
    Local Control: Liver Metastases Part 2  Other Methods
    written and compiled by doctordee  may 2001


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Metastatic Disease -- Local Control -- Treatment Options by Site - Liver  Part 2  

Liver Metastases: General Discussion
Part 1 Surgical and Ablative Methods[Webmeister..Link  this line to the page]
Part 2 Methods other than Surgical or Ablative                     
* Percutaneous Ethanol Injection 
* Hepatic Arterial Infusion [HAI]  
* Arterial Embolization and Chemoembolization
* Isolated Liver Perfusion [IHP] 
* Stop-flow Perfusion 
* Radiation/Radioisotope Embolization  

Liver Metastases-General Discussion 
Liver metastasis is a life-threatening prognostic aspect. However, tremendous strides have been made in the past decade, such as improved diagnostic capabilities, safe surgical resection, availability of safe nonsurgical ablative modalities, multimodality therapy, and aggressive approach to recurrent disease. Remember, the liver has the capacity to regenerate its tissue, not like lung or kidney.

It is now accepted that liver resection should be done surgically as the treatment of choice when the complete excision of all demonstrable tumor with clear resection margins is feasible.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10682768&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10749609&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9834411&dopt=Abstract
 [In the presence of other abdominal tumors or of inoperable lung tumors, however, this may not be the treatment of choice.]

If liver tumors are inoperable, ablative methods are probably the techniques of choice, if the tumor size and location are favorable.  If the liver tumors are inoperable, and cannot be ablated, neoadjuvant treatment with chemotherapy or one of these techniques might downsize the tumors so that they become surgically resectable.
Regional chemotherapy might be useful combined with hepatic resection or as palliative therapy. Patients with localized, unresectable hepatic metastases or coexisting serious medical condition(s) may be candidates for radiation, percutaneous ethanol injection, cryosurgery, percutaneous radiofrequency, microwave, laser, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization or chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival.  
For primary or secondary tumors of the liver, six existing minimally invasive techniques for the treatment of primary and secondary malignant hepatic tumors--radio-frequency ablation, microwave ablation, laser ablation, cryosurgical ablation, ethanol ablation, and chemoembolization have each exceeded clinical results obtained with conventional chemo- or radiation therapy. Thus, for nonsurgical patients, these techniques are becoming standard independent or adjuvant therapies. In addition, with continued improvement in technology and increasing clinical experience, one or more of these minimally invasive techniques may soon challenge surgical resection as the treatment of choice for patients with limited hepatic tumor.
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Percutaneous Ethanol Injection [PEI] & Liver Metastases 

Percutaneous interstitial [within the tissue] systems to induce hepatic tumor necrosis are classifiable in two major groups: those using chemical agents (ethanol and acetic acid) and those adopting thermal effects (hot saline, radiofrequency, laser and microwave).
Percutaneous Ethanol Injection [PEI] is the injection of ethyl alcohol in high concentration, through the skin, directly into liver tumors. This is done under ultrasound or radiographic visualization. Local infiltration or intravascular injection of ethanol leads to cell death by causing cell membrane lysis, protein denaturation, and vascular occlusion. Percutaneously injected ethanol is now used in the ablation of hepatic cysts and solid tumors.  As a treatment agent, ethanol combines the benefits of being widely available, inexpensive, efficacious, and relatively easy to administer. Optimal results require that the radiologist have considerable experience in scanning techniques and facility with percutaneous needle insertion under real-time visualization. Percutaneous ethanol injection therapy has a low complication rate.
For the latest Pubmed Search on Percutaneous Ethanol Injection and Liver Metastases:  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=percutaneous%20ethanol%20injection%20hepatic%20metastases
For discussion of complications, see the abstracts below.

Percutaneous Ethanol Injection [PEI] in the Treatment of Liver Metastases
Selected Annotated Medical Journal References

[For the full abstract, use the links provided, or search on Pubmed.  Ed.]

 
Acta Radiol 1996 Sep;37(5):655-9 
Complications following high-dose percutaneous ethanol injection into hepatic tumors. 
Tapani E, Soiva M, Lavonen J, Ristkari S, Vehmas T. 
Department of Radiology, Helsinki University Central Hospital, Finland. 
... Percutaneous ethanol injection therapy (PEIT) with a 2-10 ml ethanol dose per session is widely used in the treatment of small hepatocellular carcinoma. Larger doses have been restricted for fear of complications. The aim of the present study was to make a retrospective evaluation of the complications following treatment of hepatic tumors with high doses of ethanol (up to 200 ml). ... ....: Serious complications did not occur. Pain was a common side effect, occurring in 48% of the procedures. Immediate pain during the treatment was related to the ethanol dose and increased significantly with increasing doses (p < 0.01). Other side effects were rare. ... PEIT with doses higher than previously reported seems to be safe. This should encourage further clinical studies that aim at fully working out the clinical value of such treatment. PMID: 8915270 

J Ultrasound Med 1998 Aug;17(8):531-3 Comment in: J Ultrasound Med. 1999 Apr;18(4):314 
Complications of percutaneous ethanol ablation. 
Gelczer RK, Charboneau JW, Hussain S, Brown DL Department of Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. 
Percutaneous ethanol injection therapy performed with sonographic visualization is a steadily growing therapeutic method that can be used in the ablation of solid and cystic masses in a variety of anatomic locations.... Local infiltration or intravascular injection of ethanol leads to cell death by causing cell membrane lysis, protein denaturation, and vascular occlusion. ... percutaneously injected ethanol is now used in the ablation of hepatic cysts and solid tumors, ...As a treatment agent, ethanol combines the benefits of being widely available, inexpensive, efficacious, and relatively easy to administer. Optimal results require that the radiologist have considerable experience in ultrasonographic scanning techniques and facility with percutaneous needle insertion under real-time visualization. Alternatively, the radiologist may choose CT as a method to visualize needle placement. Percutaneous ethanol injection therapy ... has a low complication rate. We present two patients in whom hypotensive complications occurred during percutaneous ethanol injection therapy and discuss the likely causative mechanisms. PMID: 9697961 

Liver Transpl Surg 1998 Jul;4(4):271-5 
An appraisal of percutaneous treatment of liver metastases. 
Mazziotti A, Grazi GL, Gardini A, Cescon M, Pierangeli F, Ercolani G, Jovine E, Cavallari A. 
Policlinico S. Orsola, University of Bologna, Italy. 

"Percutaneous treatments, such as ethanol injection and radiofrequency, have been recently proposed for the treatment of liver metastases. The aim of this study was to evaluate the effects of these treatments in ... 8 patients who subsequently underwent liver resection." "These patients had been treated with percutaneous methods between December 1995 and May 1997.... the primary tumor was... in 1 patient, ileal leiomyosarcoma. The lesions were all initially small...The number of...[treatments]... ranged from 2 to 21. In all patients, a progression of the disease occurred... Histologic examination of all surgical specimens revealed the presence of vital neoplastic tissue; only two specimens of carcinoid tumors showed more than 50% necrosis of the nodules treated percutaneously. These results led us to express doubts as to the efficacy of percutaneous ablative treatment for liver metastases." Copyright 1998 W.B. Saunders Company. PMID: 9649639 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9649639&dopt=Abstract


Acad Radiol 1997 Sep;4(9):634-8 
Liver tumor ablation: real-time monitoring with dynamic CT. [In rabbits. ed.] 
Hahn PF, Gazelle GS, Jiang DY, Compton CC, Goldberg SN, Mueller PR. Department of Radiology, Massachusetts General Hospital, Boston 02114, USA. 
... To determine whether incomplete contact of ethanol with tumor limits the success of percutaneous ethanol injection therapy. ... Percutaneous ethanol injection was performed in seven normal New Zealand white rabbits and 18 rabbits with 1-3-cm liver tumors .... ... In normal animals, virtually all injected ethanol tracked to the hepatic capsule. As ethanol was injected into tumors, peripheral tracking, similar to that seen in normal livers, or extratumoral puddling was observed. Ethanol-tumor contact was incomplete in 16 of 18 animals (89%). Histopathologic analysis showed incomplete tumor necrosis. CONCLUSION: In this model of hepatic carcinoma metastasis, the tumor failed to hold sufficient ethanol for successful ablation by means of percutaneous ethanol injection therapy. PMID: 9288191 


Eur J Surg Oncol 2000 Feb;26(1):67-72 

Multimodality treatment for patients with hepatocellular carcinoma: a single institution retrospective series. 
Takano S, Watanabe Y, Ohishi H, Kono S, Nakamura M, Kubota N, Iwai S. 
Third Department of Surgery, Nihon University School of Medicine, Tokyo, Japan. 
... The main therapeutic options for hepatocellular carcinoma (HCC) are hepatic resection, transcatheter arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT) and regional chemotherapy (RC). ... This study retrospectively examined the results of primary treatment of 600 patients with hepatocellular carcinoma .... RESULTS: The selected primary treatment was hepatic resection for 53.7% of the cases, TAE for 31.5%, PEIT for 8.2% and RC for 6.6%,. .... The cumulative 5 and 7-year survival rates after the primary treatments were 52.% and 40.1%, respectively, for hepatic resection; 46.5% and 38.7%, for TAE; 49.6% and 33.1% for PEIT; and 16.7% and 8.3% for RC. ... To improve the treatment results for HCC, early detection is essential and various modalities of treatments in combination should be used for recurrence after primary treatment. PMID: 10718183 


Langenbecks Arch Surg 1999 Aug;384(4):339-43 
Percutaneous ethanol injection and radio-frequency ablation for the treatment of nonresectable colorectal liver metastases - techniques and results. 
Becker D, Hansler JM, Strobel D, Hahn EG. 
Department of Medicine I, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 12, D-91054 Erlangen, Germany, dirk.becker@med1.med.uni-erlangen.de 
BACKGROUND: Percutaneous ethanol injection (PEI) and radio-frequency (RF) ablation are possible palliative treatment modalities for patients with non-resectable liver metastases of colorectal carcinomas. The different techniques are explained and reviewed. ... PEI did not show promising results for the treatment of liver metastases. RF results were more encouraging; some studies showed improved mean survival times for patients when a complete necrosis of the metastases could be achieved. The maximum diameter of the necrotic area possible in a single session is about 5 cm. ... PEI and RF are palliative last-line treatment strategies for patients with non-resectable liver metastases and should only be applied if chemotherapy is not sufficient or not possible. The long-term efficacy of RF ablation in this group of patients has to be evaluated. Publication Types: Review Review, tutorial PMID: 10473853 

Br J Radiol 2000 Aug;73(872):833-9 
Percutaneous ethanol injection of the supplying artery to hepatocellular carcinoma that is not amenable to conventional treatment. 
Lin ZY, Wang JH, Hsieh MY, Yu ML, Chen SC, Chuang WL, Wang LY, Tsai JF, Chang WY. 
Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan, Republic of China. 
The purpose of this study was to evaluate the clinical usefulness of ultrasound-guided percutaneous ethanol injection of the supplying artery (PEISA) to the tumour in the palliative management of hepatocellular carcinoma (HCC) that is not amenable to conventional treatments. A total of 23 cases of HCC, measuring from 3.1 cm to larger than 15 cm (median 5.4 cm) in 17 cirrhotic patients, were treated by PEISA. PEISA was used to control rapid growth of the tumour in seven patients and to reduce abdominal discomfort caused by rapid expansion of the tumour in 10 patients. .... Following treatment, one tumour disappeared, 13 tumours shrank and nine tumours were unchanged in size. All patients with abdominal discomfort had relief after treatment. The common complications of PEISA were local pain and fever. In conclusion, PEISA is effective at treating painful HCC unsuitable for conventional treatment. Publication Types: Clinical trial PMID: 11026857 

Acta Radiol 2000 Sep;41(5):458-63 
High-dose percutaneous ethanol injection therapy of liver tumors. Patient acceptance and complications. 
Elgindy N, Lindholm H, Gunven P. 
Department of Diagnostic Radiology, Karolinska Hospital, Stockholm, Sweden. 
... To study the safety of high-dose ethanol injections in liver tumors and their acceptability as out-patient procedures under local anesthesia. ... High-dose injections with an average volume of 39 ml gave a mean pain score of 5.1, with a weak relationship between pain and volume. Other side effects and complications were unrelated to the ethanol dose. They comprised 1 syncopation, 1 occasion of hypoventilation requiring antidote to opiates, 12 short episodes of nausea or vomiting without need for i.v. fluids, 2 instances of sepsis, and 1 abscess that was drained percutaneously. Thirty-nine of the 62 sessions were performed in day care. .... Low-dose injections resulted in a mean pain score of 4.7 with the same requirement of i.v. analgesics as high doses, fewer instances of nausea and no infectious complications. ... High-dose ethanol injections in patients with liver malignancy had no mortality and a reasonable complication rate. They could be given without general anesthesia, often in day care. PMID: 11016766 


Eur J Gastroenterol Hepatol 2000 Mar;12(3):285-90 
Early detection of haemobilia associated with percutaneous ethanol injection for hepatocellular carcinoma. 
Obi S, Shiratori Y, Shiina S, Hamamura K, Kato N, Imamura M, Teratani T, Sato S, Komatsu Y, Kawabe T, Omata M. Department of Gastroenterology, University of Tokyo, Japan. 
... Haemobilia often results from iatrogenic injury caused by therapeutic procedures. ... Early diagnosis of haemobilia based on ultrasonographic findings of the gallbladder lumen effectively reduces the severity of haemobilia-related complications due to immediate interruption of the interventional procedure. PMID: 10750648 

Int J Clin Pract 1999 Jun;53(4):257-62 
Percutaneous ethanol injection therapy in 47 cirrhotic patients with hepatocellular carcinoma 5 cm or less: a long-term result. 
Lin SM, Lin DY, Lin CJ.      Liver Research Unit, Chang Gung University, Taipei, Taiwan. 
To elucidate the long-term results of percutaneous ethanol injection (PEI) for hepatocellular carcinoma (HCC), 47 cirrhotic patients with HCC < or = 5 cm after PEI were analysed. ... 5-10 ml 95% ethanol was injected into the tumour every three to seven days until the echogenicity of the tumour changed to a hyperechoic or heterogeneous one. A booster PEI was given in 34 (56%) lesions with viable tumour, which was detected by dynamic computed tomography. The one, two, three and four-year survival rates were 85%, 75%, 61% and 39% respectively for all patients. Good liver reserve significantly improved the survival rate ... The one, two, three and four-year recurrence rates were 24%, 55%, 69% and 79% for all patients. HCC recurred more frequently in patients with multiple tumours (p < 0.02). PMID: 10563068 

Am J Gastroenterol 1999 Jul;94(7):1914-7 
Standards for selecting percutaneous ethanol injection therapy or percutaneous microwave coagulation therapy for solitary small hepatocellular carcinoma: consideration of local recurrence. 
Horigome H, Nomura T, Saso K, Itoh M. First Department of Internal Medicine, Nagoya City University Medical School, Japan. 
... Percutaneous ethanol injection therapy (PEIT) and percutaneous microwave coagulation therapy (PMCT) are effective treatments for small hepatocellular carcinoma (HCC). There are no clear standards, however, for the selection of PEIT or PMCT. We determined standards based on local recurrence. ...Univariate analysis indicated that tumor cell differentiation and serum AFP concentration influenced local recurrence in the PEIT group, and tumor size did so in the PMCT group. Multivariate analysis revealed that tumor cell differentiation influenced local recurrence in the PEIT group, and tumor size did so in the PMCT group. PEIT was effective for treating well-differentiated HCC, and PMCT was effective for treating HCC measuring < or = 15 mm in diameter. PMCT was superior to PEIT for treating patients with HCC measuring < or = 15 mm in diameter. In such cases with well-differentiated HCC, PEIT was as effective as PMCT. ... The selection of PEIT or PMCT to treat patients with HCC should be based on tumor size and cell differentiation. PMID: 10406259 

Cancer 1999 Apr 15;85(8):1694-702 
Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with percutaneous ethanol injection therapy. 
Seki T, Wakabayashi M, Nakagawa T, Imamura M, Tamai T, Nishimura A, Yamashiki N, Okamura A, Inoue K. Third Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan. 
BACKGROUND: The authors compared the efficacy of percutaneous microwave coagulation therapy (PMCT) and percutaneous ethanol injection therapy (PEIT) in the treatment of patients with cirrhosis and a solitary nodular hepatocellular carcinoma (HCC) < or = 2 cm in greatest dimension. ... The overall 5-year survival rates for patients with well-differentiated HCC treated with PMCT (70%) and PEIT (78%) were not significantly different. No difference between the patterns of recurrence was observed. Among the patients with moderately or poorly differentiated HCC, overall survival with PMCT (5-year survival rate: 78%) was significantly better than with PEIT (5-year survival rate: 35%) (P = 0.03). Nine of 22 patients with moderately or poorly differentiated HCC treated with PEIT experienced recurrence in the original target subsegment. Only 2 of 25 patients treated with PMCT had a recurrence in the same subsegment as the initial tumor. ... PMCT may be superior to PEIT for the local control of moderately or poorly differentiated small HCC. PMID: 10223562 

Eur J Gastroenterol Hepatol 1998 Nov;10(11):915-8 
Comment in: Eur J Gastroenterol Hepatol. 1998 Nov;10(11):907-9 
Hepatic infarction following percutaneous ethanol injection therapy for hepatocellular carcinoma. 
Seki T, Wakabayashi M, Nakagawa T, Imamura M, Tamai T, Nishimura A, Yamashiki N, Okamura A, Inoue K. Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan. 
We report on two patients who developed hepatic infarction after undergoing percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma (HCC). In both cases, liver function parameters deteriorated immediately after the ethanol injection, and enhanced computed tomography images showed a wedge-shaped avascular low-density area due to hepatic infarction. ... When PEIT is used for patients with HCC who have previously undergone TAI, especially with SMANCS, PEIT may induce hepatic infarction. PMID: 9872612 

Abdom Imaging 1998 Nov-Dec;23(6):608-10 
Fatal thrombosis of the portal vein following single-session percutaneous ethanol injection therapy of hepatocellular carcinoma. 
Lencioni R, Cioni D, Uliana M, Bartolozzi C. Department of Oncology, University of Pisa, Italy. 
Two weeks after percutaneous ethanol injection therapy for hepatocellular carcinoma, performed by injecting 110 mL ethanol in a single session with general anesthesia, a 69-year-old woman with well-compensated liver cirrhosis developed an extensive thrombosis of the whole portal tree that caused severe uncorrectable ascites and progressive deterioration of her general condition, resulting in death 6 weeks after the procedure. PMID: 9922194 

Acta Gastroenterol Belg 1999 Jan-Mar;62(1):49-51 
Acute renal failure requiring haemodialysis after high doses percutaneous acetic acid injection for hepatocellular carcinoma. 
Van Hoof M, Joris JP, Horsmans Y, Geubel A. Department of Gastroenterology, Saint Luc University Hospital, Bruxelles, Belgium. 
Recently, ultrasound-guided percutaneous acetic acid injection has been proposed in the treatment of hepatocellular carcinoma ...We report the case of severe renal failure requiring haemodialysis that occurred in a patient with 4 cm hepatocellular carcinoma treated adequately by high dose percutaneous acetic acid injection. The risk of such a serious side effect, likely related to a direct toxic effect of acetic acid, should be of concern when considering percutaneous treatment of hepatocellular carcinoma. Acute renal failure has been reported as a complication of acetic acid poisoning, but to our knowledge, we report here the first case of acute renal failure following high dose percutaneous acetic acid injection. PMID: 10333599 



Radiol Med (Torino) 1998 Sep;96(3):238-42 
[Ultrasonography-guided percutaneous ethanol injection in large an/or multiple liver metastasis]. [Article in Italian] 
Giorgio A, Tarantino L, Mariniello N, De Stefano G, Perrotta A, Aloisio V, Del Viscovo L, Alaia A. Servizio di Ecografia ed Ecointerventistica, Ospedale D. Cotugno, Napoli. assanui@tin.it 
INTRODUCTION: Percutaneous ethanol injection (PEI) under sonographic guidance is an effective therapy for hepatocellular carcinoma on cirrhosis, while less favorable results have been reported for liver metastases. Surgery and/or other new treatments (i.e., interstitial thermotherapy) are indicated only for small metastases (< 3 cm) and surgeons no longer perform the palliative debulking of neoplastic masses. 
...thirty-three patients with 62 large (> 3.5 cm) and/or multiple liver metastases, who were not eligible for surgery nor thermotherapy, were treated with one-shot PEI under general anesthesia. The diameter of the nodules ranged 35-92 mm (mean: 39); the lesions were single in 15 patients and localized in both the right and the left lobe in 19 patients. 25-110 ml ethanol were injected per session. Post-treatment results were assessed with dynamic or dual-phase spiral CT; therapeutic success was defined as the absence of hyperdense lesion areas. 
... Complete necrosis of the metastases was shown in 10 patients (30.3%). Necrosis rate ranged 70-90% in 21 patients (64%) and was 50% in 2 patients (5.7%). Survival rates were 94%, 80%, 80% and 44% at 12, 24, 36 and 44 months, respectively. No major complications were observed. Seeding of neoplastic cells along the needle tract has been never observed to date. ...
 Metastasis diameter and number impact on long-term survival. PEI under general anesthesia allows to treat also the patients who are not eligible for other treatments and to inject large amounts of ethanol per session in different tumor areas because metastases usually set on in an otherwise healthy liver. ... One-shot PEI can cause major, even complete, tumor necrosis in large and multiple liver metastases. The absence of any important complications and the survival rates in our series seem to indicate that one-shot PEI is effective for tumor debulking in patients not eligible for surgery and other alternative treatments. Publication Types: Clinical trial PMID: 9850718 

Gastroenterol Clin Biol 1998 Apr;22(4):459-61
[Massive hepatic necrosis secondary to treatment of hepatocellular carcinoma by percutaneous alcoholization].[Article in French] 
Boucher E, Carsin A, Raoul JL, Marchetti C, Joram F, Kerbrat P. Centre Regional de Lutte contre le Cancer, Rennes. 
Fatal complication ... We report a case of massive hepatic necrosis after treatment by percutaneous ethanol injection of a 4 cm diameter hepatocellular carcinoma, which resulted in the death of the patient. The mechanism of this complication was probably an intratumoral aterioportal shunt, which allowed ethanol to spread through the blood vessels. PMID: 9762276 
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Hepatic Arterial Infusion [HAI] & Liver Metastases

Hepatic Arterial Infusion [HAI] 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. It is also useful for downgrading unresectable situations to resectable ones. 
Infusion of cytotoxic agents into the hepatic artery is a form of therapy for unresectable hepatic metastases. The recent development of a totally implantable pump has allowed prolonged infusion of chemotherapeutic agents with good compliance and quality of life. The use of agents with high hepatic extraction results in minimal systemic toxicity. Such regional chemotherapy can increase the likelihood of hepatic response compared with systemic treatment. 
For further discussion, see Introduction to Isolated Liver Perfusion. 
For the latest Pubmed/Medline Search: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=hepatic%20Intraarterial%20chemotherapy%20metastases
For further information and references for this section, see below:
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Hepatic Arterial Infusion [HAI] & Liver Metastases 
Selected Medical Journal Article Annotated Citations 
[For the full abstract, use the links provided, or search on Pubmed.  Ed.]


Oncology (Huntingt) 2000 Dec;14(12 Suppl 11):48-51 
Intrahepatic therapy for resected hepatic metastases from colorectal carcinoma. 
Alberts SR. Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA. alberts.steven@mayo.edu 
A significant number of patients with colorectal cancer will present with hepatic metastases as their only site of metastatic disease. Surgical resection in patients with a limited number of metastases will lead to long-term survival in up to one-third. However, following surgery, many of these patients will relapse within the liver, and many will develop extrahepatic metastases. The use of hepatic artery infusion alternating with systemic therapy has proven to reduce the risk of recurrent disease and improve survival... Publication Types: Review Review, tutorial PMID: 11204664 [PubMed - indexed for MEDLINE 

Gan To Kagaku Ryoho 2000 Oct;27(12):1834-7 
[Indication for hepatic resection after hepatic arterial infusion chemotherapy for multiple liver metastases of colorectal cancer]. [Article in Japanese] 
Takahashi K, Mori T, Yasuno M. Dept. of Surgery, Tokyo Metropolitan Komagome Hospital. 
The indications for hepatic resection after hepatic arterial infusion chemotherapy (HAI) for unresectable metastatic liver tumor of colorectal cancer were analyzed from the surgical outcome of hepatic resections in 23 cases of hepatic resection after HAI. ... The surgical outcome was better in the HAI for longer than 8 month and normal CEA groups. Publication Types: Clinical trial PMID: 11086424 

J Cardiovasc Surg (Torino) 2000 Feb;41(1):95-8 
Rupture of infected pseudoaneurysms in patients with implantable ports for intra-arterial infusion chemotherapy. 
Shindo S, Arai H, Kubota K, Iyori K, Ishimoto T, Kobayashi M, Suzuki O, Kamiya K, Tada Y, Sakamoto H.                     Second Department of Surgery, Yamanashi Medical University, Japan. 
Intra-arterial hepatic chemotherapy via implantable reservoirs is being used increasingly. In our department, five patients have undergone emergency surgery since 1991 because of rupture of an infected pseudo-aneurysm at the site of entry of the catheter. Surgical procedures included removal of the catheter and the reservoir, and closure of the affected artery with or without reconstruction. Of these patients, three (60%) died from uncontrollable sepsis. The poor prognosis emphasizes the need, in patients with carcinoma, for strict aseptic technique and hemostasis at the time of catheter placement, and for careful device maintenance. PMID: 10836231 

Recent Results Cancer Res 1998;147:3-12 
Are there indications for intraarterial hepatic chemotherapy or isolated liver perfusion? The case of liver metastases from colorectal cancer. 
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. Liver metastases from colorectal cancer represent one of the best indications, and many trials have demonstrated that IAHC is an efficient treatment. .... Liver toxicity and extrahepatic progression are the two main limiting factors that can be reduced using new protocols and combinations with systemic chemotherapy. ... Isolated liver perfusion adds to IAHC an extracorporal extraction and allows the use of higher doses of chemotherapy. Its efficacy has been suggested in small phase II trials; however, its relative complexity and the lack of clear demonstration of its efficacy compared to the most recent and effective systemic chemotherapies used alone or in combination with IAHC prevent the recommendation of its use outside clinical trials. IAHC and isolated liver perfusion are two active locoregional treatments that can be combined with surgical resection and/or systemic chemotherapy ... PMID: 9670263 

Ann Ital Chir 1996 Nov-Dec;67(6):793-7 
[Locoregional chemotherapy of liver metastasis from colorectal carcinoma]. [Article in Italian] 
Zamparelli G, Pancera G, Pessi MA, Dallavalle G, Pirovano M, Valsecchi R, Labianca R, Samori G, Luporini G. Divisione Oncologia Medica, Azienda Ospedaliera San Carlo Borromeo di Milano. 
Hepatic metastases are a major cause of death in patients with colorectal carcinoma. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients and surgical resection is feasible in approximately 20% of patients. Infusion of cytotoxic agents into the hepatic artery is the most promising form of therapy for unresectable hepatic metastases. The recent development of a totally implantable pump has allowed prolonged infusion of chemotherapeutic agents with a good compliance and quality of life of the patients. The rationale for hepatic arterial infusion (HAI) present an anatomical and pharmacological basis with the use of agents with high hepatic extraction resulting in minimal systemic toxicity. ...PMID: 9214270 

Ann Surg Oncol 2000 Aug;7(7):490-5 
Surgery after downstaging of unresectable hepatic tumors with intra-arterial chemotherapy. 
Meric F, Patt YZ, Curley SA, Chase J, Roh MS, Vauthey JN, Ellis LM. 
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. 
... This retrospective study was performed to assess the outcome among patients who underwent hepatic resection or tumor ablation after hepatic artery infusion (HAI) therapy down-staged previously unresectable hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (CRC). ... CONCLUSIONS: Hepatic resection or ablation after tumor downstaging with HAI therapy is a viable option for patients with unresectable HCC. However, given the high rate of recurrence of metastases from CRC, hepatic resection or ablation after downstaging with HAI should be used with caution. PMID: 10947016 

Clin Radiol 1999 Apr;54(4):221-7 
Hepatic arterial infusion chemotherapy using percutaneous catheter placement with an implantable port: assessment of factors affecting patency of the hepatic artery. 
Seki H, Kimura M, Yoshimura N, Yamamoto S, Ozaki T, Sakai K. 
Department of Radiology, Niigata University School of Medicine, Japan. 
... To assess the factors affecting patency of the hepatic artery during hepatic arterial infusion chemotherapy (HAIC) with an implantable port system inserted percutaneously. ... We consider that it is important for long-term patency of the hepatic artery during HAIC to use fixed catheter-tip method for percutaneous catheter placement instead of conventional method, and to select patients without prior TACE. Publication Types: Clinical trial Controlled clinical trial PMID: 10210340 

Zhonghua Zhong Liu Za Zhi 1996 Sep;18(5):365-7 
[The clinical efficacy of hepatic artery infusion chemotherapy and chemoembolization in the treatment of liver metastases]. [Article in Chinese] 
Zeng X, Wang S, Wei C. 
Department of Radiology, Wuhan General Hospital of Guangzhou Miliary Region. 
The efficacy and clinical experience of transcatheter hepatic artery infusion chemotherapy alone or chemoembolization in 118 patients with hepatic metastases were reviewed. Hepatic arterial infusion chemotherapy followed by embolization with lipiodol suspension and gelatin sponge pieces was carried out in 72 cases, infusion chemotherapy followed by embolization with lipiodol suspension in 32, and arterial infusion chemotherapy alone in 14. The results showed that the clinical efficacy of the first method was the best while that of the third method was the worst. The best effect was seen in patients with the single and hypervascular metastatic focus. The overall survival rate was 86.0%, 25.0%, 3.0% in 1 year, 3 years and 5 years, respectively. PMID: 9387277 

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Arterial Embolization and Chemoembolization & Liver Metastases


Despite frequent tumor recurrence, the long-term outcome after liver resection for hepatic metastases from leiomyosarcoma is superior to that after chemotherapy and chemoembolization. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10749609&dopt=Abstract
However, embolization or chemoembolization and intra-arterial infusion chemotherapy could be of significant use for liver metastases previously unresectable, made resectable by treatment-caused shrinking of tumor bulk [downgrading]. Also, this regional therapy may offer new hope for those sarcoma patients who have liver metastases resistant to combination systemic chemotherapy, either for downgrading of tumors prior to surgical resection, or for palliation. Embolization or chemoembolization is not curative by itself, and additional therapy is required to eradicate residual disease.
Side effects and complications might include: liver pain, liver enzyme blood level increase, liver abscess, gastrointestinal reaction [paralytic ileus] requiring a nasogastric tube, urinary electrolyte losses requiring supplements, and occasionally mild but transient low white cell or platelet count. 
The normal liver presents a double circulation: 75% from portal circulation and 25% from hepatic artery. In malignant primary and secondary lesions the blood support is given by hepatic artery. Anticancer drugs mixed with some 'embolic' particles such as polyvinyl alcohol and gelatin powder can be injected selectively in the arteries that feed tumors. This causes clotting in those arteries, and infarcts tumors. Additionally the anticancer drugs work on the tumor. Their work is enhanced by their not being quickly washed away by the blood circulation [which has been clotted or slowed]. Radio-opaque contrast media can also be present in the mixture, and the progress of the mixture monitored radiologically. 
Chemoembolization using an emulsion of Lipiodol ultra-fluid (LUF) and drugs is a recent tool in liver regional therapy. LUF has been shown to be taken up by hepatocellular carcinoma and retained for a long period of time in the tumor bed. Chemoembolization causes massive shrinkage due to ischemia, and increases the local drug intensity and drug exposure. 
The hepatic artery is reached by advancing a catheter from the femoral or other artery to the hepatic artery. The catheter can be advanced into the artery that feeds the majority of the tumor blood supply, and the embolization material is injected, followed by the chemotherapy regimen previously decided upon mixed with LUF, until the feeder artery no longer transports liquid. 
Side Effects and Complications are obvious ones: liver trauma, liver failure, artery rupture, infection, abscess, reaction to the injected materials, the side effects due to the injected materials, fever, pain, misdirected drainage of the injected material resulting in damage to other structures. Risk factors for hepatic failure after embolization include poor hepatic functional reserve, high-dose infusion of chemotherapeutic agents, and a history of multiple embolization procedures.

 References for this section are below.

The latest Pubmed Searches on this subject are: 
LMS & liver embolization
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=hepatic%20leiomyosarcoma%20embolization 
Sarcoma & liver embolization
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=hepatic%20sarcoma%20embolization 
LMS & liver chemoembolization
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=hepatic%20leiomyosarcoma%20chemoembolization 
Sarcoma & liver chemoembolization
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=hepatic%20sarcoma%20chemoembolization

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Arterial Embolization and Chemoembolization & Liver Metastases 
Selected Medical Journal Article Annotated Citations

[For the full abstract, use the links provided, or search on Pubmed.  Ed.]



Ann Surg 2000 Apr;231(4):500-5 
Hepatic metastases from leiomyosarcoma: A single-center experience with 34 liver resections during a 15-year period. 

Lang H, Nussbaum KT, Kaudel P, Fruhauf N, Flemming P, Raab R. 
Klinik fur Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany. hauke.lang@uni-essen.de 

... To describe a large single-center experience with hepatic resection for metastatic leiomyosarcoma. ... the role of liver resection for hepatic metastases from leiomyosarcoma has not been defined. 
...The records of 26 patients who between 1982 and 1996 underwent a total of 34 liver resections for hepatic metastases from leiomyosarcoma were reviewed. There were 23 first, 9 second, and 2 third liver resections. The records were analyzed with regard to survival and predictive factors. 
...In the 23 first liver resections, there were 15 R0, 3 R1, and 5 R2 resections. Median survival was 32 months after R0 resection and 20.5 months after R1/2 resection. The 5-year survival rate was 13% for all patients and 20% after R0 resection. 
...In 10 patients with extrahepatic tumor at the time of the first liver resection, 6 R0 and 4 R2 resections were achieved. After R0 resection, the median survival was 40 months (range 5-84 months), with a 5-year survival rate of 33%. 
...After repeat liver resection, the median survival was 31 months (range 5-51 months); after R0 resection, median survival was 31 months and after R1/2 resection it was 28 months. There was no 5-year survivor in the overall group after repeat liver resection. 
... Despite frequent tumor recurrence, the long-term outcome after liver resection for hepatic metastases from leiomyosarcoma is superior to that after chemotherapy and chemoembolization. Although survival after tumor debulking also seems to be more favorable than after nonoperative therapy, these data indicate that only an R0 resection offers the chance of long-term survival. The presence of extrahepatic tumor should not be considered a contraindication to liver resection if complete removal of all tumorous masses appears possible. In selected cases of intrahepatic tumor recurrence, even repeated liver resection might be worthwhile. In view of the poor results of chemoembolization and chemotherapy in hepatic metastases from leiomyosarcoma, liver resection should be attempted whenever possible. PMID: 10749609 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10749609&dopt=Abstract


Gan To Kagaku Ryoho 1997 Sep;24(12):1878-81 
[A case of liver metastasis of gastric leiomyosarcoma successfully treated by transarterial hepatic chemo-embolization and intra hepato-arterial chemotherapy repeated with infusion-a-port]. [Article in Japanese] 

Miya A, Yasuda S, Morimoto O, Tsuji Y, Shiozaki K, Baba M, Ishida H, Masutani S, Tatsuta M, Kawasaki T, Satomi T. 
Dept. of Surgery, Sakai Municipal Hospital. 

The patient was a 68-year-old male, who underwent total gastrectomy for giant leiomyosarcoma of the stomach and then had multiple hepatic metastases one year and six months later. Thus, transarterial hepatic chemo-embolization therapy with Lipiodol, adriamycin and gelfoam was given. Moreover, using a reservoir catheter and infusion arterial port, intermittent arterial infusion therapy with adriamycin, cyclophosphamide, and vincristine was attempted. In the metastasis lesion where there were rich blood vessels, Lipiodol was accumulated and the tumor was reduced on abdominal CT. The result indicated the efficacy of this treatment. PMID: 9382556 



Gan To Kagaku Ryoho 1997 Sep;24(12):1741-4 
[A case of liver metastases from leiomyosarcoma in the chest wall which was made resectable by chemoembolization]. [Article in Japanese] 

Mori K, Yamada S, Kosaka A, Watabiki Y, Ohara M, Yamazaki M, Shikata A, Hoshiya Y. 
Dept. of Surgery, Shimizu Municipal Hospital. 
We here report a recently experienced case in which TAE and intra-arterial infusion chemotherapy for treatment of liver metastases of leiomyosarcoma in the chest wall caused a shrinking of the metastasized focus, thus facilitating liver resection. ... A 38-year-old man ... Resection of leiomyosarcoma in his chest wall was done in May 1994. However, a local recurrence was noted in September 1995, and the tumor was removed. Then, he received systemic chemotherapy with CDDP (100 mg) and ADM (45 mg). Abdominal CT and ultrasonic examinations made in February 1996 revealed liver metastases at S2, 5,8. Angiography detected densely stained images of tumors at a number of sites along with S2, 5,8. Since these were thought unresectable, TAE therapy with EPIR (30 mg) and lipiodol (4 ml) was attempted 3 times. Then, a reservoir for intra-hepatic arterial infusion was implanted in April, 1996 and EPIR at a dose of 30 mg (150 mg in total) was given through arterial infusion, resulting in tumor disappearance at S5, 8 but further growth of the tumor metastasizes at S2. Therefore, a resection of the left lateral segment of liver was done August 23. Though he was discharged in October, metastasis was found in the thoracic spine in December. Thus, he underwent resection of the vertebral arch including the tumor. PMID: 9382521 

Ital J Gastroenterol 1996 Feb-Mar;28(2):98-101 
Diagnostic imaging of primary hepatic leiomyosarcoma: a case report. 
Civardi G, Cavanna L, Iovine E, Buscarini E, Vallisa D, Buscarini L. 
I Divisione di Medicina Generale, Ospedale Civile, Piacenza, Italy. 
Primary hepatic leiomyosarcoma is a very rare tumour only eighteen cases having been reported in the literature. A new case of this tumour is reported here, in which a complete diagnostic imaging work-up was performed, leading to the pathologic diagnosis, obtained with ultrasonically-guided coarse needle biopsy. Transarterial chemoembolisation, a new therapeutic option for this disease, was attempted without success. Review of reported cases PMID: 8782003 

Cancer 1995 Apr 15;75(8):2083-8 
Gastrointestinal leiomyosarcoma metastatic to the liver. Durable tumor regression by hepatic chemoembolization infusion with cisplatin and vinblastine. 
Mavligit GM, Zukwiski AA, Ellis LM, Chuang VP, Wallace S. Department of Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. 
... Gastrointestinal leiomyosarcoma metastatic to the liver is considered most resistant to any combination of systemic chemotherapy containing doxorubicin and/or ifosphamide. ... Fourteen patients with gastrointestinal leiomyosarcoma metastatic to the liver were treated with hepatic chemoembolization infusion consisting of polyvinyl alcohol sponge particles mixed with cisplatin powder (150 mg) followed by an intrahepatic arterial infusion of vinblastine (10 mg/m2). ... Ten major (> 50% regression) tumor responses were observed (70%) in patients lasting from 8 to 31+ months (median, 12 months) after an average of two hepatic chemoembolization procedures, usually 4 weeks apart. Transient side effects included right upper quadrant pain requiring narcotics, significant hepatic enzyme elevation, particularly of lactic dehydrogenase with a minimal increase in bilirubin, paralytic ileus requiring nasogastric suction up to 72 hours, urinary electrolyte losses (potassium+, magnesium++, sodium+) requiring supplements, and occasionally mild but transient leukopenia and thrombocytopenia. ... Hepatic chemoembolization infusion appears to induce a high rate of durable tumor response in patients with notoriously chemoresistant gastrointestinal leiomyosarcoma metastatic to the liver. PMID: 7697597 

Gan To Kagaku Ryoho 1994 Sep;21(13):2233-6 
[Analysis of cases with liver abscess following transcatheter arterial chemoembolization (TAE) for malignant hepatic tumors]. [Article in Japanese] 
Ishikawa H, Kanai T, Ono T, Shimoyama Y, Aizawa K, Ishida H, Saitoh Y, Hata H, Aoki A, Okuda S, et al. 
Dept. of Surgery and Radiology, Hiratsuka City Hospital. 
... These results suggest the major factor leading to abscess formation is biliary infection. Therefore, a previous bilio-enteric anastomosis should be regarded as a risk factor for liver abscess following TAE. PMID: 7944448 

Gan To Kagaku Ryoho 1993 Jan;20(1):141-3 
[Hepatic metastases from jejunal leiomyosarcoma treated effectively by repeated transarterial embolization with carboplatin]. [Article in Japanese] 
Kokufu I, Kurokawa E, Akashi H, Mizumoto S, Kishibuchi M, Aoki Y, Inoue Y. Dept. of Surgery, Minoh City Hospital. 
A 67-year-old man ... was diagnosed as having jejunal leiomyosarcoma and multiple liver metastases after examination. The jejunal leiomyosarcoma was resected by operation. Unresectable liver metastases were repeatedly treated by transarterial embolization with carboplatin and Lipiodol, and a significant reduction was achieved. ... He has remained well presently for 1 year 10 months after operation. PMID: 8380684 

Cancer 1991 Jul 15;68(2):321-3 
Regression of hepatic metastases from gastrointestinal leiomyosarcoma after hepatic arterial chemoembolization. 
Mavligit GM, Zukiwski AA, Salem PA, Lamki L, Wallace S. Department of Clinical Immunology, University of Texas M.D. Anderson Cancer Center, Houston 77030. 
Two patients with gastrointestinal leiomyosarcoma metastatic to the liver were treated by hepatic chemoembolization with cisplatin and polyvinyl sponge followed by hepatic arterial infusion of vinblastine. Effective palliation in terms of durable tumor regression was achieved in both patients after two chemoembolization-infusion procedures. These results suggest that regional therapy may offer new hope for the subset of sarcoma patients who have liver metastases resistant to combination systemic chemotherapy. PMID: 2070331 

Zhonghua Yi Xue Za Zhi (Taipei) 2000 Nov;63(11):838-43 
Abdominal wall necrosis following transcatheter arterial chemoembolization for hepatocellular carcinoma. 

Liu HJ, Chen TS, Lee RC, Ho DM, Lin JT, Chu LS, Chang FY. 
Division of Gastroenterology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, Taiwan 112, ROC. 
. We advise that embolization of the IMA in patients who have received radiotherapy should be avoided, if possible. PMID: 11155762 

Hepatogastroenterology 2000 Nov-Dec;47(36):1706-10 
Transcatheter arterial embolization for advanced hepatocellular carcinoma resulting in a curative resection: report of two cases. 

Mizoe A, Yamaguchi J, Azuma T, Fujioka H, Furui J, Kanematsu T. 
Department of Surgery II, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
 
...We experienced 2 patients with advanced hepatocellular carcinoma which were initially considered to be unresectable due to the extreme extension of the primary lesions. Therefore, transcatheter hepatic arterial embolization with lipiodolization were selected as the treatments of choice. Thereafter, these tumors markedly decreased in size and, as a result, curative resections could subsequently be performed. The pathological examination of the resected specimens revealed necrosis and hyaline degeneration in the main tumors. Viable tumor cells, however, still remained adjacent to the main tumors. Such evidence indicated the limited efficacy of transcatheter hepatic arterial embolization with lipiodolization and the necessity of performing surgical treatment in combination with transcatheter hepatic arterial embolization with lipiodolization. Based on these findings, transcatheter hepatic arterial embolization with lipiodolization both appear to be a good mode of therapy for advanced hepatocellular carcinoma, and in selected patients, subsequent surgery can also be considered. PMID: 11149037 


Am J Clin Oncol 2000 Oct;23(5):449-54 
Phase I clinical trial of oral furtulon and combined hepatic arterial chemoembolization and radiotherapy in unresectable primary liver cancers, including clinicopathologic study. 
Zeng ZC, Tang ZY, Wu ZQ, Ma ZC, Fan J, Qin LX, Zhou J, Wang JH, Wang BL, Zhong CS. 
Department of Radiation Oncology, Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical University, PR China. 
Surgical resection has been accepted as the only curative therapy for primary liver cancer (PLC). Unfortunately, most patients are surgically unresectable when they seek treatment. An alternative therapeutic approach for some of these patients is transcatheter arterial chemoembolization. However, this is not curative by itself, and additional therapy is required to eradicate residual disease. .... PMID: 11039502 



Digestion 2000;62(2-3):208-12 
Multimicrobial sepsis including Clostridium perfringens after chemoembolization of a single liver metastasis from common bile duct cancer. 
Eckel F, Lersch C, Huber W, Weiss W, Berger H, Schulte-Frohlinde E. 
Department of Medicine II, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. florian.eckel@lrz.tum.de 
"We conclude that antibiotic prophylaxis is recommendable for chemoembolization of liver metastasis in patients with risk factors like intestinal biliary reflux (bilioenteric anastomosis or papillotomy and biliary stenting) and bile duct cancer, otherwise severe sepsis including clostridium bacteremia may occur." [edited] Copyright 2000 S. Karger AG, Basel. PMID: 11025370 

Acta Radiol 2000 Mar;41(2):156-60 
Ischemic complications of transcatheter arterial chemoembolization in liver malignancies. 
Tarazov PG, Polysalov VN, Prozorovskij KV, Grishchenkova IV, Rozengauz EV. 
Division of Angio/Interventional Radiology, St. Petersburg Research Institute of Roentgenology and Radiation Therapy, Russia. 
... To determine the frequency, character, methods of treatment, and outcome of ischemic complications after transcatheter hepatic artery chemoembolization (TACE). .. Ischemic complications appeared in 13 (4.6%) and included the following: hepatic (n=6) and splenic abscess (n= 1), cholecystitis (n=3), and bile duct necrosis (n=3). The treatment was US-guided drainage in 12 cases and systemic antibacterial therapy in 1. No negative influence of these complications on survival of patients was detected. ... Serious ischemic complications of TACE occur in about 5% of patients and can be successfully managed without open surgery. These complications do not worsen the survival of patients. PMID: 10741789 

Bull Soc Sci Med Grand Duche Luxemb 1999;(2):29-36 
Complications and hospitalisation--duration after chemoembolisation for liver metastases. 
Rauh S, Duhem C, Ries F, Dicato M. 
Dpt. of Hemato-Oncology, Centre Hospitalier, Luxembourg. 
In a retrospective study, all patients of the hemato-oncology department of the Centre Hospitalier who were treated from 1988 to 1997 by chemoembolisation for liver metastases were analysed for treatment-related hospitalisation duration, side effects and complications, in order to assess the treatment burden. Major side-effects were: pain in 17 of 29 patients, nausea in 8, vomiting in 7, persistent hiccup in 3, fever in 12, a temporary confusional state in 4 patients. 1 patient experienced syncope, 2 patients developed homolateral pleural effusions, 1 patient suffered transient supraventricular arrhythmias. Major complications included 1 hemoperitoneum (under anticoagulant therapy), 1 hemorrhagic gastritis, 1 acute cholecystitis due to inflammatory tumoral choledochal obstruction and one iatrogenous acute pancreatic ischemic necrosis. Two patients died of post-embolic acute hepatic insufficiency, one 10 days, one 41 days after the last treatment session). In summary, chemo-embolisation of liver metastases is a complication-burdened treatment in a strictly palliative setting with inestimable efficacy. The treatment modalities have to be discussed with the patient beforehand and preferably in controlled study setting. Large randomised trials may indicate patients' subgroups for benefit. PMID: 11100173 

Cardiovasc Intervent Radiol 1999 Jul-Aug;22(4):293-7 
Hepatic chemoembolization: effect of intraarterial lidocaine on pain and postprocedure recovery. 
Hartnell GG, Gates J, Stuart K, Underhill J, Brophy DP. 
Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, 1 Deaconess Road, Boston, MA 02215, USA. 
... Intraarterial lidocaine during chemoembolization reduces the severity and duration of pain after chemoembolization resulting in faster recovery thus reducing the length of hospitalization. PMID: 10415218 



Zhonghua Zhong Liu Za Zhi 1996 Sep;18(5):365-7 
[The clinical efficacy of hepatic artery infusion chemotherapy and chemoembolization in the treatment of liver metastases]. [Article in Chinese] 
Zeng X, Wang S, Wei C. Department of Radiology, Wuhan General Hospital of Guangzhou Miliary Region. 
The efficacy and clinical experience of transcatheter hepatic artery infusion chemotherapy alone or chemoembolization in 118 patients with hepatic metastases were reviewed. Hepatic arterial infusion chemotherapy followed by embolization with lipiodol suspension and gelatin sponge pieces was carried out in 72 cases, infusion chemotherapy followed by embolization with lipiodol suspension in 32, and arterial infusion chemotherapy alone in 14. The results showed that the clinical efficacy of the first method was the best while that of the third method was the worst. The best effect was seen in patients with the single and hypervascular metastatic focus. The overall survival rate was 86.0%, 25.0%, 3.0% in 1 year, 3 years and 5 years, respectively. PMID: 9387277 

Eur Radiol 1997;7(3):323-6 
Arteritis following intra-arterial chemotherapy for liver tumors. 
Belli L, Magistretti G, Puricelli GP, Damiani G, Colombo E, Cornalba GP. 
Department of Radiology, Ospedale Multizonale, Viale Borri 57, I-21100 Varese, Italy. 
... with transcatheter chemoembolization (TACE) during selective arterial catheterization... Arteritis is a possible referred side effect which can lead to tortuosity of the arteries, stenosis and occlusion of vessels. In our hospitals 117 consecutive patients were treated with TACE from January 1990 to December 1992.... Selective angiography performed 30-62 days after the first chemoembolization showed artery stenosis in 7 patients and thrombosis in 2 cases related to toxic arteritis due to chemoembolization. Reports about arteritis during TACE treatments are discussed. PMID: 9087350 

Clin Radiol 1997 Jan;52(1):36-40 
Arteriovenous shunting in hepatocellular carcinoma: its prevalence and clinical significance. 
Ngan H, Peh WC. 
Department of Diagnostic Radiology, University of Hong Kong, Queen Mary Hospital, Hong Kong. 
Arteriovenous shunting has been reported in hepatocellular carcinoma (HCC) and is a recognized contraindication to treatment by transcatheter arterial chemoembolization. This study aims to determine the prevalence of arteriovenous shunting in patients presenting with HCC and the development of shunts in those with inoperable HCC being treated with repeated chemoembolization. In a group of 292 Chinese patients ... hepatic angiograms demonstrated arteriovenous shunting in 91 cases (31.2%); shunting into the portal vein was observed in 84 (28.8%) and shunting into the hepatic vein in seven (2.4%). The hepatic angiograms of a separate group of 171 Chinese patients (144 men, 27 women: mean age 55.4 years) undergoing chemoembolization for inoperable HCC were analysed. Arteriovenous shunting developed during treatment in 20 patients (11.7%). Of these 20 patients, one had shunting into the hepatic vein while 19 (11.1%) had arterioportal shunting. Arteriovenous shunting occurred through the tumour or portal vein tumour thrombus in 13 patients, and occurred at sites remote from the tumour in the other seven patients. Shunting disappeared on repeat angiograms in three patients. ... The recognition of development of arteriovenous shunting during chemoembolization of HCC is important as it has a direct bearing on patient management and prognosis. PMID: 9022578 

Cancer 1996 Nov 15;78(10):2216-22 Comment in: Cancer. 1996 Nov 15;78(10):2039-42 
Positron emission tomography with F-18-fluorodeoxyglucose to evaluate the results of hepatic chemoembolization. 
Vitola JV, Delbeke D, Meranze SG, Mazer MJ, Pinson CW. 
Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2675, USA. 
... Positron emission tomography (PET) using F-18-flurodeoxyglucose (18FDG) is an imaging modality allowing direct evaluation of cellular glucose metabolism. The purpose of this study was to examine the role of 18FDG-PET in monitoring chemoembolization therapy of patients with liver metastases from adenocarcinoma. ... patients were evaluated with 18FDG-PET before and 2-3 months after interventional therapy. All patients underwent transcatheter arterial chemoembolization. A total of nine PET studies were performed. ... Twenty-five of 34 lesions had decreased 18FDG uptake ...as expected in successful tumor chemoembolization. These findings were associated with a significant decrease in serum tumor marker levels ... after treatment. However, there were 3 new lesions, and 6 of the 34 lesions demonstrated persistent or increased 18FDG uptake after treatment ... consistent with the presence of residual viable tumor. These findings led to further interventional therapy in all patients. ... 18FDG-PET allows monitoring of response to treatment with hepatic chemoembolization in patients with liver metastases from adenocarcinoma. PET is a useful diagnostic tool and has the potential to be used to guide further interventional therapy. PMID: 8918417 

Acta Chir Belg 1996 Feb;96(1):37-40 
Initial experience with the use of preoperative transarterial chemoembolization in the treatment of liver metastasis. 
Ceelen W, Praet M, Villeirs G, Defreyne L, Pattijn P, Hesse U, de Hemptinne B. 
Department of Surgery, Gent University Hospital, Belgium. 
We retrospectively evaluated the influence of preoperative Transarterial Chemoembolization (TAE) on technique and complications, tumour histology, and disease-free survival after surgery for hepatic metastasis. In a 2-year period, a total of 23 patients were treated. In a first group of 14 patients, preoperative TAE was performed; in a second group of 9 patients only surgical resection was done. Extensive tumour necrosis was seen in the majority of patients treated with TAE; in tumours with an important fibrotic component, embolization was less effective. No significant effect was seen on operating time, transfusion requirement or perioperative complication rate. In the group of patients who underwent TAE, survival rate was 93% after a mean follow-up period of 15.5 months (SD: 12.5); recurrence was seen in only 8% of the survivors. In the second group, however, mortality was 33% after a median follow-up of 17.5 months (SD: 10), and recurrence was present in 66.7% of the survivors. These results indicate that preoperative TAE reduces the recurrence rate in the first postoperative year. Thereby survival may be improved in patients with resectable metastatic liver cancer. Publication Types: Clinical trial Randomized controlled trial PMID: 8629387 

J Surg Oncol 1995 Oct;60(2):116-21 
Hepatic artery chemoembolization or embolization for primary and metastatic liver tumors: post-treatment management and complications. 
Berger DH, Carrasco CH, Hohn DC, Curley SA. 
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. 
...The morbidity rate following HACE and HAE in this study was 5.1%. The major complications included portal vein thrombosis, hepatic abscess, and liver failure. The treatment-related mortality rate was 4.1%. Fever and ileus were the most common management problems ... Median survival for patients with liver metastases varied according to histologic type, .... Morbidity and mortality ... can be minimized by proper selection and careful management of patients. HACE or HAE alone was not curative in any of these 121 patients. An understanding of treatment-related side effects is necessary to aid in the management of patients .... PMID: 7564377 

Radiology 1994 Dec;193(3):743-6 
Multiple intrahepatic aneurysms following transcatheter arterial embolization. Work in progress. 
Aso N, Matsunaga N, Fukuda T, Sakamoto I, Ashizawa K, Aikawa H, Isomoto I, Hayashi K, Fukushima T, Morikawa M. 
Department of Radiology, Nagasaki University School of Medicine, Nagasaki, Japan. 
... To discuss the mechanism of multiple intrahepatic aneurysm formation after transcatheter arterial embolization (TAE) performed in five patients with hepatocellular carcinoma. ... TAE was performed with gelatin sponge particles and iodized oil as embolic materials. Mitomycin C was also used in four cases. ... Three to 14 aneurysms 1-6 mm in diameter were found in third-to sixth-order branches of the hepatic arteries at repeat angiography performed 25-45 days after TAE. Follow-up angiograms in three cases revealed that most aneurysms were no longer apparent except in one patient in whom two aneurysms remained and were larger than before. In none of the five cases were any signs of aneurysm rupture noted. ... Radiologists should be aware of this complication of TAE. It is speculated that the main cause of aneurysm formation in these patients was the embolic agents used.  PMID: 7972817 

Minerva Chir 1994 Apr;49(4):281-5 
Chemoembolization in liver malignant involvement. Experiences on 17 cases. 
Fiorentini G, Campanini A, Dazzi C, Davitti B, Graziani G, Priori T, Ricci Bitti R, Angelini L. 
Department of Medical Oncology, City Hospital Santa Maria delle Croci, Ravenna. 
INTRODUCTION. Liver invasion is the major cause of organ failure in patients with primary liver cancer and metastatic large bowel cancer. Furthermore it causes high morbidity in many other carcinomas. The normal liver presents a double circulation: 75% from portal circulation and 25% from hepatic artery. In malignant primary and secondary lesions the blood support is given by hepatic artery. Antineoplastic drugs mixed to selectively injecting embolic particles, such as polyvinyl alcohol and gelatin powder (Gelfoam), can be injected to infarct tumors and to obtain a therapeutical advantage. Chemoembolization using an emulsion of Lipiodol ultra-fluid (LUF) and drugs is a recent tool in liver regional therapy. LUF has been shown to be taken up hepatocellular carcinoma and retained for a long period of time in the tumor bed. Chemoembolization causes massive shrinkage due to ischemia and increasing the local drug intensity and drug exposure...PMID: 8072703 

Acta Radiol 1994 Mar;35(2):143-6 
Iodized oil in the portal vein after arterial chemoembolization of liver metastases--a caution regarding hepatic necrosis. 
Tarazov PG. Department of Diagnostic Radiology, Central Research Institute of Roentgen Radiology, St. Petersburg, Russia. 
Of 20 patients with hepatic metastases from colorectal cancer treated by arterial chemoembolization, 4 showed iodized oil in peripheral branches of the portal vein. Aseptic necrosis of both the tumor and normal parenchyma in corresponding liver segments developed in 2 of these patients. They were successfully treated with antibiotics and percutaneous drainage. In the 2 remaining patients, the procedure was interrupted before complete arterial occlusion when oil was detected in the portal vein on fluoroscopy, and there was no complication. Appearance of iodized oil in the portal vein during arterial chemoembolization of colorectal liver metastases is an unfavorable event signaling the risk of liver necrosis. PMID: 8172739 

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Isolated Liver Perfusion [IHP] & Liver Metastases 


Unquestionable indications for Surgical Resection are either solitary metastases or metastases limited to one liver lobe, since resection provides the best long-time results. In multilocular metastases or non-resectable liver metastases other treatments must be explored [RFA, microwave, conventional chemotherapy]. Where conventional systemic chemotherapy is chosen, but is ineffective, there are alternative methods of delivering the chemotherapy agent that maximizes tumor exposure. 
Because of the mainly arterial supply of liver metastases, the different procedures of regional chemotherapy-intra arterial infusion, isolated liver perfusion, and/or chemoembolisation can provide the tumor with high drug concentrations without provoking systemic side effects. These procedures do not prevent the appearance of extra-hepatic recurrence or metastases. 
Hepatic Arterial Infusion [HAI] has been used for many years to treat liver tumors (primary or secondary) if no extrahepatic tumor exists, when no resection is feasible, and when no active systemic chemotherapy is available. Liver toxicity and extrahepatic progression are the two main limiting factors that can possibly be reduced using new protocols and combinations with systemic chemotherapy. 
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. [What this means is the two blood vessels feeding the liver (the portal vein and the hepatic artery), and the vein leaving the liver (the hepatic vein) are hooked up to a heart-lung machine. The chemotherapy and other agent[s] are injected into the liver circulation, but do NOT get into the rest of the body's circulation. The liver's blood circulation is ISOLATED from the rest of the body. After perfusing the liver for an hour with the high concentration chemotherapy agent[s], the liver is given a 'washout' and then reconnected to the systemic circulation. This allows higher concentration of toxic chemicals to be given to the liver, and spares the rest of the body the side effects.] 
HAI and isolated liver perfusion are two active locoregional treatments which can be combined with surgical resection and/or systemic chemotherapy for downgrading of unresectable tumors, for treatment of unresectable chemotherapy resistant tumors, and for palliation of severe disease. Responses obtained by drugs delivered as continuous infusion into the hepatic artery have been kept lower because often the drugs' rapid uptake and detoxification by liver cells results in relatively low systemic drug levels. 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. Observation for leakage of perfusate must be carried out. 


Complications 
Death within 30 days of perfusion due to multiple organ failure. These patients had more than 50% of liver volume occupied by cancer. In patients with massive liver tumour, there is a significant risk of developing multiple organ failure. Deaths also occurred from necrotizing pancreatitis and hepatic arterial thrombosis-both deaths were related directly to the hepatic arterial catheter. 
All surviving patients can develop reversible hepato- and renal toxicity. Postoperative bleeding or coagulopathies can develop. The most frequent side effects were mild to moderate chemical hepatitis and reversible bone marrow suppression. It may be difficult to distinguish between toxicity from the drug regimen and that from the perfusion procedure itself. 
Latest Pubmed Search on this topic:  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=isolated%20liver%20perfusion%20metastases
References for this section are below. 
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Isolated Liver Perfusion & Liver Metastasis
Selected Medical Journal Annotated Citations



[For the full abstract, use the links provided, or search on Pubmed.  Ed.]


Oncol Res 1999;11(11-12):529-37 


 A clinical-pharmacological evaluation of percutaneous isolated hepatic 
 infusion of doxorubicin in patients with unresectable liver tumors.

 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.  PMID: 10905565  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10905565&dopt=Abstract




(Current Oncology Reports)Volume 3 | Number 4 | 2001 | Melanoma 
Isolated Limb Perfusion for Extremity Soft-Tissue Sarcomas, In-Transit Metastases, and Other Unresectable Tumors: Credits, Debits, and Future Perspectives 
by Alexander M. M. Eggermont, MD, PhD, Timo L. M. ten Hagen, PhD 
Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-a (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees, leading to approval of TNF in Europe. We have also reported on the success of this regimen against ... drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway. 

Surgery 2001 Feb;129(2):176-87 
Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. 
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. Publication Types: Clinical trial PMID: 11174711 

Gan To Kagaku Ryoho 2000 Oct;27(12):1801-4 
[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] 
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. Publication Types: Clinical trial Clinical trial, phase i PMID: 11086416  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11086416&dopt=Abstract

Hepatogastroenterology 2000 May-Jun;47(33):776-81 
Isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques: from laboratory to the clinic towards a percutaneous procedure. 
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. ... PMID: 10919031 

Ann Surg Oncol 1999 Oct-Nov;6(7):658-63 Comment in: Ann Surg Oncol. 1999 Oct-Nov;6(7):631-2 
Isolated organ perfusion does not result in systemic microembolization of tumor cells. 
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. PMID: 10560851 

Eur J Surg Oncol 1999 Apr;25(2):179-85 
Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan. 
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. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies. ...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. Publication Types: Clinical trial Clinical trial, phase i PMID: 10218462 

Gan To Kagaku Ryoho 1998 Jul;25(9):1266-8 
[The long-term results of percutaneous isolated hepatic perfusion for patients with advanced hepatocellular carcinoma]. [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. PMID: 9703804 

Recent Results Cancer Res 1998;147:120-6 
Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia TNF alpha and melphalan: Swedish experience. 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.  Publication Types: Clinical trial Clinical trial, phase i PMID: 9670274 

Recent Results Cancer Res 1998;147:67-82 
Percutaneous isolated liver chemoperfusion for treatment of unresectable malignant liver tumors: technique, pharmacokinetics, clinical results. 
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. 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. PMID: 9670270 

Recent Results Cancer Res 1998;147:3-12 
Are there indications for intra arterial hepatic chemotherapy or isolated liver perfusion? The case of liver metastases from colorectal cancer. 
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. PMID: 9670263 

Surgery 1998 Jun;123(6):622-31 
First experience and technical aspects of isolated liver perfusion for extensive liver metastasis. 
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. 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. PMID: 9626312 


Semin Surg Oncol 1998 Apr-May;14(3):262-8 
Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy in the treatment of irresectable liver metastases? 
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. 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. .... 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. Publication Types: Clinical trial Clinical trial, phase i Clinical trial, phase ii Review, tutorial PMID: 9548610 


Surg Oncol 1994 Apr;3(2):103-8 
Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. 
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. 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. Publication Types: Clinical trial Clinical trial, phase i PMID: 7952389 

J Clin Oncol 1994 Dec;12(12):2723- 


        Percutaneous hepatic vein isolation and high-dose hepatic arterial 
        infusion chemotherapy for unresectable liver tumors.

        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). 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. ...
        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. ...    Publication Types:      Clinical Trial    PMID: 7989950 


Chirurg 1982 Sep;53(9):571-3 
[Isolated liver perfusion with 5-fluorouracil (5-FU) in the human]. [Article in German] 
Aigner K, Walther H, Tonn JC, Krahl M, Wenzl A, Merker G, Schwemmle K. 
In two patients with liver metastases from colorectal cancer an isolated perfusion of the liver with 5-fluorouracil was performed. The primary tumors had been resected 5 weeks and 11 months before the perfusion treatment. By means of special cannulation system the hepatic artery and the portal vein were both arterialized. The patients recovered well after the operation. Sonographic measurements of the metastases showed colliquation areas in the tumours postoperatively. PMID: 7172834 

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Stop-flow Perfusion & Liver Metastases. 

See article below. 
See also Introduction to Isolated Liver Perfusion. 

Radiol Med (Torino) 1997 Apr;93(4):410-7 
[Antiblastic hypoxic stop-flow perfusion in the treatment of liver metastasis: preliminary results]. 
[Article in Italian] 
Roversi R, Cavallo G, Ricci S, Rossi G, Roversi M, Fiorentini G. 
Servizio di Radiologia Diagnostica, Ospedale Bellaria-C.A. Pizzardi, Bologna. 
...27 patients (14 men and 13 women aged 35 to 71 years; average: 59 years), with 3-11 months' follow-up (average: 5 months) were treated for hepatic metastases (17/22 from colorectal, 10/22 from other primary tumors) with hypoxic locoregional hepatic perfusion. Sixteen of 22 patients had been pretreated with resection, systemic chemotherapy or freeflow locoregional infusion. Our protocol consists in blocking arterial flow with an occlusion balloon catheter inflated in the hepatic artery; the main catheter channel is connected with a pump system and 250-300 ml saline with 30-40 mg Mitomycin C are perfused in the arterial hepatic system. Embolization with a gelatin sponge is performed after the end of perfusion. ... 19/27 patients are still alive, and 8/27 are dead but death was caused by the progression of intrahepatic disease in only 2/27 (7%). Iatrogenic lesions of the arterial wall were shown at follow-up DSA in 15/22 patients (56%). Thirteen CR (48%) and 9 PR (33%) were demonstrated at CT follow-up, amounting to 81% of objective responses. Follow-up showed a clinical CR in 12/18 symptomatic patients (66%). No case of hematologic toxicity was observed. Mean CEA values changed from 129 to 10.60. Twelve of 27 patients exhibited mild posttreatment sequels, none of them lasting longer than three days; ischemic cholecystitis was seen in 3/15 cases (14%). ... The occlusion catheters on the market are not optimal for this procedure; the axillary percutaneous approach is advantageous. CR rate was very high in our series but the objective response rate doses do not differ from those in the series with free-flow procedures. The highest CR rate was observed in untreated patients and in hypervascularized lesions; the rate of clinical sequels was low, clinical CR rates were high and there was no hematologic toxicity. This well-tolerated procedure provides good local disease control, but the high rate of deaths from extrahepatic progression suggests that systemic chemotherapy and long-step intraarterial perfusion be combined. Publication Types: Clinical trial PMID: 9244920 

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Radiation/Radioisotope Embolization for Inoperable Liver Metastases  
See below, and See Radiation page for further discussion. 


UM physicians report promising results for TheraSphere, new treatment option for inoperable liver cancer
15 MAY 2001 University of Maryland Medical Center News Release
Cancer specialists from the University of Maryland Greenebaum Cancer Center report that early results of a new treatment for inoperable liver cancer, known as TheraSphere, are promising. They will report their findings at the 37th annual meeting of the American Society of Clinical Oncologists on May 15. The Greenebaum Cancer Center in Baltimore is the first in the nation to successfully perform the procedure. 
Forty-five patients have undergone the procedure there since its introduction last fall, according to David Van Echo, M.D., professor of medicine at the University of Maryland School of Medicine and director of the New Drug Development Program at the Greenebaum Cancer Center. Most patients have shown a positive response, as marked by a reduction in tumor size or number of lesions, with minimal side effects,ö says Dr. Van Echo. 
TheraSphere is a unique new targeted therapy that spares healthy tissue while providing radiation directly to liver tumors, says Dr. Van Echo. Millions of microscopic glass beads containing the radioactive element, yttrium 90, are delivered via catheter into the femoral and hepatic arteries and transported directly to the liver. This mechanism allows a more concentrated dose precisely where it is needed most. Preliminary results have been very promising. 
The most dramatic improvements have been noted in patients with gastrointestinal carcinoid tumors --those that develop in certain hormone-making cells û also called neuroendocrine cells -- of the digestive system. Extremely interesting is the fact that of three neuroendocrine patients treated with TheraSphere, all had tumors that completely disappeared,ö says Dr. Van Echo. Also showing favorable response to TheraSphere are patients with colorectal tumors. Of seven patients in this category, two have died of progressive cancer outside the liver, but the other five are doing well six months after treatment, says Dr. Van Echo. They had not been helped by conventional chemotherapy and the average length of survival with this particular diagnosis is three to six months. With TheraSphere treatment, they are all healthy, living longer and enjoying a higher quality of life. 
TheraSphere was approved by the U.S. Food and Drug Administration (FDA) last March for the treatment of liver cancer that cannot be treated surgically. The FDA granted MDS Nordion, which makes TheraSphere, a Humanitarian Device Exemption. This exemption, which permits the FDA to approve devices based on proof of patient safety alone, encourages further research and development for diseases that affect few patients. 
Our experience thus far indicates that the procedure does have benefit for the patient and we have a better understanding of who is most likely to benefit, says Dr. Van Echo. Those less responsive to TheraSphere as a treatment option are patients who have larger liver tumors, for example. 
TheraSphere is a non-surgical outpatient procedure. Patients can return home the same day and treatment poses no safety threat to caregivers or family members. Side effects can include vomiting, mild fever, abdominal pain and gastric ulcers. Toxicities are evident in about 20 percent of patients treated. And though patients initially were treated with a single dose, the procedure is being evaluated as a two-part process in which the right lobe of the liver is treated and the left lobe is treated two to four weeks later. 
We are delivering the same amount of treatment using the sequential approach, says Dr. Van Echo. But by splitting the dose, we are exposing the surrounding tissue to less radiation and decreasing the chance of the patient developing gastrointestinal toxicities. 
The University of Maryland Greenebaum Cancer Center remains the only institution nationwide treating patients, other than those with primary liver cancer, with TheraSphere. Though fewer than 10,000 Americans are diagnosed with liver cancer each year, it is a rapidly fatal disease with few treatment options, says Dr.Van Echo. Surgery remains the preferred treatment, but fewer than 15 percent of patients qualify for that option due to the advanced progression of the disease. And, though liver cancer is more prevalent in other countries such as Africa and Asia, it is on the rise in the United States due to the increasing number of persons who have the Hepatitis B or C virus. 

Int J Radiat Oncol Biol Phys 1990 Mar;18(3):619-23 
Tolerance of the liver to the effects of Yttrium-90 radiation. 
Gray BN, Burton MA, Kelleher D, Klemp P, Matz L. University Department of Surgery, Royal Perth Hospital, Western Australia. 
There are no reliable data documenting the tolerance of the human liver to ionizing radiation from a continuous Yttrium-90 source. As Yttrium-90 incorporated into microspheres is being used to treat patients with liver cancer, it is imperative that the tolerance of the human liver to this form of radiation damage be determined. Four patients with metastatic liver cancer were treated with Yttrium-90 to deliver radiation doses above that considered tolerable when given by conventional external sources. Patients were monitored with serial estimations of liver function tests and between 7 and 9 months after treatment liver biopsies were performed. Histological examination of the liver biopsies confirmed only minimal changes in the normal liver parenchyma. These data indicate that the human liver may tolerate relatively large radiation doses when delivered by Yttrium-90 microspheres embedded in the liver parenchyma as a number of discrete point sources. PMID: 2318695 

Radiother Oncol 1996 Dec;41(3):233-6 
Clearance of parenchymal tumors following radiotherapy: analysis of hepatocellular carcinomas treated by proton beams. 
Ohara K, Okumura T, Tsuji H, Min M, Tatsuzaki H, Chiba T, Tsujii H, Akine Y, Itai Y. Department of Radiology, University Hospital, University of Tsukuba, Japan. 
Clearance of a parenchymal tumor following radiotherapy was determined by using follow-up CT scans of 18 hepatocellular carcinoma tumors treated with focused proton beams. Regression analysis of the daily decrement (DD) and the diameter (D) of a tumor mass in each CT observation interval, DD = a*Db, showed that the exponent b was 3.0 or larger in early periods and 2.0 or smaller in late periods. This suggests that the clearance depends initially on the tumor volume, subsequently on the tumor surface area, and then it becomes much more moderate, possibly due to radiation damage to the parenchymal tissues. PMID: 9027939 




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