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Liver Metastases: IHP, Radioisotope Embolization, Radiotherapy
written and compiled by doctordee
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Isolated Liver Perfusion [IHP]

Unquestionable indications for Surgical Resection are either solitary metastases or metastases limited to one liver lobe, since surgical resection provides the best long-time results. Sometimes surgeons will operate on one side of the liver, and then wait for recovery to operate on the other side.

For 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 to it.

Because of the mainly arterial supply of liver metastases, the different procedures of regional chemotherapy:

intra arterial infusion
isolated liver perfusion
embolization
chemoembolisation
and/or
radioisotope embolization

can provide the tumor/s in the liver 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, and the vein leaving the liver 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.

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Annotated References With More Information for this section: see below

Isolated Liver Perfusion Annotated References

Isolated Liver Perfusion & Liver Metastasis
Selected Medical Journal Annotated Citations

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


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

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


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

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


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

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


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

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


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

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

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

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


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

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


8.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.
Fetch PMID: 10905565


9. 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. Clinical trial
Fetch PMID: 11174711


10. 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. Clinical trial, phase i
Fetch PMID: 11086416


11. 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. ...
Fetch PMID: 10919031


12. Ann Surg Oncol 1999 Oct-Nov;6(7):658-63 Comment in: Ann Surg Oncol. 1999 Oct-Nov;6(7):631-2
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.
Fetch PMID: 10560851


13. 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. Clinical trial, phase i
Fetch PMID: 10218462


14. 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.
Fetch PMID: 9703804


15. 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. Clinical trial, phase i
Fetch PMID: 9670274


16. 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.
Fetch PMID: 9670270


17. 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.
Fetch PMID: 9670263


18. 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. Fetch
Fetch PMID: 9626312


19. 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. phase ii Review,
Fetch PMID: 9548610


20. 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. Clinical trial, phase
Fetch PMID: 7952389


21. 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. ... Clinical Trial
Fetch PMID: 7989950

updated Nov 2003
doctordee
Radioisotope Embolization

Tiny beads of glass or resin, called microspheres, can be impregnated with Yttrium-90, a radioisotope. These beads can be injected into the hepatic artery, the main artery feeding the liver cells, and liver tumor cells. Tumor intake of the microspheres is much higher than that of normal liver tissue. The microspheres serve not only to embolize [block or clot off supplying blood vessels to the tumor] but also to irradiate the tumor locally. This would spare normal tissue from having as great an exposure to the radiation as the tumor would get.

This has been used for liver tumors which no longer respond to chemoembolization.

Yttrium-90 impregnated GLASS microspheres are called TheraSpheres. There is some concern that the glass is heavier than the resin, and tends to settle out downward during administration.

Yttrium-90 impregnated RESINS microspheres are called SirSpheres. The resin, being lighter, is hoped to distribute more evenly in the blood supply. I believe that SirSpheres are in clinical trial for liver tumors only, at this time.

This is a news release of May 2001, from the University of Maryland Medical Center:

"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."

"Forty-five patients have undergone the procedure there since its introduction last fall, ...Most patients have shown a positive response, as marked by a reduction in tumor size or number of lesions, with minimal side effects,..."

"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."

"... 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."

"... 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. ... by splitting the dose, we are exposing the surrounding tissue to less radiation and decreasing the chance of the patient developing gastrointestinal toxicities. ... "


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


For up to date information,

Search Pubmed for Yttrium microspheres and cancer

Yttrium Microspheres Annotated References
Yttrium Radioisotope Impregnated Microspheres & Liver Metastasis
Selected Medical Journal Annotated Citations

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


1: Eur J Nucl Med Mol Imaging. 2002 Jun;29(6):815-20. Epub 2002 Mar 29.
!Evaluating 90Y-glass microsphere treatment response of unresectable colorectal liver metastases by [18F]FDG PET: a comparison with CT or MRI.
Wong CY, Salem R, Raman S, Gates VL, Dworkin HJ.
Department of Nuclear Medicine, William Beaumont Hospital, 3601 W. Thirteen Mile Road, Royal Oak, MI 48073-6769, USA. owong@beaumont.edu

The purpose of this prospective study was to evaluate yttrium-90 glass microsphere treatment of unresectable liver metastases by ...([18F]FDG PET), and to compare the effectiveness of ... PET for this purpose with that of computed tomography (CT) or magnetic resonance imaging (MRI) and determination of the serum carcinoembryonic antigen (CEA) level.
Thirteen hepatic lobes from eight consecutive patients with colorectal cancer referred for 90Y-glass microsphere treatment of unresectable liver metastases who underwent both baseline (pretreatment) and 3-month posttreatment PET were studied. ...Following treatment, serum CEA decreased significantly, correlating with PET but not with CT or MRI. Thus, the study demonstrated a significant difference between the metabolic and the anatomic response after 90Y-glass microsphere treatment for unresectable liver metastases in colorectal cancer. PET appears to be an accurate indicator of treatment response. Clinical Trial
Fetch PMID: 12029557


2: Semin Oncol. 2002 Apr;29(2):152-9.
Radioembolization for hepatic metastases.
Herba MJ, Thirlwell MP.
Departments of Diagnostic Radiology and Oncology, McGill University Health Center, Montreal General Hospital, Montreal, Canada.

In a phase I/II study, 37 patients with metastatic liver disease, predominantly from colorectal cancer (n = 33) were treated between 1986 and 1994 by intrahepatic arterial embolization of radioactive yttrium 90 (Y 90) glass microspheres. The calculated total liver dose increased in stages from 5,000 cGy to 15,000 cGy. Mean follow-up was 8 months (range, 1 to 49). No major procedural, hematologic, or pulmonary complications occurred. ...Complications are low and if the tumor pattern is nodular with some hypervascularity, beneficial effects are observed clinically and on imaging studies. Copyright 2002, Elsevier Science (USA). All rights reserved.
Fetch PMID: 11951213


3: Nucl Med Biol. 1999 Jan;26(1):149-57.
Treatment of lung tumor colonies with 90Y targeted to blood vessels: comparison with the alpha-particle emitter 213Bi.
Kennel SJ, Stabin M, Yoriyaz H, Brechbiel M, Mirzadeh S.
Life Sciences Division, Oak Ridge National Laboratory, TN 37831-6101, USA. sj9@ornl.gov

An in vivo lung tumor model system for radioimmunotherapy of lung metastases was used to test the relative effectiveness of the vascular- targeted beta-particle emitter 90Y, and alpha-particle emitter, 213Bi. Yttrium-90 was shown to be stably bound by CHXa" DTPA-MAb 201B conjugates and delivered efficiently to lung tumor blood vessels. Dosimetry calculations indicated that the lung received 16.2 Gy/MBq from treatment with 90Y MAb 201B, which was a sevenfold greater absorbed dose than any other organ examined. Therapy was optimal for 90Y with 3 MBq injected. ... Yttrium-90 was found to be slightly more effective against larger tumors than 213Bi, consistent with the larger range of 2 MeV beta particles from 90Y than the 8 MeV alpha particles from 213Bi. Treatment of EMT-6 tumors growing in immunodeficient SCID mice with 90Y or 213Bi MAb 201 resulted in significant destruction of tumor colonies; however, 90Y MAb 201B was toxic for the SCID mice, inflicting acute lung damage. In another tumor model, IC-12 rat tracheal carcinoma growing in SCID mouse lungs, 90Y therapy was more effective than 213Bi at destroying lung tumors. However, 90Y MAb 201B toxicity for the lung limited any therapeutic effect. We conclude that, although vascular-targeted 90Y MAb can be an effective therapeutic agent, particularly for larger tumors, in this model system, acute damage to the lung may limit its application.
Fetch PMID: 10096515

4: Br J Radiol. 1997 Aug;70(836):823-8.
Tumour-to-normal uptake ratio of 90Y microspheres in hepatic cancer assessed with 99Tcm macroaggregated albumin.
Ho S, Lau WY, Leung TW, Chan M, Chan KW, Lee WY, Johnson PJ, Li AK.
Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

The selective delivery of a high dose of radiation to malignant hepatic tumours by infusion of non-biodegradable yttrium-90 (90Y) microspheres via the hepatic artery while sparing the non-tumorous liver parenchyma depends on the tumour-to-normal uptake ratio (T/N) of the therapeutic radiopharmaceutical. Using intrahepatic arterial technetium-99m macroaggregated albumin (99Tcm-MAA), the effect of tumour type, tumour vascularity assessed by hepatic angiography (HAG), tumour size and the degree of extrahepatic shunting on the T/N was investigated in 377 patients with hepatocellular carcinoma (HCC) and 25 patients with colorectal liver metastases. ... Overall there was no correlation between T/N and tumour size. Large tumours (> 20 cm) had a significantly lower T/N, probably due to necrosis in the tumour centres. A decrease in mean T/N with increasing percentages of lung shunting was observed in HCC. Determination of T/N by simulation with 99Tcm-MAA is recommended before internal radiation therapy with 90Y microspheres.
Fetch PMID: 9486047


5: J Nucl Med. 1996 Jun;37(6):958-63.
Comment in: J Nucl Med. 1996 Jun;37(6):963-4. J Nucl Med. 1997 Jul;38(7):1169-70.
Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancies.
Tian JH, Xu BX, Zhang JM, Dong BW, Liang P, Wang XD.
Department of Nuclear Mecicine, The Great Wall Hospital, Beijing, China.

Treatment of liver malignancies ... remains a serious problem because of the difficulty of delivering adequate therapeutic agents to the lesions while sparing the surrounding normal tissue. In an attempt to overcome this obstacle, intratumoral injection of 90Y, a beta-emitter, was performed.

... Twenty-seven hepatocellular carcinomas and six liver metastases were studied, most of which had failed other therapeutic modalities. Guided by ultrasound, 90Y-glass microspheres (GMS) were carefully injected into predetermined tumor sites. The procedure was repeated at 3--4-wk intervals where indicated. Echographic, clinical and laboratory follow-up was conducted at regular intervals. RESULTS: Twelve to 32 mo after treatment, 27 patients were still alive, with dramatic improvement of their clinical condition: 90.6% of the tumor foci became smaller, with echogenic or blood flow changes on liver sonograms. ... Repeat biopsy in nine patients showed complete tumor destruction in eight. Six patients died of either end-stage disease or wide dispersion of the tumor.
...The intratumoral administration of 90Y-GMS under ultrasound guidance yielded a higher cure rate for liver malignancy with no severe side effects. The higher radiation dosage delivered by injected 90Y to the periphery of the lesions (up to 28,215-75,720 cGy) was thought to account for the successful outcome. These results show that intratumoral radionuclide injection is feasible for treatment of malignant lesions inside the body.
Fetch PMID: 8683320


6: Br J Cancer. 1995 Feb;71(2):322-5.
Adjuvant internal radiation therapy in a model of colorectal cancer-derived hepatic metastases.
Burton MA, Gray BN.
School of Science and Technology, Charles Sturt University, Wagga Wagga, Australia.

Selective internal radiation therapy (SIR therapy) is a technique whereby metastatic liver cancer is irradiated by embolising microspheres containing the radionuclide yttrium-90 into the hepatic arterial circulation. To date this technique has [been used] ... to treat established metastases in the liver.

This study evaluated the use of two intrahepatic radiation doses delivered on radioactive microspheres for the treatment of small, growing micrometastases. Three groups of five rats were each inoculated with tumour spheroids into the portal vein. The resultant liver micrometastases were treated with either 10 or 20 MBq of yttrium-90 microspheres or a sham dose of non-radioactive microspheres injected into the portal vein 2 days following tumour inoculation. ... These results indicate a potential role for SIR therapy in an adjuvant setting with colorectal cancer.
Fetch PMID: 7841048


7: Radiother Oncol. 1992 Oct;25(2):137-9.
Glass yttrium-90 microspheres for patients with colorectal liver metastases.
Anderson JH, Goldberg JA, Bessent RG, Kerr DJ, McKillop JH, Stewart I, Cooke TG, McArdle CS.
University Department of Surgery, Royal Infirmary, Glasgow, UK.

Total calculated uniform liver doses of up to 150 Gy were achieved using glass yttrium-90 microspheres administered via the hepatic artery and targeted to tumour using angiotensin II in seven patients with colorectal liver metastases. No toxicity was observed. Hepatic metastatic progression was delayed in six patients. ...
Fetch PMID: 1438931


8. Aust N Z J Surg. 1992 Feb;62(2):105-10.
Regression of liver metastases following treatment with yttrium-90 microspheres.
Gray BN, Anderson JE, Burton MA, van Hazel G, Codde J, Morgan C, Klemp P.
University Department of Surgery, Royal Perth Hospital, Western Australia.

Selective internal radiation (SIR) therapy is a technique developed by our group for concentration of Yttrium-90 microspheres into liver metastases. The technique involves laparotomy, insertion of the catheter into the hepatic artery, redistribution of liver blood flow with vaso-active agents and incremental embolization of Yttrium-90 containing microspheres (SIR spheres) into the liver. Twenty-nine patients with non-resectable liver metastases from primary adenocarcinoma of the large bowel were treated by this technique and followed for a minimum of three months to assess evidence of tumour regression. ... SIR therapy results in a high rate of tumour regression in patients with liver metastases secondary to large bowel cancer.
Fetch PMID: 1586298


9. J Surg Oncol. 1989 Nov;42(3):192-6.
Selective internal radiation (SIR) therapy for treatment of liver metastases: measurement of response rate.
Gray BN, Burton MA, Kelleher DK, Anderson J, Klemp P.
University Department of Surgery, Royal Perth Hospital Perth, Western Australia.

Ten patients with liver metastases from primary tumors in the colorectum were treated with selective internal radiation (SIR) therapy. This involved the embolisation of yttrium-90-containing microspheres into the hepatic artery at the time of laparotomy. The microspheres were concentrated in the microvasculature of the tumour nodules by the concurrent administration of angiotensin II. The radiation dose being delivered to liver parenchyma was measured at the time of operation by use of an intraoperative radiation detection probe. All nine patients in whom the preoperative carcinoembryonic antigen (CEA) level was elevated experienced a decrease in CEA levels posttreatment. Intraoperative dosimetry confirmed the poor correlation between total radioactivity used and radiation dose received by normal liver parenchyma.
Fetch PMID: 2811384


10: Can Assoc Radiol J. 1989 Aug;40(4):206-10.
Treatment of liver tumors with yttrium-90 microspheres alone.
Blanchard RJ, Morrow IM, Sutherland JB.
Department of Surgery, University of Manitoba, Winnipeg.

Fifteen patients with liver metastases and one patient with hepatoma were treated by infusing 15 microns diameter plastic microspheres containing yttrium-90 into the hepatic artery. Twenty additional patients were screened but were found to be unsuitable for treatment. Follow-up angiography was done in 13 of the 16 treated patients. In five patients there was a reduction in tumor volume by more than 50% and in another two patients there was a smaller reduction. In six patients gastritis or gastric ulceration occurred and in three this was demonstrated to be due to unintended infusion of microspheres into the gastric circulation. For patients treated with yttrium-90 microspheres, mean survival time after referral was 62 weeks and in the untreated group it was 30 weeks, although this difference was not significant. We conclude that yttrium-90 microspheres alone can effect reduction in the size of liver tumors in some patients in whom their use is feasible.
Fetch PMID: 2766018


11: Cancer Chemother Pharmacol. 1989;23 Suppl:S68-73.
Hepatic arterial chemotherapy for primary and metastatic liver cancers.
Ensminger W.
Department of Medicine, University of Michigan Medical School, Ann Arbor.

Hepatic arterial chemotherapy represents a means of selectively exposing hepatic tumor to cytotoxic agents. Although 5-fluoro-2'-deoxyuridine has been shown to generate a higher response rate in the treatment of colorectal liver metastases than that achieved by intravenous infusion, responses are largely incomplete and rarely of long duration. This review describes the rationale for the use of the thymidine analogs 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine in hepatic arterial infusions and indicates how combination therapy adding radiotherapy, specifically with hepatic arterially administered yttrium-90 microspheres, might generate a new, more efficient and effective therapeutic approach.
Fetch PMID: 2647314


12: J Surg Res. 1983 Jan;34(1):17-24.
Internal radiotherapy for hepatic metastases I: The homogeneity of hepatic arterial blood flow.
Stribley KV, Gray BN, Chmiel RL, Heggie JC, Bennett RC.

Internal radiotherapy, in the form of arterially infused yttrium-90-labeled microspheres, theoretically appears encouraging as a method of treatment for hepatic metastases. Previous investigators have assumed a homogeneous distribution of these microspheres and given dosages of isotope based solely on an estimated liver mass. The purpose of this study has been to establish the homogeneity of isotope distribution in liver substance when 15 micrometers microspheres are arterially injected. This has been done in three mammalian species, with the results expressed as a mean percentage coefficient of variation of 28 +/- 5%. Also demonstrated is the fact that 15 micrometers particles, while not penetrating to the venous circulation, achieve a more homogeneous spread throughout the liver than larger particles. It has been demonstrated that to achieve this maximum homogeneity distribution, 4000 beads/g of liver tissue are required. This equates in the therapeutic situation to a maximum activity of 4 Ci/g of infused microspheres. These results are considered significant in that they indicate criteria necessary to achieve the maximum homogeneity of therapeutic agent within liver substance when it is administered by this method, and will allow confidence limits to be attached to direct in vivo measurement of hepatic irradiation.
Fetch PMID: 6823100


13: J Surg Res. 1983 Jan;34(1):25-32.
Internal radiotherapy for hepatic metastases II: The blood supply to hepatic metastases.
Stribley KV, Gray BN, Chmiel RL, Heggie JC, Bennett RC.

...Internal radiotherapy in the form of yttrium-90 microspheres infused into the hepatic artery appears to be a promising method of therapy. One criterion required for the success of this treatment is that of a differentially greater arterial supply to tumor as opposed to liver tissue. This arterial hypervascularity of tumor has been demonstrated before. However, some conflict has been reported as to the maintenance of this state as tumor size increases. Using 15 micrometers Cobalt-57 microspheres for studying salivary adenocarcinoma implants in DA rat livers, these experiments have demonstrated a constant blood flow in the tumor periphery of 3.9 times that within the normal hepatic parenchyma, regardless of tumor size. Also demonstrated is a progressive decrease in central tumor arterial blood flow after a tumor diameter of 6 mm has been exceeded. Arterial hypervascularity of liver tissue adjacent to the tumor has been demonstrated while an intermediate zone of liver tissue appeared hypovascular, suggesting the presence of shunting. In three humans with metastatic liver disease, hepatic artery infusion of particulate radiotracer has demonstrated the peripheral tumor hypervascularity and relative central tumor hypovascularity with good correlation obtained with the images of the metastases on conventional colloidal hepatic scintigraphy. This method allows assessment of the patient's suitability for internal radiotherapy by enabling assessment of the tumor vascularity and the degree of potentially dangerous extrahepatic irradiation.
Fetch PMID: 6681644


14: Dis Colon Rectum. 1979 Sep;22(6):371-5.
Internal radiation therapy of hepatic cancer.
Grady ED.

Established cancer in the liver can, in selected patients who have a good arterial circulation in these tumors, be effectively treated by intrahepatic artery radioactive yttrium-90 resin microspheres. Even in unselected patients treated in the last five years by the author, 17 of 25 patients treated have had good objective regression of cancers, improvement of symptoms and prolongation of life. Treatment is relatively simple and associated with few side effects. ...
Fetch PMID: 498890


15: J Surg Oncol. 1978;10(4):327-36.
Treatment of symptomatic metastatic cancer to the liver from primary colon and rectal cancer by the intraarterial administration of chemotherapy and radioactive isotopes.
Ariel IM, Padula G.

Sixty-five patients were referred for treatment with symptoms resulting from metastatic cancer to the liver from the GI tract. ... The first group of 40 patients were subjected to a laparotomy and insertion of a catheter into the hepatic artery and a second group had the catheter inserted percutaneously and a bolus of cancer chemotherapeutic agents injected into the catheter. In both groups, chemotherapy in the form of 5-fluorouracil was supplemented by internal irradiation delivered from the intraarterial administration of Yttrium 90 microspheres. Forty percent of the patients who had an indwelling catheter performed at celiotomy manifested an objective response and in 60% a significant subjective improvement occurred. In the 25 patients whose catheter was inserted percutaneously, the response rate was roughly similar, in that 35% demonstrated an objective response and 65% demonstrated a subjective response.
Fetch PMID: 692139
Radiotherapy

Leiomyosarcoma is not always a good subject for irradiation. There have been some LMS tumors that have continued to grow splendiferously despite and during heavy irradiation. Other LMS tumors may have seemed to respond to the radiation, but recur and regrow at a later date. LMS is considered a radioresistant tumor. For irradiation of LMS, usually 70 Grays of radiation is used, and this is a very heavy dose.

While it is not such a good idea to irradiate the liver in its entirety, sometimes tumors on or in the liver grow large. Radiotherapy that is aimed just at the tumor can be used to shrink such a tumor, to make it operable, or for palliation.

One football sized liver tumor was irradiated by Fermi Lab with its high-energy fast neutrons, and the woman was still alive, and her tumor was still shrinking, two years later.

Proton beam, because it is a particle beam that does not go beyond the target area, is also a useful treatment modality if there is one large tumor in the area. Proton Beam irradiation spares normal tissue posterior to the target area from radiation damage. Proton Beam Irradiation of tumors is currently done at Loma Linda Hospital in California, and Massachusetts General Hospital in Boston. There is a new facility opening up at the University of Indiana, as well.

IMRT, gamma knife, and stereotactic radiosurgery are methods which use Xrays [gamma rays] to irradiate tumors. These rays go through the entire body, so that normal tissue also gets irradiated. IMRT, gamma knife, and stereotactic modalities try to use so many different angles, so that the tumor gets irradiated heavily, and the surrounding tissues, not so much.


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.
Fetch PMID: 9027939


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