are anticipated.</b> The role of adjuvant chemotherapy after resection is still controversial, although two recent studies show a clear benefit. <b>For the moment, local tumour ablative therapies such as cryotherapy and radiofrequency therapy should be considered as an adjunct to hepatic resection in those cases in which resection can not deal with all of the tumour lesions. In these cases, there seems a beneficial effect of a combined treatment consisting of resection and local tumour ablation. At this stage, there are no randomised data that local tumour ablation is as effective as resection. For a selected group of patients with unresectable liver metastases, there may be a chance to turn unresectable disease to resectable disease by aggressive neo-adjuvant chemotherapy</b> or portal vein embolisation. <b>For patients with unresectable disease, many different chemotherapy schedules may be used based on systemic drug administration. Regional chemotherapy and isolated liver perfusion should only be used within a study design.</b> [This is a discussion of colorectal metastases, but is probably relevant to LMS liver mets as well.  Editor.]  
&&url PMID: 11978527 


5: Int J Clin Oncol. 2002 Apr;7(2):82-90. 
<b>Isolated hepatic perfusion chemotherapy for unresectable malignant hepatic tumors. </b>
Ku Y, Tominaga M, Iwasaki T, Fukumoto T, Kuroda Y. 
Department of Gastroenterological Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. yonson@med.kobe-u.ac.jp 

Treatment failure with conventional approaches, including systemic and regional chemotherapy, for refractory advanced primary or metastatic hepatic cancers has evoked periodic waves of enthusiasm for isolated hepatic perfusion (IHP) over the past 50 years. With technical refinements of the procedure and the introduction of a novel biochemical regimen combining tumor necrosis factor and melphalan, several hepatobiliary-oncological centers initiated clinical trials of IHP in the 1990s. In parallel, a percutaneous technique of IHP has been developed in this era as a minimally invasive, simple form of IHP, and phase I and II studies have been done in some specialized centers. This study attempts to review past and current techniques of IHP, and to outline their possible role in the treatment of unresectable hepatic tumors, with special reference to hepatocellular carcinoma and colorectal hepatic metastases.  
&&url PMID: 12018114 

6: Semin Oncol. 2002 Apr;29(2):136-44.  
<b>Transarterial perfusion of liver metastases. </b>
Weinreich DM, Alexander HR. 
Metabolism Section, Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA. 

Progressive growth of unresectable metastatic or primary malignancies confined to the liver is a significant clinical problem. ... A number of physiological and anatomic features of the liver make it an ideal organ for regionally directed therapy to allow dose intensification to the cancer-burdened area while reducing or eliminating unnecessary systemic toxicity. To that end, complete vascular isolation and perfusion of the liver using a recirculating extracorporeal circuit, also called isolated hepatic perfusion (IHP), has been under clinical evaluation at our institution and others. In this article, we review the current results with IHP and its potential utility in the treatment of patients with unresectable hepatic malignancies.  
&&url PMID: 11951211 


7: Cancer J. 2002 Mar-Apr;8(2):181-93.  
<b>Isolation perfusion of the liver. </b>
Carroll NM, Alexander HR Jr. 
Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1502, USA. 

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, ... Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.  
&&url PMID: 12004803 


8.Oncol Res 1999;11(11-12):529-37 
<b>A clinical-pharmacological evaluation of percutaneous isolated hepatic infusion of doxorubicin in patients with unresectable liver tumors. </b>
Hwu WJ, Salem RR, Pollak J, Rosenblatt M, D'Andrea E, Leffert JJ, Faraone S, Marsh JC, Pizzorno G. 
Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. hwuw@mskcc.org 

A dose escalation study of hepatic arterial infusion of doxorubicin during hemodynamic isolation of the liver ... was conducted to: 1) study the pharmacokinetics of regional doxorubicin therapy, and 2) define therapeutic efficacy in the treatment of  unresectable liver tumors. Eighteen patients with unresectable primary or metastatic tumor in the liver were treated with 57 procedures.  harmacokinetic studies were performed on all treatments. Hepatic extraction ratio of doxorubicin remained constant at 60.3+/-12.1%. independent of the dose escalation. The calculated intrahepatic concentration of doxorubicin ranged from 30 to 88 microg/ml when the dosage of doxorubicin was escalated from 50 to 120 mg/m2. Dose-limiting  systemic toxicity (grade 4 myelosuppression) was observed at 120 mg/m2. Twelve of 14 patients who received more than one treatment at 90 or 120  mg/m2 were evaluable for disease response: there were 4 partial  responses, 3 minor responses, I stable disease, and 4 progressive  disease. 
The median overall survival of responders was 23 months, and  for nonresponders it was 8 months. We have demonstrated a dose-response  effect of hepatic infusion of doxorubicin at 90 and 120 mg/m2 in  advanced hepatic malignancies. The isolated hepatic perfusion system  improves the therapeutic index of doxorubicin and provides pharmacologic  justification for its use in the treatment of unresectable hepatic  malignancies, especially metastatic melanoma and sarcoma. 
&&url PMID: 10905565 


9. Surgery 2001 Feb;129(2):176-87 
<b>Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. </b>
Bartlett DL, Libutti SK, Figg WD, Fraker DL, Alexander HR. 
Surgery Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 

... Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. .... Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival. ...: There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). .... 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 were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater. ... IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.  Clinical trial 
&&url PMID: 11174711 


10. Gan To Kagaku Ryoho 2000 Oct;27(12):1801-4 
<b>[Phase I study of super high-dose chemotherapy for liver cancer with percutaneous isolated hepatic perfusion (PIHP) and peripheral blood stem cell transplantation (PBSCT)]. [Article in Japanese]</b>
 Takahashi T, Ku Y, Tominaga M, Iwasaki T, Fukumoto T, Takamatsu M, Tsuchida S, Sendou H, Suzuki Y, Kuroda Y. First Dept. of Surgery, Kobe University School of Medicine. 

The aim of this study was to evaluate the phase I aspects of super high-dose chemotherapy for advanced liver cancer with combined use of PIHP and PBSCT.  Clinical trial, phase i 
&&url PMID: 11086416 


11. Hepatogastroenterology 2000 May-Jun;47(33):776-81 
<b>Isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques: from laboratory to the clinic towards a percutaneous procedure.</b> 
Eggermont AM, van IJken MG, van Etten B, van der Sijp JR, ten Hagen TL, Wiggers T, Oudkerk M, de Boeck G, de Bruijn EA.              
Department of Surgical Oncology, University Hospital Rotterdam-Den Hoed Cancer Center (UHR-DHCC), The Netherlands. eggermont@chih.azr.nl 

... The success of and our extensive experience with TNF alpha-based isolated limb perfusions in patients with unresectable extremity soft tissue sarcomas made us explore the possibilities for a similar approach for the treatment of hepatic metastases. After experience with the classic surgical isolated hepatic perfusion in pigs and in patients, we concluded that the classic surgical approach was associated with serious drawbacks i.e., magnitude of the procedure with morbidity, lack of repeatability of the procedure, complexity and costs. .... ...We aim to develop step by step a fully percutaneous approach for isolated hypoxic hepatic perfusion. ... 
&&url PMID: 10919031 


12. Ann Surg Oncol 1999 Oct-Nov;6(7):658-63 Comment in: Ann Surg Oncol. 1999 Oct-Nov;6(7):631-2 
<b>Isolated organ perfusion does not result in systemic microembolization of tumor cells.</b>
Wu PC, McCart A, Hewitt SM, Turner E, Libutti SK, Bartlett DL, Alexander HR. 
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 

... Isolated organ perfusion with hyperthermia and melphalan with or without tumor necrosis factor-alpha has been effectively used to treat regionally confined, unresectable malignancies of both the limb and liver. Many patients, however, will eventually relapse at distant sites. We used reverse transcription-polymerase chain reaction (RT-PCR) to determine whether significant tumor microembolization occurs in patients undergoing isolated limb perfusion (ILP), isolated hepatic perfusion (IHP), or hepatic resection. ...Primers specific for the human tyrosinase gene or carcinoembryonic antigen gene were designed for RT-PCR to screen melanoma or colon adenocarcinoma, respectively. RNA from human melanoma lines (Pmel and 1286) and human colon adenocarcinoma lines (H508 and HT29) were used to generate positive control cDNA. ......RT-PCR is a highly sensitive method of detecting tumor cells in perfusate or blood. Manipulation of the limb or liver followed by resection or isolated hyperthermic perfusion does not cause detectable release of circulating tumor cells. The late development of distant metastases observed in many of these patients does not correlate with the ability to measure circulating tumor cells during regional therapy. 
&&url PMID: 10560851 


13. Eur J Surg Oncol 1999 Apr;25(2):179-85 
<b>Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan.</b> 
Lindner P, Fjalling M, Hafstrom L, Kierulff-Nielsen H, Mattsson J, Schersten T, Rizell M, Naredi P.                        
Department of Surgery, Sahlgrenska University Hospital, Goteborg, Sweden.

 ... To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions. ... A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillary vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h. ... Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. <b>Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma</b> showed a partial response while no patients with liver metastases from colorectal cancer showed any response. <b>The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies.</b> ...IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies. Clinical trial, phase i 
&&url PMID: 10218462 


14. Gan To Kagaku Ryoho 1998 Jul;25(9):1266-8 
<b>[The long-term results of percutaneous isolated hepatic perfusion for patients with advanced hepatocellular carcinoma].</b> [Article in Japanese] 
Ku Y, Tominaga M, Iwasaki T, Fukumoto T, Muramatsu S, Kusunoki N, Kuroda Y, Matsumoto S, Hirota S. 
First Dept. of Surgery, Faculty of Medicine, Kobe University. 

... These results indicated that PIHP achieved a 5-year survival rate of approximately 40% in patients with multiple advanced hepatocellular carcinoma in the absence of distant organ metastases and marked vascular invasion, and yielded complete long-term remission in some of these patients. 
&&url PMID: 9703804 


15. Recent Results Cancer Res 1998;147:120-6 
<b>Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia TNF alpha and melphalan: Swedish experience.</b> 
Hafstrom L, Naredi P. 
Department of Surgery, University Hospital, Umea, Sweden. 

A phase I trial was performed to determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF) and melphalan (Alkeran) under mild hyperthermic conditions. Eleven patients with unresectable metastatic malignancies in the liver (malignant melanoma, leiomyosarcoma, colorectal cancer) underwent the procedure. Compared to our earlier experience with melphalan and cis-platinum under hyperthermic conditions (41.7 degrees C), this phase I study with TNF 30-200 micrograms and melphalan ).5 mg/kg body weight under 39 degrees C hyperthermia neither improved the response rate nor decreased the serious adverse effects. Two patients died within the first postoperative month owing to coagulopathy or multiple organ failure. Five patients were reoperated owing to postoperative bleeding. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma and none of five patients with liver metastases from colorectal cancer showed a partial response. Clinical trial, phase i 
&&url PMID: 9670274 


16. Recent Results Cancer Res 1998;147:67-82 
<b>Percutaneous isolated liver chemoperfusion for treatment of unresectable malignant liver tumors: technique, pharmacokinetics, clinical results. </b>
Ku Y, Iwasaki T, Fukumoto T, Tominaga M, Muramatsu S, Kusunoki N, Sugimoto T, Suzuki Y, Kuroda Y, Saitoh Y. 
First Department of Surgery, Kobe University School of Medicine, Japan. 

We have developed a single-catheter technique for percutaneous isolated liver chemoperfusion (PILP) with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) for the treatment of malignant liver tumors. We report here the surgical technique, pharmacokinetics, and effectiveness of PILP in multiple advanced liver tumors. ... Two of forty-six patients died early; one of necrotizing pancreatitis and the other of hepatic arterial thrombosis. Both deaths were related directly to the hepatic arterial catheter. <b>Excluding these two deaths, the treatments were well tolerated. The major side effects were mild to moderate chemical hepatitis and reversible myelosuppression. ..., the results suggest a role of multiple treatment courses of PILP in the induction of long-term remission, especially for patients responsive to the first treatment. </b>
&&url PMID: 9670270 


17. Recent Results Cancer Res 1998;147:3-12 
<b>Are there indications for intra arterial hepatic chemotherapy or isolated liver perfusion? The case of liver metastases from colorectal cancer.</b> 
Rougier P. 
Service d'hepato-gastroenterologie, Hopital Ambroise Pare, Boulogne, France. 

Intraarterial hepatic chemotherapy (IAHC) has been used for many years to treat liver tumors (primary or secondary) if no extrahepatic extension exists, when no resection is feasible, and when no active systemic chemotherapy is available. ... IAHC and isolated liver perfusion are two active locoregional treatments which can be combined with surgical resection and/or systemic chemotherapy and warrant further development, if possible, in randomized trials. 
&&url PMID: 9670263 


18. Surgery 1998 Jun;123(6):622-31 
<b>First experience and technical aspects of isolated liver perfusion for extensive liver metastasis.</b>
Oldhafer KJ, Lang H, Frerker M, Moreno L, Chavan A, Flemming P, Nadalin S, Schmoll E, Pichlmayr R.             
Department of Abdominal and Transplantation Surgery, Hannover Medical School, Germany. 

... New drugs and modalities for locoregional tumor treatment in recent years may offer new potential for isolated liver perfusion in patients with nonresectable liver tumors. The purpose of this study was to prove the feasibility of arterial isolated liver perfusion and to assess the tolerance of perfusion with high-dose tumor necrosis factor (TNF). ... Twelve patients with extensive liver metastases previously treated unsuccessfully with systemic chemotherapy underwent isolated hyperthermic liver perfusion using a heart-lung machine. High doses of mitomycin were administered in the first six and a combination of TNF and melphalan in the last six patients. ... No operative death occurred and no direct postoperative liver failure was observed in any patient. In cases of variations of the arterial hepatic blood supply, the perfusion was done through the splenic artery or an angiography catheter. <b>Histologic analysis of tumor biopsy specimens obtained on the first postoperative day revealed major tumor necrosis in 8 of 12 patients. ... Isolated arterial perfusion of the liver is a complex surgical procedure that is feasible in patients with anatomic variations of the hepatic artery. The remarkable histologic response to perfusion in several pretreated patients, especially after application of high-dose TNF and melphalan, suggests that this modality is very effective in tumor killing.</b> &&url 
&&url PMID: 9626312 


19. Semin Surg Oncol 1998 Apr-May;14(3):262-8 
<b>Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy in the treatment of irresectable liver metastases? </b>
Vahrmeijer AL, Van Der Eb MM, Van Dierendonck JH, Kuppen PJ, Van De Velde CJ. 
Department of Surgery, Leiden University Medical Center, The Netherlands. 

The prognosis of patients with irresectable liver metastases derived from colorectal cancer is invariably poor; unfortunately, these tumours show only minor responses to conventional anticancer agents. The best responses have been obtained by fluoropyrimidines delivered as continuous infusion into the hepatic artery (HAI): their rapid uptake and detoxification by liver cells results in relatively low systemic drugs levels. This approach increases mean survival duration from 17 to 26 months and, in few patients, causes "down-staging" that may result in resectability. <b>To improve opportunities for chemotherapy, the technique of 1-hour recirculating perfusion of the vascularly isolated liver (isolated hepatic perfusion, IHP) was developed. If leakage to the systemic circulation is negligible-and the compounds used do not readily cause hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered systemically.</b> .... However, despite preliminary data that indicate impressive clinical responses are obtained, improvement over HAI will probably be minor. Because IHP is a complicated way of drug delivery, one could argue that its use is justified only when it has the potential to kill all tumour cells in the liver. We critically discuss the possibilities of IHP and/or the use of gene therapy in an IHP setting.  phase ii Review,  
&&url PMID: 9548610 


20. Surg Oncol 1994 Apr;3(2):103-8 
<b>Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. </b>
Hafstrom LR, Holmberg SB, Naredi PL, Lindner PG, Bengtsson A, Tidebrant G, Schersten TS. 
Department of Surgery, Sahlgrenska Hospital, Goteborg, Sweden. 

In an open study of unresectable liver tumours, isolated regional perfusion with hyperthermia and cytotoxic drugs has been tested in 29 patients. Four patients had primary hepatocellular cancer, 10 patients had metastases from malignant melanoma, remaining from breast cancer, colorectal cancer, midgut carcinoids and miscellaneous primaries. At laparotomy the proper hepatic artery and portal vein were canulated and connected to a pump oxygenator. The inferior vena cava was canulated with a triple lumen catheter (Perfufix) allowing for porto-caval shunting, drainage of lower body and renal veins to the heart and separate drainage of liver veins to the pump oxygenator. Liver perfusion was performed with a mean flow of 900 ml per min. Melphalan and cis-platinum 0.5 mg/kg body-weight were added to the perfusate for 1 h after liver temperature reached 40 degrees C.<b> Four patients died within 30 days of perfusion due to multiple organ failure. These patients had more than 50% of liver volume occupied by cancer. All surviving patients developed reversible hepato- and renal toxicity. Partial tumour regression was registered in 20% of the patients. Five patients have survived more than three years. Hyperthermic liver perfusion is feasible but in patients with massive liver tumour, there is a significant risk of developing multiple organ failure. </b>Clinical trial, phase 
&&url PMID: 7952389 


21. J Clin Oncol 1994 Dec;12(12):2723- 
<b>Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors. </b>
Ravikumar TS, Pizzorno G, Bodden W, Marsh J, Strair R, Pollack J, Hendler R, Hanna J, D'Andrea E. 
Section of Surgical Oncology, Yale School of Medicine, New Haven, CT. 

... This prospective, nonrandomized trial evaluated a percutaneous isolated chemotherapy perfusion approach for treating advanced primary and metastatic liver tumors. Chemotherapy was administered via hepatic artery catheter and hepatic venous blood isolated by a novel percutaneous double-balloon inferior vena cava (IVC) catheter was passed through a detoxification/filtration cartridge in a venovenous bypass circuit. ... Among 23 patients enrolled onto the study, 58 procedures were performed on 21 patients. Twelve patients received dose escalations of fluorouracil (5-FU) (1,000 mg/m2 to 5,000 mg/m2), and nine received dose escalations of doxorubicin (50 mg/m2 to 120 mg/m2). Pharmacokinetic studies included drug accumulation in the liver, extraction by detoxification filters, systemic exposure, and alterations of half-life. Each patient received two treatments at 3-week intervals. Those showing stabilization or response received additional treatments. ... There was a direct relationship between dose and peak concentration of drug entering the hepatic veins. The system functioned efficiently throughout the dose range, with extraction efficiencies ranging from 64% to 91% (P < .001). The hepatic vein drug levels showed a sixfold increase in 5-FU with dose escalation from 1,000 to 5,000 mg/m2, and a twofold increase in dox with dose escalation from 50 to 120 mg/m2 (P < .001, filter-mediated drug extraction). <b>The treatments were accomplished with only an overnight hospital stay and no mortality. The common procedure-related toxicity was transient hypotension (grade I to II), due to catecholamine depletion by the filter. Dose-limiting toxicity (leukopenia) was observed in patients receiving 5-FU at a dose of 5,000 mg/m2 and doxorubicin at a dose of 120 mg/m2. Significant tumor response (> 95% reduction) was obtained in two patients receiving doxorubicin at 90 mg/m2 and 120 mg/m2.</b> ... The use of a double-balloon catheter to isolate and detoxify hepatic venous blood during intraarterial therapy is technically feasible, safe, and allows administration of large doses of intrahepatic chemotherapy at short intervals. ... Clinical Trial 
&&url PMID: 7989950 

updated Nov 2003
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