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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.07.004 on February 9, 2004

Annals of Surgical Oncology 11:290-297 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Regional Treatment Options for Patients With Ocular Melanoma Metastatic to the Liver

Elizabeth D. Feldman, MD, James F. Pingpank, MD and H. Richard Alexander, Jr., MD

From the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Correspondence: Address correspondence and reprint requests to: H. Richard Alexander, Jr., MD, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, Building 10, Room 2B07, Bethesda, MD 20892-1502; Fax: 301-402-1788; E-mail: richard_alexander{at}nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 LOCOREGIONAL THERAPIES
 SUMMARY
 REFERENCES
 
Ocular melanoma is the most common primary ocular malignancy and has a significant predilection for metastasis to the liver. More than 40% of patients have hepatic metastases present at initial diagnosis, and the liver becomes involved in up to 95% of individuals who develop metastatic disease. The median survival of patients after diagnosis of liver metastasis ranges from 2 to 7 months. Metastatic disease localized to the liver has proven to be resistant to most available chemotherapy and immunotherapy regimens. Recognition of the grave prognosis associated with liver metastasis from ocular melanoma has led to the evaluation of new regional treatment modalities primarily designed to control tumor progression in the liver, including hepatic arterial chemotherapy, hepatic artery chemoembolization, regional immunotherapy, isolated hepatic perfusion, and percutaneous hepatic perfusion. This article reviews the efficacy, outcomes, and morbidities of the multiple locoregional therapies available today.

Key Words: Regional therapy • Liver metastases • Chemoembolization • Isolation perfusion • Intra-arterial chemotherapy • Immunotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
LOCOREGIONAL THERAPIES
 SUMMARY
 REFERENCES
 
Uveal melanoma is the most common primary intraocular malignancy in adults1 and represents 5% to 6% of all melanoma diagnoses.2 The incidence of ocular melanoma is reported to be 3500 to 4000 per year.2,3 The 5-year overall survival for patients with ocular melanoma is estimated to be 50% to 70%.4 Factors related to the primary tumor that influence prognosis include lesion size, cell type, location, scleral or extrascleral invasion, number of mitoses, extension beyond Bruch’s membrane, and optic nerve invasion.5 Approximately 40% to 60% of patients will ultimately develop metastases.6

Uveal melanomas have a significant predilection for metastasis to the liver.1 Up to 40% of patients have been reported to have hepatic metastases present at initial diagnosis, and the liver becomes involved in up to 95% of individuals who develop metastatic disease.7 The liver is the sole or dominant site of metastases in more than 80% of patients, and the metastasis occurs via hematogenous spread.6,8–11 Despite aggressive therapy, the median survival of patients after diagnosis of liver metastases is reported to be 2 to 7 months,12 and the 1-year survival is estimated to be 10%.13,14 Other less common sites of metastasis include the lungs, bones, skin, and lymph nodes, as well as the pancreas, heart, spleen, adrenal glands, gastrointestinal tract, kidneys, ovaries, and thyroid.

Some have attempted to define prognostic factors for those with metastatic uveal melanoma. A study of 201 patients with metastatic ocular melanoma treated at one institution between 1968 and 1991 determined by multivariate analysis that only the metastasis-free interval and the serum alkaline phosphatase level were significant predictors of survival.13 Leyvraz et al.15 showed, in a multivariate analysis of 30 patients with disease confined to the liver treated with hepatic intra-arterial administration of fotemustine, that the baseline lactate dehydrogenase (LDH) level was a strong prognostic factor for survival (Fig. 1).



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  		FIG. 1. Overall survival and lactate dehydrogenase (LDH) level. On the basis of a multivariate analysis, only the pretreatment LDH level was an independent prognostic factor for survival in 30 patients with ocular melanoma metastatic to the liver. Reprinted from the Journal of Clinical Oncology, vol 15(7), pp 2589–2595, 1997, with permission from the American Society of Clinical Oncology.15

 
Metastatic uveal melanoma has proven to be resistant to most available immunotherapy and chemotherapy regimens.16 Many systemic treatment strategies using (1) immunotherapy,7 such as interleukin-2; (2) chemotherapy, including dacarbazine (DTIC), cisplatin, temozolomide,13 or lomustine17; or (3) the antiangiogenic agent thalidomide,12 alone or in combination, have been used for patients with metastatic ocular melanoma. However, none has been associated with an outcome that is significantly better than the reported natural history of the disease. The use of DTIC and BCNU (carmustine) resulted in 4 partial responses (PR) in 25 patients treated with this regimen.18 The Southwest Oncology Group reported 1 complete response (CR) and 5 PRs in 64 patients treated with DTIC or cisplatin.19 Similarly, the M. D. Anderson Cancer Center reported a series of 129 patients who received chemotherapy, 99 of whom had not received prior systemic chemotherapy.13 Most of the drug regimens used DTIC, either alone or in combination with other agents. Only 1 patient treated with DTIC, BCNU, vincristine, and bleomycin demonstrated a PR. The Eastern Cooperative Oncology Group trials conducted by Albert et al.20 in 1996 confirmed these results. Fifty-one patients with metastatic uveal melanoma, 46 (90%) of whom had liver metastases, were treated with various chemotherapeutic regimens, with no objective responses.

Several groups have explored the use of chemotherapy in combination with immunotherapy agents. A phase II trial conducted by Nathan et al.17 included 23 patients (20 of whom were assessable) treated with bleomycin, vincristine, lomustine, DTIC, and intercycle interferon alfa-2b. They observed an overall response rate (all partial) of 17%; the patients who responded had primarily liver disease. Pyrhonen et al.21 also conducted a phase II trial with a bleomycin, vincristine, lomustine, DTIC, and human leukocyte interferon regimen. Four of 20 patients with metastatic uveal melanoma achieved a PR. Similarly, Becker et al.7 treated 48 patients with metastatic uveal melanoma with subcutaneous interleukin-2, interferon 2-alpha, and fotemustine either intravenously or intra-arterially (if disease was restricted to the liver). They demonstrated an overall response rate of 14.5%; one patient achieved a CR, and an additional six patients experienced a PR.

Because of the limited efficacy of systemic regimens, the characteristic biology of metastatic spread confined to the liver, and very limited survival associated with liver metastases, the investigation of measures to control hepatic disease progression seems justified. A number of regional treatment strategies (therapy directed to the liver) are in clinical development for individuals with ocular melanoma metastatic to the liver (Table 1Go).


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  		TABLE 1. Review of locoregional therapies for patients with ocular melanoma metastatic to the liver
 

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  		TABLE 1A. Review of locoregional therapies for patients with ocular melanoma metastatic to the liver (continued)
 

   LOCOREGIONAL THERAPIES
TOP
 ABSTRACT
 INTRODUCTION
 LOCOREGIONAL THERAPIES
SUMMARY
 REFERENCES
 
Surgery
Only a few anecdotal reports of resection of apparently solitary hepatic metastases have been reported to yield long-lasting control of disease. Fournier et al.22 excised solitary hepatic metastases in two patients; one patient survived for 3 years after resection, and the other was in good clinical condition 1 year after surgery despite possible metastasis to other sites. Similarly, Gunduz et al.23 described a patient who received two serial hepatic resections of metastatic uveal melanoma. The patient was without evidence of disease 2 years after the second procedure. More recently, Aoyama et al.24 reported a series of patients with metastatic ocular melanoma who underwent surgical resection of all disease. The median recurrence-free and overall survival in 12 patients, 7 of whom had liver-only disease, was 19 and 27 months, respectively. Aoyama et al. noted that most patients had diffuse metastases that precluded the possibility of surgical intervention and that the cohort represented a highly selected group of patients. Surgical resection was considered in <10% of those who presented with metastatic disease. Together, these data indicate that surgical resection is associated with long-term survival in a very select minority of individuals with ocular melanoma metastatic to the liver and may be influenced by unusually indolent tumor biology.

Hepatic Artery Chemoembolization
Several groups have reported their experiences with chemoembolization for patients with uveal melanoma metastatic to the liver.25–27 Hepatic artery chemoembolization (HACE) combines hepatic artery embolization with simultaneous infusion of concentrated doses of chemotherapeutic drugs.28 The theoretical advantages of this technique include rendering the tumor ischemic, achieving high drug concentrations within the tumor, and minimizing systemic toxicity. The tumor becomes ischemic because the afferent blood supply for macroscopic hepatic tumors is predominantly the hepatic artery.28–30 Tumor drug concentrations are reported to be 10 to 25 times higher then those achieved by infusion alone,31,32 and the dwell time of the agents is markedly prolonged.33,34 In addition, systemic toxicity is minimized because 85% of the drug is retained in the liver.35

Patients who may be considered candidates for HACE must have disease limited to the liver, a patent portal venous system (because they must be able to tolerate hepatic arterial occlusion), and no evidence of biliary obstruction. The reason for the last criterion is that as the resistance to bile outflow increases pressure in the sinusoids, portal inflow decreases and the liver becomes more dependent on arterial blood flow. Patients with >50% hepatic replacement by tumor, serum LDH >425 IU/L, aspartate aminotransferase >100 IU/L, and a total bilirubin >=2 mg/dL may have a greater dependence on hepatic arterial circulation and are at increased risk of acute hepatic failure after HACE.36

Carrasco et al.25 performed some of the preliminary work with this technique in their attempts to control ocular melanoma metastatic to the liver by using chemoembolization with polyvinyl sponge material and cisplatin. They reported regressions in two patients that lasted 19 and 6 months after one or two treatments. Similarly, Mavligit et al.26 treated 30 patients with HACE by using an admixture of cisplatin and polyvinyl sponge. The overall response rate was 46%, with 1 CR and 13 PRs and a median overall survival of 11 months. Treatment-related morbidity was limited and transient. Most recently, Feun et al.27 conducted a phase I trial of HACE with cisplatin, thiotepa, and lipiodol for primary and metastatic liver cancer, including three patients with ocular melanoma. Two of the three patients achieved PRs that lasted >=3 and 16 months. Treatment-related mortality was not inconsequential; 4 of 30 patients succumbed to gram-negative sepsis or cardiac events.

Hepatic Arterial Chemotherapy
Systemic chemotherapy is limited by the inherent inability to deliver high concentrations of drug to tumor cells without systemic toxicity. Hepatic arterial infusion (HAI) of chemotherapy with floxuridine-based regimens has been associated with higher response rates compared with systemic therapy for patients with colorectal cancer metastatic to the liver.37 Direct infusion of high-dose chemotherapy into the hepatic artery increases the amount of drug to which the tumor is exposed proportional to the hepatic parenchyma, as well the systemic circulation, and should theoretically improve the therapeutic index.38 The most common method of administering HAI is via a catheter placed during laparotomy and connected to a subcutaneously implanted pump.38 Typically, the catheter tip is positioned adjacent to the hepatic artery via the gastroduodenal artery.

Cantore et al.37 reported a series of patients with ocular melanoma metastatic to the liver treated with HAI by using a carboplatin-based chemotherapy. They achieved an overall response rate of 38% and a median survival of 15 months. The principal toxicity was myelosuppression. Leyvraz et al.15 further validated the efficacy of HAI in a phase II trial of 30 patients treated with intra-arterial fotemustine through an implanted hepatic artery catheter. They noted an objective response rate of 40% (four CRs and eight PRs), a median duration of response of 11 months, and a median overall survival of 14 months. The principal toxicity was again myelosuppression; six patients developed significant neutropenia or thrombocytopenia.

Hepatic Artery Immunoembolization
Regional infusion of immunotherapeutic agents is also under investigation. Keilholz et al.39 infused lymphokine-activated killer cells via the hepatic artery or portal vein in five patients but found no objective responses. Similarly, Patel et al.40 reported a response in the liver when using HACE with BCNU to treat metastatic uveal melanoma.

Sato et al.41 have developed a novel hepatic artery immunoembolization approach by using granulocyte-macrophage colony-stimulating factor emulsified in ethiodized oil. Granulocyte-macrophage colony-stimulating factor was used to stimulate antigen-presenting cells in the liver metastases while the tumors were also embolized. Sato et al. treated 13 patients with melanoma metastatic to the liver (12 with uveal melanoma) in a phase I clinical study. They reported 1 CR, 4 PRs, and 5 patients with stable disease among 12 assessable patients. On the basis of these results, they have initiated a phase II clinical trial. Interestingly enough, two patients developed immune responses in distant metastases; this implies that this regional treatment may also have systemic immunological effects (Fig. 2).



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  		FIG. 2. An inflammatory response developed in a subcutaneous metastasis after immunoembolization of liver metastases with granulocyte-macrophage colony-stimulating factor. A subcutaneous metastasis was removed from a patient after immunoembolization of liver. The subcutaneous tumor was significantly infiltrated with mononuclear cells, and this was accompanied with a hemorrhagic change. Immunohistochemical staining revealed that infiltrating mononuclear cells were CD3 lymphocytes, of which approximately 40% to 50% were positive for CD8. Top: Stain, hematoxylin and eosin; magnification, x100. Bottom: Immunohistochemical staining with CD8; original magnification, x200. Reprinted from Seminars in Oncology, vol 29, Sato T, Locoregional immuno(bio)therapy for liver metastases (review), 160–7, Copyright 2002, with permission from Elsevier.56

 
Isolated Hepatic Perfusion
The concept of hyperthermic isolated hepatic perfusion (IHP) was introduced more than 40 years ago as an alternative means of achieving high concentrations of cytotoxic anticancer drugs or biological agents in the liver for patients with unresectable metastases confined to the liver.42 IHP is a regional treatment in which the vascular supply to the liver is isolated and perfused via an extracorporeal circuit while the systemic circulation is maintained on a separate venovenous bypass circuit.43 Multiple groups have described the technique and its results.44–47 Quebbeman et al.45 performed isolated hyperthermic liver perfusions on four patients via the gastroduodenal artery with a perfusate composed of blood products, buffer, heparin, and cefamandole at 42°C. Two patients had colorectal cancer, and the others had cutaneous melanoma, all metastatic to the liver. All of the tumors demonstrated extensive central necrosis. More recently, Hafström et al.47 reported a 20% response rate by using standard response criteria in 29 patients treated with cisplatin and mitomycin. Five of the 29 patients survived longer than 3 years.

Phase I and II trials conducted in the surgery branch have reported results of the use of IHP with melphalan with and without tumor necrosis factor specifically for patients with ocular melanoma metastatic to the liver43,48–50 (Table 2). Results in 22 patients with ocular melanoma treated with a 60-minute IHP with melphalan with or without tumor necrosis factor demonstrated an overall response rate of 62%, with 2 CRs and 11 PRs.50 The overall median response rate in this series was 11 months, and 2 patients survived longer than 3 years after IHP. There was one treatment-related mortality (5%) secondary to coagulopathy followed by multisystem organ failure and death.


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  		TABLE 2. Response dataa
 
A subsequent study of 29 patients treated with IHP with melphalan alone has been completed and has confirmed the findings of the surgery branch investigators.51 They reported 3 patients with CRs, all of which were >=1 year, and 15 with PRs, with a mean duration of 10 months (overall response rate of 62%). On multivariate analysis, baseline LDH was a highly significant independent prognostic factor for response and survival. The liver was the initial site of progression in more than two thirds of patients whose disease recurred, and the median actuarial overall survival was only 1 year. These findings suggest that further refinements in therapy to prolong the duration of response will be important, considering the intensive nature of this type of treatment.

Percutaneous Hepatic Perfusion
Percutaneous hepatic perfusion is a promising variation of IHP in which HAI of a chemotherapeutic agent is administered via a percutaneously placed catheter. Hepatic venous hemofiltration is accomplished by using a double-balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an active charcoal filter (Fig. 3). Several clinical trials using different catheter designs have been reported that used doxorubicin or 5-fluorouracil to treat patients with colorectal or hepatocellular carcinoma metastatic to the liver.52,53 A phase I trial is presently being conducted by the surgery branch at the National Cancer Institute using this system with escalating doses of melphalan to treat patients with unresectable hepatic malignancies metastatic to the liver, including uveal melanoma.54 The device can effectively remove approximately 80% of the delivered melphalan (Fig. 4) and can cause significant regression of metastatic ocular melanoma to the liver55 (Fig. 5).



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  		FIG. 3. Schema for a percutaneous hepatic perfusion. The liver is perfused with melphalan for 30 minutes via a percutaneously placed catheter positioned in the proper hepatic artery. Hepatic venous hemofiltration is accomplished with a double-balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent to the systemic circulation through an activated charcoal filter (Delcath Systems, Inc., Stamford, CT). Top: Schematic diagram of the Delcath system. Bottom: Venogram demonstrating the double-balloon catheter positioned in the retrohepatic inferior vena cava.

 


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  		FIG. 4. Pharmacokinetics of melphalan during percutaneous hepatic perfusion, demonstrating a high regional area under the concentration-time curve compared with systemic blood. Drug levels were assessed at regular intervals in the hepatic artery, the hepatic venous effluent (HVE) before and after hemofiltration, and the systemic blood. During the infusion of melphalan, the HVE concentrations before filtration remained high, and the blood levels after hemofiltration and in the systemic circulation remained low. In general, approximately >=80% of infused drug is filtered and removed with this system.

 


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  		FIG. 5. Response to percutaneous hepatic perfusion: computed tomographic (CT) scan of a 45-year-old woman with ocular melanoma metastatic to the liver treated by using percutaneous hepatic perfusion with melphalan who had a partial response. Top: Representation of tumor burden in the liver before treatment. Bottom: CT scan at the same level 4 months after treatment.

 

   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 LOCOREGIONAL THERAPIES
 SUMMARY
REFERENCES
 
Uveal melanoma metastatic to the liver remains an incurable disease. Unlike the experience with colorectal carcinoma metastatic to liver, surgery is not considered a first-line approach secondary to the diffuse, multifocal nature of the hepatic disease. Systemic chemotherapy and immunotherapy regimens have had minimal efficacy for patients with metastatic ocular melanoma. HACE has been explored to a limited degree for patients with ocular melanoma, but reports of response are still anecdotal. HAI with fotemustine has an overall response rate of 38% in patients with uveal melanoma, but the overall survival was still disappointingly short.

IHP is a promising technique for the treatment of ocular melanoma metastatic to the liver. Although the reported response rate is more than 60% for ocular melanoma metastatic to the liver, IHP is associated with potential morbidity, and the number of patients with ocular melanoma treated with IHP is still limited. Percutaneous hepatic perfusion has the potential for less morbidity, and its efficacy in this clinical setting deserves further evaluation. In conclusion, current treatment modalities need further refinement and new ones need to be developed to improve the outlook for patients with uveal melanoma metastatic to the liver.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.

The authors thank Dr. David Weinreich and Romi Sawhney for their assistance with the preparation of this manuscript.


   FOOTNOTES
 
This article reviews the efficacy, outcome, and morbidity of various locoregional therapies for patients with ocular melanoma metastatic to the liver. These include surgery, hepatic arterial chemotherapy, hepatic artery chemoembolization, hepatic artery immunoembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion.

Received for publication July 11, 2003. Accepted for publication November 7, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 LOCOREGIONAL THERAPIES
 SUMMARY
 REFERENCES
 

  1. McCartney A. Pathology of ocular melanoma. Br Med Bull 1995; 51: 678–93.[Abstract/Free Full Text]
  2. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology 2003; 110: 956–61.[CrossRef][Medline]
  3. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83: 1664–78.[CrossRef][Medline]
  4. Shields JA, Shields CL, De Potter P, Singh AD. Diagnosis and treatment of uveal melanoma. Semin Oncol 1996; 23: 763–7.[Medline]
  5. Seddon JM, Albert DM, Lavin PT, Robinson N. A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol 1983; 101: 1894–9.[Abstract]
  6. Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. Acta Ophthalmol Scand 1995; 73: 340–4.[Medline]
  7. Becker JC, Terheyden P, Kampgen E, et al. Treatment of disseminated ocular melanoma with sequential fotemustine, interferon alpha, and interleukin 2. Br J Cancer 2002; 87: 840–5.[CrossRef][Medline]
  8. Rajpal S, Moore R, Karakousis CP. Survival in metastatic ocular melanoma. Cancer 1983; 52: 334–6.[CrossRef][Medline]
  9. Shields CL. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Trans Am Ophthalmol Soc 2000; 98: 471–92.[Medline]
  10. Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for large posterior uveal melanomas (> or =8-mm thick) in 354 consecutive patients. Ophthalmology 2002; 109: 1838–49.[CrossRef][Medline]
  11. Tuomaala S, Eskelin S, Tarkkanen A, Kivela T. Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci 2002; 43: 3399–408.[Abstract/Free Full Text]
  12. Soni S, Lee DS, DiVito JJ, et al. Treatment of pediatric ocular melanoma with high-dose interleukin-2 and thalidomide. J Pediatr Hematol Oncol 2002; 24: 488–91.[CrossRef][Medline]
  13. Bedikian AY, Legha SS, Mavligit G, et al. Treatment of uveal melanoma metastatic to the liver. Cancer 1995; 76: 1665–70.[CrossRef][Medline]
  14. Gragoudas ES, Egan KM, Seddon JM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology 1991; 98: 383–90.[Medline]
  15. Leyvraz S, Spataro V, Bauer J, et al. Treatment of ocular melanoma metastatic to the liver by hepatic arterial chemotherapy. J Clin Oncol 1997; 15: 2589–95.[Abstract/Free Full Text]
  16. Pyrhonen S. The treatment of metastatic uveal melanoma. Eur J Cancer 1998; 34 (Suppl 3): S27–30.
  17. Nathan FE, Berd D, Sato T, et al. BOLD+interferon in the treatment of metastatic uveal melanoma: first report of active systemic therapy. J Exp Clin Cancer Res 1997; 16: 201–8.[Medline]
  18. Einhorn LH, Burgess MA, Gottlieb JA. Metastatic patterns of choroidal melanoma. Cancer 1974; 34: 1001–4.[CrossRef][Medline]
  19. Kataoka K, Liu PY, Sondak VK, Flaherty LE. Survival and response to treatment in patients (PTS) with metastatic melanoma from intraocular primaries (MMIP) on SWOG studies (abstract). Proc Am Soc Clin Oncol 1995; 14: 410.
  20. Albert DM, Ryan LM, Borden EC. Metastatic ocular and cutaneous melanoma: a comparison of patient characteristics and prognosis. Arch Ophthalmol 1996; 114: 107–8.[Medline]
  21. Pyrhonen S, Hahka-Kemppinen M, Muhonen T, et al. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma. Cancer 2002; 95: 2366–72.[CrossRef][Medline]
  22. Fournier GA, Albert DM, Arrigg CA, Cohen AM, Lamping KA, Seddon JM. Resection of solitary metastasis. Approach to palliative treatment of hepatic involvement with choroidal melanoma. Arch Ophthalmol 1984; 102: 80–2.[Abstract]
  23. Gunduz K, Shields JA, Shields CL, Sato T, Mastrangelo MJ. Surgical removal of solitary hepatic metastasis from choroidal melanoma. Am J Ophthalmol 1998; 125: 407–9.[CrossRef][Medline]
  24. Aoyama T, Mastrangelo MJ, Berd D, et al. Protracted survival after resection of metastatic uveal melanoma. Cancer 2000; 89: 1561–8.[CrossRef][Medline]
  25. Carrasco CH, Wallace S, Charnsangavej C, Papadopoulos NE, Patt YZ, Mavligit GM. Treatment of hepatic metastases in ocular melanoma. Embolization of the hepatic artery with polyvinyl sponge and cisplatin. JAMA 1986; 255: 3152–4.[Abstract]
  26. Mavligit GM, Charnsangavej C, Carrasco CH, et al. Regression of ocular melanoma metastatic to the liver after hepatic arterial chemoembolization with cisplatin and polyvinyl sponge. JAMA 1988; 260: 974–6.[Abstract]
  27. Feun LG, Reddy KR, Scagnelli T, et al. A phase I study of chemoembolization with cisplatin, thiotepa, and lipiodol for primary and metastatic liver cancer. Am J Clin Oncol 1999; 22: 375–80.[CrossRef][Medline]
  28. Soulen MC. Chemoembolization of hepatic malignancies. Oncology 1994; 8: 77–84.
  29. Lien WM, Ackerman NB. The blood supply of experimental liver metastases. II. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 1970; 68: 334–40.[Medline]
  30. Lin G, Lunderquist A, Hagerstrand I, Boijsen E. Postmortem examination of the blood supply and vascular pattern of small liver metastases in man. Surgery 1984; 96: 517–26.[Medline]
  31. Konno T. Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium. Cancer 1990; 66: 1897–903.[CrossRef][Medline]
  32. Egawa H, Maki A, Mori K, et al. Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats. J Surg Oncol 1990; 44: 109–14.[Medline]
  33. Nakamura H, Hashimoto T, Oi H, Sawada S. Transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology 1989; 170: 783–6.[Abstract/Free Full Text]
  34. Sasaki Y, Imaoka S, Kasugai H, et al. A new approach to chemoembolization therapy for hepatoma using ethiodized oil, cisplatin, and gelatin sponge. Cancer 1987; 60: 1194–203.[CrossRef][Medline]
  35. Daniels JR, Sternlicht M, Daniels AM. Collagen chemoembolization: pharmacokinetics and tissue tolerance of cis-diamminedichloroplatinum(II) in porcine liver and rabbit kidney. Cancer Res 1988; 48: 2446–50.[Abstract/Free Full Text]
  36. Charnsangavej C, Carrasco CH, Wallace S, Richli W, Haynie TP. Hepatic arterial flow distribution with hepatic neoplasms: significance in infusion chemotherapy. Radiology 1987; 165: 71–3.[Abstract/Free Full Text]
  37. Cantore M, Fiorentini G, Aitini E, et al. Intra-arterial hepatic carboplatin-based chemotherapy for ocular melanoma metastatic to the liver. Report of a phase II study. Tumori 1994; 80: 37–9.[Medline]
  38. Choti MA, Bulkley GB. Management of hepatic metastases. Liver Transpl Surg 1999; 5: 65–80.[CrossRef][Medline]
  39. Keilholz U, Scheibenbogen C, Brado M, et al. Regional adoptive immunotherapy with interleukin-2 and lymphokine-activated killer (LAK) cells for liver metastases. Eur J Cancer 1994; 30A: 103–5.
  40. Patel SK, Sullivan K, Aoyama T, et al. Hepatic artery chemoembolization (HAC) with BCNU for treatment of metastatic uveal melanoma (abstract). Proc Am Soc Clin Oncol 2001; 20: 356.
  41. Sato T, Terai M, Huandong Y, et al. Systemic immune response after immunoembolization of liver metastasis with granulocyte-macrophage colony stimulating factor (GM-CSF). Proc Am Assoc Cancer Res 2002; 43: 914.
  42. Ausman RK. Development of a technic for isolated perfusion of the liver. N Y State J Med 1961; 61: 3393–7.
  43. Alexander HR, Bartlett DL, Libutti SK. Isolated hepatic perfusion: a potentially effective treatment for patients with metastatic or primary cancers confined to the liver. Cancer J Sci Am 1998; 4: 2–11.[Medline]
  44. Schwemmle K, Link KH, Rieck B. Rationale and indications for perfusion in liver tumors: current data. World J Surg 1987; 11: 534–40.[CrossRef][Medline]
  45. Quebbeman EJ, Skibba JL, Petroff RJ Jr. A technique for isolated hyperthermic liver perfusion. J Surg Oncol 1984; 27: 141–5.[Medline]
  46. Skibba JL, Quebbeman EJ. Tumoricidal effects and patient survival after hyperthermic liver perfusion. Arch Surg 1986; 121: 1266–71.[Abstract]
  47. Hafström LR, Holmberg SB, Naredi PLJ, et al. Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. Surg Oncol 1994; 3: 103–8.[CrossRef][Medline]
  48. Alexander HR, Bartlett DL, Libutti SK, Fraker DL, Moser T, Rosenberg SA. Isolated hepatic perfusion with tumor necrosis factor and melphalan for unresectable cancers confined to the liver. J Clin Oncol 1998; 16: 1479–89.[Abstract/Free Full Text]
  49. Libutti SK, Bartlett DL, Fraker DL, Alexander HR. Technique and results of hyperthermic isolated hepatic perfusion with tumor necrosis factor and melphalan for the treatment of unresectable hepatic malignancies. J Am Coll Surg 2000; 191: 519–30.[CrossRef][Medline]
  50. Alexander HR, Libutti SK, Bartlett DL, Puhlmann M, Fraker DL, Bachenheimer LC. A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2000; 6: 3062–70.[Abstract/Free Full Text]
  51. Alexander HR, Libutti SK, Pingpank JF, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003; 9: 6343–9.[Abstract/Free Full Text]
  52. Curley SA, Newman RA, Dougherty T, et al. Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study. Ann Surg Oncol 1994; 1: 389–99.[Abstract]
  53. Ku Y, Tominaga M, Iwasaki T, et al. Percutaneous hepatic venous isolation and extracorporeal charcoal hemoperfusion for high-dose intraarterial chemotherapy in patients with colorectal hepatic metastases. Surg Today 1996; 26: 305–13.[CrossRef][Medline]
  54. Pingpank JF, Libutti SK, Chang RA, et al. A phase I feasibility study of hepatic arterial melphalan infusion with hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies. Paper presented at: Annual Meeting of the American Society of Clinical Oncology; May 31 to June 3, 2003; Chicago, IL.
  55. Weinreich DM, Alexander HR. Transarterial perfusion of liver metastases. Semin Oncol 2002; 29: 136–44.[CrossRef][Medline]
  56. Sato T. Locoregional immuno(bio)therapy for liver metastases (review). Semin Oncol 2002; 29: 160–7.[CrossRef][Medline]



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