locoregional management of hepatic metastasis from primary uveal melanoma
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Locoregional Management of HepaticMetastasis From Primary Uveal Melanoma
Takami Sato
Uveal melanoma is the most common primary ocular malignancy in adults and has a significantpredilection for metastasis to the liver. Despite successful treatment of the primary uveal mela-noma, up to 50% of patients will subsequently develop a systemic metastasis, with the liverinvolved in up to 90% of these individuals. Metastatic uveal melanoma has proven to be resistantto currently available systemic chemotherapies. Recognition of the poor prognosis associated withliver metastasis has led to the evaluation of various locoregional treatment modalities primarilydesigned to control tumor progression in the liver, including surgical resection, hepatic arterialchemotherapy, transarterial chemoembolization (TACE), immunoembolization, radiosphere, drug-eluting beads, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion. This articlereviews the efficacies, and morbidities of currently available locoregional therapies.Semin Oncol 37:127-138 © 2010 Elsevier Inc. All rights reserved.
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ocoregional treatment of malignant hepatic tu-mors is most beneficial when (1) systemic che-motherapy is not effective or beneficial, (2) the
iver is the only or dominant site of involvement, or (3)here is an urgent need to control local progression ofisease for symptom control or palliation. Metastaticveal melanoma fulfills these criteria for locoregionalepatic treatment. Uveal melanoma is the most com-on primary intraocular malignant tumor in adults.1,2
he incidence of uveal melanoma is 4.3 cases perillion population, with a slightly higher rate in males
4.9 cases per million) when compared with females3.7 cases per million). Up to 50% of patients withveal melanoma subsequently develop systemic metas-asis within 2 to 5 years after the initial diagnosis andreatment3; however, clinically evident metastatic dis-ase at the time of initial presentation is uncommon,ndicating that there is early subclinical metastasis in
ost cases.4 Unlike cutaneous melanoma, which me-astasizes to various sites including regional lymphodes, uveal melanoma commonly metastasizes to the
iver. The liver is the predominant organ involved in0% to 90% of cases with metastatic uveal melanoma5–7
epartment of Medical Oncology, Jefferson Medical College of ThomasJefferson University, Philadelphia, PA.
ddress correspondence to Takami Sato, MD, PhD, Professor of Medi-cine and Medical Oncology, Department of Medical Oncology, Jef-ferson Medical College of Thomas Jefferson University, 1015 WalnutSt, Suite 1024, Philadelphia, PA 19107. E-mail: [email protected]
270-9295/ - see front matter2010 Elsevier Inc. All rights reserved.
toi:10.1053/j.seminoncol.2010.03.014
eminars in Oncology, Vol 37, No 2, April 2010, pp 127-138
nd it tends to be the first manifestation of metastaticisease.7,8 Approximately 90% of metastatic uveal mel-noma patients die with liver metastasis.6 Despite sig-ificant improvement in diagnosis and treatment ofrimary uveal melanoma,2 mortality owing to this tu-or has remained unchanged over the past 3 decades.4
n general, after the development of liver metastases,he survival estimates range from 2 to 9 months.5,7
ystemic chemotherapy has failed to show clinical ef-cacy against metastatic uveal melanoma. The chemo-herapeutic drugs commonly used for the treatment ofetastatic cutaneous melanoma rarely induce re-
ponses in patients with uveal melanoma, especiallyhen the liver is involved with metastatic disease.8,9
acarbazine (DTIC)-based chemotherapies that haveeen used for the treatment of metastatic cutaneouselanoma are ineffective in the treatment of metastatic
veal melanoma.8–10
The treatment of progressive growth of metastaticveal melanoma confined to the liver is still a majorlinical challenge. To improve the quality of life ofatients and to potentially prolong their survival, vari-us locoregional treatments have been developed. Inhis review, current strategies for management of he-atic metastasis from primary uveal melanoma are dis-ussed.
IAGNOSTIC PROCEDURE TOETECT METASTATIC UVEAL MELANOMA
Despite the controversy over lead-time bias, it is theeneral consensus that early discovery of hepatic me-
astasis will provide benefit to patients by facilitating127
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ursuit of various treatment options. In defining a fol-ow-up program for uveal melanoma patients, one mustefine the high-risk population for systemic metastasisnd the best modality to detect early hepatic metasta-is. Traditionally, clinico-histopathological characteris-ics have been used to identify high-risk patients, in-luding location, size, tumor cell type, mitotic activity,ascular architecture, tumor-infiltrating lymphocytes,nd the presence of extrascleral extension.11 Recently,ytogenetic investigations of primary uveal melanomasave revealed that the majority of choroidal and ciliaryody melanomas are characterized by nonrandom al-ernations in chromosomes 1, 3, 6, and 8.12 Monosomy
and trisomy 8, partial duplication of 8q, or iso-chro-osome 8q are the most frequent karyotypic abnormal-
ties present in approximately 50% of cases.12 Recentnvestigation has indicated that monosomy 3 is a signif-cant predictor of poor prognosis.13 Approximately0% of patients with monosomy 3 in their primaryumor have died of metastases within 4 years after thenitial diagnosis, whereas tumors with normal chromo-ome 3 status (disomy 3) rarely gave rise to metastaticisease.13 Chromosome 8 abnormalities are associatedith large tumor size and aggressive histology.14 Con-
idering historical and recently discovered risk factors,pecial attention should be given to uveal melanomaatients who have the following characteristics: largeize (�15 mm in basal diameter, �7 mm in thickness),xtrascleral extension, intra-ocular recurrence, epithe-ioid cell dominancy, monosomy 3, and chromosomeq amplification. Since these patients tend to developystemic metastases within 3 years, more frequent of-ce visits (every 3 months) with imaging of the liverhould be recommended for the first 2 to 3 years afternitial treatment of primary uveal melanoma.
In terms of the preferred modality for the detectionf early-stage hepatic metastasis from uveal melanoma,here has not been a comparison among the routinelyvailable imaging techniques such as computed tomog-aphy (CT) scan, magnetic resonance imaging (MRI), orltrasound of the liver. More importantly, there are alsoignificant geographic disparities in diagnostic screen-ng for metastatic uveal melanoma.15 At the diagnosis ofrimary uveal melanoma, six of 36 (17%) North Amer-
can specialists, versus 54 of 57 (95%) European spe-ialists performed at least one type of liver imagingtudy (CT scan MRI, ultrasonography, or nuclear med-cine) (P � .0001). On follow-up, only one of 36 (3%)orth American specialists, versus 45 of 57 (79%) Eu-
opean specialists obtained a liver imaging study (P �0001).15 The importance of serial liver imaging needso be emphasized among physicians who follow high-isk uveal melanoma patients.
It has been reported that standard liver functionhemistries are not adequate to detect early-stage he-atic metastasis.16,17 The sensitivity of individual liver
unction tests is low and ranged from 0.27 to 0.67, with h
actate dehydrogenase (LDH) being the most sensi-ive.17 A report from a European institution indicatedhat annual screening with liver function tests andbdominal ultrasound will identify 59% of patientshile they are still asymptomatic and that semi-annual
creening will detect more than 95% of such patients.17
ur institutional experience indicates that MRI of theiver is the most sensitive modality to detect a smallepatic metastasis from uveal melanoma. We haveeen able to detect small hepatic metastases on routinencologic follow-up, while standard CT images areegative (Figure 1). Those patients whose metastasesere found on routine follow-up imaging of the liverave been offered participation in clinical trials of lo-oregional treatments directed toward hepatic metas-asis. We strongly recommend that liver images, espe-ially MRI of the abdomen, should be included in theoutine follow-up of high-risk primary uveal melanomaatients.
URGICAL AND ABLATIVE TREATMENT
Since the liver is the first and in many cases the onlyite of metastasis in uveal melanoma patients, a localreatment aimed at controlling liver metastases holdsromise in managing this otherwise highly chemo-re-istant tumor. Total resection of the solitary metastasisn the liver or other sites18,19 offers a distinct survivaldvantage. We reported protracted survival with sur-ery for visceral metastases from uveal melanoma.mong 12 patients with metastatic uveal melanoma,ine of whom had hepatic metastases. Median recur-ence-free and overall survival (OS) periods after com-lete resection were 19 months (range, 6–78 months)nd greater than 27 months (range, 11–86 months),espectively. Recurrence-free and overall 5-year sur-ival rates of those patients were 15.6% and 53.3%,espectively.18
It is important to emphasize that surgical interven-ion has been offered to only a small fraction of uvealelanoma patients with metastasis. Only 9% of patientsith metastases were eligible for surgical intervention
n our series of patients. The majority of patients hadultiple hepatic metastases in both lobes of the liver
nd required nonsurgical approaches. Furthermore, its of note that all patients whose time to systemic
etastasis was less than 5 years developed furtherystemic recurrence within 2 years after surgery. Inontrast, of eight patients whose time to systemic me-astases was greater than 5 years, four either wereecurrence-free or developed second metastasis morehan 4 years after surgery. Similar results were reportedy Hsueh et al.19 Although 70% of 112 uveal melanomaatients had liver metastasis, only five patients wereandidates for surgical removal of hepatic metastasis.nfortunately, three of these five patients could not
ave complete tumor resection due to the presence of
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Locoregional management of hepatic metastasis 129
ultiple metastases. One of the two patients who un-erwent complete resection of hepatic metastasis sub-equently developed another hepatic metastasis.19
ournier et al treated two patients with solitary hepaticetastases with local resection.20 One patient survivedyears after partial hepatectomy; the second patientas alive 1 year after surgery with tumor recurrence
lsewhere. Despite the potential benefit of surgicalntervention, most uveal melanoma patients with he-atic metastases were not surgical candidates due toultiple tumors in both lobes of the liver. The key
actors to predict benefit from surgical interventionnclude complete resection of metastasis and a time toystemic metastasis of more than 5 years after initialreatment of primary uveal melanoma. Careful preop-rative screening including laparoscopic evaluationhould be considered to select patients for surgicalntervention.
Multimodality treatments, including surgical resec-ion of liver metastasis followed by adjuvant regional orystemic therapy, have been evaluated in an effort tomprove the survival of these patients. Salmon et aleported the result of surgical treatment of 75 patientsith uveal melanoma metastatic to the liver.21 On ab-ominal exploration, 74 of 75 (98.5%) patients wereound to have metastasis to both lobes of the liver.acroscopic curative surgery was possible in 27.5%.
igure 1. Detection of early hepatic metastases by MRI. Roesions. CT scan of the abdomen did not show any of the abhe diagnosis of metastatic melanoma. (A, B) T1-weighed Mf miliary hepatic metastases from uveal melanoma.
ignificant debulking of the tumor in the liver was p
erformed in 49% of the patients. The remaining 23%f the patients were found to have disease far toodvanced to make surgical resection of the tumor pos-ible. Intra-arterial hepatic chemotherapy with fote-ustine and/or DTIC-platinum for four to nine cyclesas given to 67 patients. Of the 61 patients who com-leted treatment with surgery plus chemotherapy,edian survival was 10 months. When curative resec-
ion was possible, survival increased to 22 monthsP � .001). Since complete resection of hepatic metas-asis itself showed potential survival benefit withoutny additional treatment, the role of adjuvant intrahe-atic arterial chemotherapy remains to be investigated
n a future clinical study.There are no large series that address the usefulness
f radiofrequency ablation (RFA) for hepatic metasta-is from primary uveal melanoma. Most of these pa-ients are either included in larger series reporting theesults of RFA in patients with liver metastasis fromarious primary sites or published as a case report.22,23
s indicated for primary hepatocellular carcinomaHCC), RFA or cryoablation would be applicable toatients with a few hepatic metastases whose surgicalorbidity would be high. Local ablative treatments of
iver tumors have also been combined with hepaticesection and transarterial treatments24–26 and this ap-
llow-up MRI of the liver revealed small but multiple hepaticlesions detected by the MRI. Subsequent biopsy confirmedes; (C, E) magnified images of A and B; (D) demonstration
utine fonormalRI imag
roach might be useful for metastatic uveal melanoma
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hat is difficult to control with transarterial treatmentlone.
ATIONALE FOR TRANSARTERIAL TREATMENTOR METASTATIC MELANOMA TO THE LIVER
From the anatomic and physiologic points of view,he liver is the organ that allows interventional transar-erial treatments to achieve control of the cancer whileeducing or eliminating unnecessary systemic toxic-ty.27–29 It is well established that both primary andecondary liver tumors derive their blood supply fromhe hepatic artery,30 while approximately 50% of thexygen supply to normal liver is from the portal sys-em.31,32 This makes intrahepatic arterial embolizationreatment especially attractive from both the deliverynd safety points of view since the tumor can be madeschemic while uninvolved liver is spared. Further-
ore, the intratumoral concentration of chemothera-eutic drug is reportedly 10 times higher when it wasiven through the artery rather than the portal vein.33
any drugs exhibit preferential extraction when deliv-red intrahepatically and they can achieve quite favor-ble liver/systemic drug concentration ratios, thusinimizing the systemic toxicities associated with
hemotherapy. Intrahepatic administration allows theelivery of chemotherapeutic agents at much higheroncentration directly to hepatic metastases and thecclusion of the hepatic artery results in selective de-rivation of blood supply to tumors. Based on thebove concept and the cumulative experience in thereatment of HCC and metastatic colon cancer, hepatic-rtery directed treatments have been explored for thereatment of metastatic uveal melanoma. However,omparison of individual treatments has not been con-ucted in a prospective manner and the numbers ofatients in individual clinical trials are too small toevelop any universal consensus regarding the choicef treatment among available transarterial treatments.
HEMOEMBOLIZATION
Transarterial chemoembolization (TACE) consists ofepatic artery embolization with simultaneous infusionf concentrated doses of chemotherapeutic drugs. Pa-ients considered for TACE must have disease limited tor dominant in the liver, a patent main portal vein, ando sign of liver failure such as elevation of total biliru-in (�2.0 mg/dL), ascites, or hepatic encephalopathy.iliary obstruction, bile duct stent, and previous majoriliary surgery except cholecystectomy are relativeontraindications due to an increased incidence ofostprocedure liver abscess.34 Various chemotherapeu-ic medications have been used with either transient orermanent occlusion of hepatic arteries (Table 1).35–40
owever, it remains unclear which chemotherapeutic
rugs or occlusive agents are best for TACE in meta- ttatic uveal melanoma. The studies in patients withrimary HCC41 suggest that the embolization proce-ure itself, rather than the chemotherapeutic medi-ines, provides the major impact on hepatic metasta-es.
The use of chemoembolization as a therapeutic mo-ality for liver metastases of uveal melanoma was firstublished by Carrasco et al.42 They reported two casesith tumor regression that lasted 19 and 6 months afterACE with cisplatin and polyvinyl sponge (PVS). Fol-
owing this, Mavligit et al reported a larger series withACE using cisplatin and PVS in which a 46% responseate with one complete response (CR) and 13 partialesponses (PRs) was achieved in 30 patients with met-static uveal melanoma to the liver.39 The median OSas 11 months. A subsequent review of data from 201atients with metastatic uveal melanoma from the M.D.nderson Cancer Center revealed a 36% overall re-ponse rate for TACE versus less than 1% for systemichemotherapy and a median survival of 14.5 months inesponding patients.9 Huppert et al recently reportedhe results of TACE with cisplatin or carboplatin in 14atients with uveal melanoma metastatic to the liver.38
n a total of 34 procedures, cisplatin was used in 31rocedures at 100 mg/m2 body surface area in patientsith serum creatinine concentration �1.1 mg/dL and
arboplatin was used at 200 mg/m2 body surface arean three procedures when serum creatinine concentra-ion was 1.1–1.5 mg/dL. Eight patients (57%) achievedPR, four patients (29%) had stable disease (SD), and
wo patients (14%) had tumor progression. Medianime to progression was 8.5 months (range, 5–35onths). Median survival after first TACE was 14.5onths in responders compared to 10 months in non-
esponders (P � .18, not significant) and 11.5 monthsrange, 3–69 months) in all patients.
We also conducted a phase II trial of TACE using,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) in combi-ation with ethiodized oil followed by infusion of aransiently occlusive agent, gelatin sponge particles.37
total of 29 patients were treated using TACE withCNU. Among 24 evaluable patients, one patientchieved a CR, four patients achieved a PR, and 13atients had SD. Median OS of the entire intent-to-treatroup of patients was 5.2 months (range, 0.1–27.6onths); for patients with CR or PR, 21.9 months
range, 7.4–27.6 months); SD, 8.7 months (range, 2.9–4.4 months); and progressive disease (PD), 3.3onths (range, 1.6–5.6). Importantly, while control ofepatic metastases was obtained, progression was seen
n extrahepatic sites such as the spine, lung, lymphodes, and brain in more than two thirds of patients.37
Survival benefit from TACE tends to be obtained inatients with smaller tumor volumes. In our TACEtudy with BCNU,37 patients who had less than 20% ofiver replaced with tumor had a better survival than
hose with 20% to 50% tumor in the liver (median, 19.0
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Locoregional management of hepatic metastasis 131
5.6 months, respectively). Huppert et al also reportedhat, among patients who received TACE with cisplatinr carboplatin, seven patients with metastases occupy-
ng less than 25% of liver volume had a median survivalf 17 months compared to 11 months in seven patientsith tumor involvement of more than 25% (P � .02).lso noted was a greater incidence of PR in patientsith less than 25% liver involvement, compared to
hose with more than 25% liver involvement (86% v9%).38 Vogl et al. reported their experience in embo-
ization of small numbers of hepatic metastasis in 12veal melanoma patients using super-selective TACEechnique.36 Six patients presented with a solitary liveretastasis (6–12 cm in size) and six patients with
ligonodular metastases (n �6). The embolization con-isted of infusion of a maximum of 10 mg/m2 mitomy-in C and a maximum of 15 ml iodized oil, followed byn injection of 200–450 mg resorbable microspheresor vascular occlusion. Depending on the size, location,nd arterial supply of the tumor, the tip of the catheter
Table 1. Embolization of Hepatic Metastasis
FirstAuthor,
Year Technique Therapeutic Agent P
Mavligit,19889
TACE Cisplatin, PVS
Bedikian,19959
TACE Cisplatin � otherdrugs, PVS
Bedikian,19959
TACE Cisplatin � otherdrugs, PVS
Sato,199539
TACE Cisplatin, PVS/GF
Huppertt,200938
TACE Cisplatin/carboplatin,PVS
Patel,200537
TACE BCNU disolved inethiodized oil, GF
Vogle,200736
TACE Mitomycin C,ethiodized oil,resorbablemicrospheres
Shartma,200835
TACE Cisplatin �doxorubicin �mitomicin C,PVS/GF
Sato,200849
TAIE GM-CSF emulsified inethiodized oil, GF
CR, complete response; GF, Gelfoam; PR, partial response; PVS,zation; TAIE, transarterial immunoembolization; GM-CSF, gra
as advanced further into the segmental arteries for t
uperselective embolization using a Tracker catheterBoston, MA). Among 12 patients, three achieved a PRnd five had SD without significant side effects. Theedian survivals of patients with SD and PR after TACEere significantly long at 15.7 months and 21.0onths, respectively, while patients with PD survived
nly 8.3 months (P � .01). In aggregate, these datandicate that patients with smaller tumor volumes ben-fit more from TACE.
Angiographic findings also provide useful informa-ion in predicting a response to TACE. Sharma et alreated 21 patients with a mixture of 50 mg cisplatin,0 mg doxorubicin, and 10 mg mitomycin C emulsifiedith ethiodized oil.35 After infusion of the chemother-
peutic agents, embolization was performed with ei-her absorbable gelatin sponge or 300–500 �m polyvi-yl alcohol (PVA) particles. Of 20 evaluable patients,here were 13 with SD but no CRs or PRs. The medianS of patients was 271 days. Patients with lesions thatad a nodular angiographic appearance had longer OS
s Responses
OverallSurvival
(mo) Comments
1 CR, 13 PR,7 SD
11 Morbidity short-lived
1 CR, 15 PR,6 SD
6 No previoustreatment
0 CR, 5 PR,2 SD
�6 Second-linetreatment
0 CR, 0 PR,8 SD
6.6
0 CR, 8 PR,4 SD
11.5 Tumor involvement�25% had betterresults
1 CR, 4, PR,13 SD
5.2 Tumor involvement�20% of liver hadlonger survival
0 CR, 3 PR,5 SD
21 Oligometastases(n �6)Hypervasculartumor responded
0 CR, 0 PR,13 SD
9 Tumors with nodularangiographicpattern had longersurvival
2 CR, 8 PR,10 SD
14.4 Higher dose ofGM-CSF correlatedto longer survival
l sponge; SD, stable disease; TACE, transarterial chemoemboli-–macrophage colony-stimulating factor.
No. ofatient
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31
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earance (median OS, 750 v 109 days; P � .0002).nterestingly, the infiltrative pattern was associatedith certain features of primary uveal melanoma.43
iliary body involvement by the primary tumor (Fisherxact test, P � .01), extrascleral tumor extension (P �01), and deletion of metastasis modifier locus on chro-
osome 8p containing the metastasis-suppressor geneZTS1 (P � .17) were found to be associated with thenfiltrative pattern of hepatic metastases.
Retention of ethiodized oil in the tumors after TACEs also a predictive marker for good clinical re-ponse.36,44 Vogl et al reported that PD was found onlyn patients with a lower degree of lipiodol enhance-
ent in their series of uveal melanoma patients whoeceived TACE with mitomycin C mixed with ethio-ized oil. The patients who achieved CR or PR showedignificant accumulation of ethiodized oil in their he-atic metastases.36 This is also consistent with our
nstitutional experience with more than 100 uveal mel-noma patients who received embolization of hepaticetastases.
MMUNOEMBOLIZATION
Despite better disease control than can bechieved with systemic chemotherapy, the majorityf uveal melanoma patients treated with TACE sub-equently experience progression of systemic extra-epatic metastases after successful control of theirepatic metastases. Of 17 patients who achieved CR,R, or SD after TACE with BCNU, 12 patients expe-ienced progression of extrahepatic metastases as annitial sign of disease progression; eight patients hadrogression in extrahepatic metastases alone.37 Ex-rahepatic progression was seen in various sites in-luding the spine, lung, lymph nodes, and brain. Inn attempt to overcome this limitation, we haveeveloped a novel approach for TAE of hepatic me-astasis by replacing chemotherapeutic medicationsith an immunological stimulant, granulocyte–mac-
ophage colony-stimulating factor (GM-CSF) (immu-oembolization). GM-CSF was chosen for the follow-
ng reasons: (1) GM-CSF stimulates macrophages andncrease the cytotoxicity of monocytes toward ma-ignant melanoma cell lines in vitro45; (2) geneticallyngineered tumor cells that produce GM-CSF inducepecific, long-lasting antitumor immunity in animalodels, as well as in patients;46,47 and (3) GM-CSF
lso stimulates accessory functions of monocytes byncreasing the expression of the surface human leu-ocyte antigen (HLA)-DR molecule and the secretionf interleukin-1.48 Immunoembolization with GM-SF is designed to destroy hepatic metastases by the
schemic effects of embolization, to stimulate anti-en-presenting cells such as dendritic cells and
upffer cells by GM-CSF, facilitating antigen uptake, mnd to possibly enhance systemic immunity againstumor cells.
Based on the above rationale, a phase I clinical trial ofmbolization with GM-CSF was conducted in patientsith malignant hepatic tumors. Thirty-one uveal mela-oma patients with less than 50% involvement of the liverere treated with immunoembolization of hepatic metas-
ases with various doses of GM-CSF.49 There were noreatment-related deaths or life-threatening events ob-erved up to and including the 2,000-�g dose level ofM-CSF. Among 31 evaluable patients, there were twoRs, eight PRs, and 10 patients with SD in the hepaticetastases. The median OS of intent-to-treat patients was
4.4 months. Multivariate analyses indicated that femaleender, high doses of GM-CSF (�1,500 �g), and regres-ion of hepatic metastases (CR and PR) were correlated toonger OS.49 The result of the phase I trial with immuno-mbolization was compared to our institutional historicalontrol of patients who were treated with chemoembo-ization using BCNU (�50% involvement of the liver with
etastases).50 Compared with 19 patients who receivedhemoembolization, the 16 patients who received high-ose immunoembolization had significantly better OSGM-CSF v BCNU, 20.4 v 9.8 months, P � .005) androgression-free survival in systemic (extrahepatic) sitesGM-CSF v BCNU, 12.4 v 4.8 months, P � .001). Based onhese encouraging results, a randomized phase II clinicalrial in ongoing, in which uveal melanoma patients withepatic metastasis receive embolization of the hepaticrtery with or without 2,000 mcg of GM-CSF.
ELECTIVE INTERNAL RADIATION THERAPY
Selective internal radiation therapy (SIRT, radioac-ive microspheres) has been used to deliver high-doseadiation to tumor, while minimizing damage to sur-ounding normal tissues. The pure beta-emitting iso-ope 90Y has been used most commonly for treatmentf hepatic tumors. The therapeutic advantage in thispproach is based on the unique dual vascular supplyf the liver. It is known that hepatic tumors receive0% to 100% of afferent blood exclusively from theepatic artery.30 Due to their size (20–60�m), 90Yicrospheres infused into the hepatic artery become
rapped within microarteries. There are three timesore arterial vessels supplying hepatic tumors than
upplying the normal liver parenchyma. Therefore, theicrospheres lodge preferentially within the vascula-
ure of liver tumors, with minimal amounts lodging inhe normal liver parenchyma and, ideally, no amountsistributing to other organs, particularly to the lung.he microspheres permanently embed in the tumor,here 90Y has a 64.2-hour half-life with an average
nergy of 0.94 MeV, yielding tissue penetration of 2.5m and a maximum range of 1.1 cm, thus relatively
paring the normal liver surrounding the tumor. The
ajority of the dose is delivered over the first 14 days
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Locoregional management of hepatic metastasis 133
y continuous low-dose radiation (�50 cGy/min). Overhe past few years, clinical investigation of this therapyas shown promising results in patients with hepa-oma51–53 or metastatic disease from colorectal can-er,54,55 neuroendocrine cancer,56 breast cancer, andther tumor types,57 supporting the efficacy and safetyf the use of 90Y for treatment of hepatic tumors.
In our institution, a total of 12 uveal melanomaatients (five men and seven women; ages 48–81ears, median 65) with hepatic metastases were treatedith SIRT because of tumor progression after TAE (n �
), complications of TAE (n � 1), or patient preferencen � 2).58 Patients were treated as follows: both he-atic lobes on separate occasions (n � 7), one loben � 3), or the whole liver (n � 2). Treatment dose peratient was reduced by 25% since all patients werereviously treated with some form of TAE. The meanotal SIRT dose delivered was 1.0 GBq (range, 0.62–.47 GBq). Five patients had an increase in hepaticnzymes (grade 1–4) at 1-month follow-up. No proce-ure-related deaths or serious adverse events were ex-erienced. Best tumor response was as follows: CRn � 0), PR (n � 0), SD (n � 8), PD (n � 4), with aedian follow-up of 7.8 months (range, 1.0–16.0onths). The median time to liver progression was 7.0onths (range, 1.0–15.5 months). Nine of the 12 pa-
ients, including two patients with greater than 25%retreatment tumor burden, died due to progression of
iver disease (n � 6), extrahepatic disease (n � 1), oroth (n � 2). The median OS after SIRT was 10.8onths (range, 1.0–19.0 months). Three patients (East-
rn Cooperative Oncology Group [ECOG] perfor-ance status 0) are still alive at 13.5 to 19.0 months
median, 16.2 months) following SIRT. Although this issmall study performed at a single institution in heavilyretreated patients, the potential efficacy of radio-phere treatment in metastatic uveal melanoma wasuggested. Our observation is supported by a reportrom Kennedy et al.59 They treated 11 patients (sixemales, five males) with 12 radiosphere treatments atve centers. All patients had bilobar disease with morehan four metastatic lesions. With a median activity of.55 GBq delivered per treatment, toxicity was minimalith one grade 3 gastrointestinal toxicity, a gastriclcer that healed within 6 weeks with supportive care.o treatment-related death was observed. No patientseveloped radiation-induced liver disease (RILD). Fol-
ow-up positron emission tomography (PET)/CT scanst 3 months post-treatment showed one CR, six PRs,ne SD, and one PD by Response Evaluation Criteria Inolid Tumors (RECIST). Based on these encouragingata, we have started a phase II clinical trial to prospec-ively investigate the safety and efficacy of SIRT using0Y SIR-Spheres (Sirtex Medical, Wilmington, MA) inveal melanoma patients with hepatic metastases. Pa-ients are stratified based on their history of previous
ransarterial embolization of the hepatic artery. The 6afety and efficacy of treatments will be separatelynalyzed in these two patient cohorts.
RUG-ELUTING BEADS
Over the last few years, efforts have been made toeliver a more accurate dose of drugs to the liver overmore prolonged period. Embolization of vessels sup-lying malignant hypervascular tumor(s) with drug-luting beads delivers a local, controlled, sustainedose of chemotherapeutic medications to the tumor(s).rug-eluting beads (DC/LC Beads, Biocompatibles, Sur-
ey, UK) comprise a range of hydrogel microsphereshat are biocompatible, hydrophilic, non-resorbable,recisely calibrated, and capable of loading chemother-peutic medications including doxorubicin and irinote-an. Bead microspheres are produced from biocompat-ble PVA hydrogel that has been modified withulfonate groups for the controlled loading and deliveryf chemotherapeutic drugs. Drug-eluting beads arevailable in various size ranges to occlude the bloodow in the various sizes of blood vessels to the targetissue and to deliver a local and sustained dose of drugirectly to the tumor. Drug-eluting beads can be loadedith doxorubicin and used for treatment of HCC,60
holangiocarcinoma, neuroendocrine cancers, andetastatic melanoma. Varela et al, in their recent studyith doxorubicin-loaded beads in 27 patients with cir-
hosis-related HCC and large multifocal HCC, observedresponse rate of 75% (66.6% on intention-to-treat).61
rug-eluting beads also have been loaded with therinotecan for the treatment of patients with metastaticolorectal cancer.62
Recently, Fiorentini et al reported the result of theirhase II trial using irinotecan-eluting beads for uvealelanoma metastatic to the liver. Ten patients withepatic metastasis from uveal melanoma, eight mennd two women, with a mean age of 65 years (range,5–81 years), were treated with TACE-containingeads preloaded with irinotecan (100 mg). Followinghe drug-eluting bead treatment, three patients had aajor response with evidence of metastases reduction
f 90%, three patients had a reduction of 80%, and fouratients experienced reductions between 70% and0%. Treatment-related morbidity was short-lived and
ncluded upper right quadrant abdominal pain (grade 2fter 12 TACE procedures, and grade 3 after 3 TACErocedures). There was one case of transient paralytic
leus lasting 4 days, and two cases of nonicteric hepa-itis. No hematologic toxicity or alopecia was reported.he percentage of liver involvement was linked toesponse: three patients with oligonodular metastases,p to 25% substitution, obtained nearly complete re-uction of metastases. Three patients with multipleodular metastases occupying up to 75% of the liverad less evidence of response. The median survival was
.5 months (range, 4–9 months); eight patients were
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134 T. Sato
live at the time of publication. Two patients with 75%nd 60% of liver replacement with metastases died afterand 6 months, respectively, due to rapid progression
n the liver. A phase II clinical trial for metastatic uvealelanoma using doxorubicin-eluting beads is ongoing
n the United States.
EPATIC INTRA-ARTERIAL CHEMOTHERAPY
Hepatic intra-arterial chemoinfusion with an agenthat has a rapid systemic clearance rate and a highepatic extraction rate allows maximum local drugxposure. Regional chemotherapy concepts are mostlyased on the use of implantable hepatic catheters inrder to deliver intra-arterial chemotherapy directly toepatic lesions. Thus, a higher concentration of che-otherapeutic agents can be locally delivered, with
ower systemic toxicity. The results of intrahepaticrterial chemotherapy for metastatic uveal melanomare summarized in Table 2. Leyvraz et al initially re-orted the results of intrahepatic chemoinfusion with
otemustine.63 Thirty-one patients were subjected toaparotomy to place a totally implantable catheter intohe hepatic artery and received fotemustine 100 mg/m2
s a 4-hour infusion, first once a week for four timesnd then, after a 5-week rest period, every 3 weeksntil progression or intolerable toxicity. A responseate of 40% with a median duration of response being1 months was obtained. The median OS was 14onths. LDH appeared to be the strongest prognostic
actor for survival. Subsequently, a total of 101 patientsrom seven centers were treated with hepatic intra-rterial infusion of fotemustine using the same regi-en.64 Catheter-related complications occurred in 23%
f patients; however, this required treatment discon-
Table 2. Intrahepatic Arterial ChemotherapyFirst Author,
Year Technique Therapeutic Agent No. of Pa
Leyvraz, 199763 HAI Fotemustine 31
Peters, 200664 HAI Fotemustine 101
Siegel, 200665 HAI Fotemustine 18 ocular,
Becker, 200266 HAI Fotemustine IV or HAI withS.C. interferon-alpha �IL-2
HAI 23, IV
Cantore, 199467 HAI Carboplatin 8Bedikian, 19959 HAI Various regiments 38
Alexander, 200369 IHP Melphalan 29
Noter, 200473 IHP Melphalan 8van Iersel, 200872 IHP Melphalan 12Pingpank, 200475 PHP Melphalan 10
CR, complete response; HAI, hepatic arterial infusion; IHP, isoresponse; SD, stable disease; N/A, not applicable.
inuation in only 10% of the patients. Of the 101 pa-ients, 15 had a radiologic CR and 21 achieved a PR forn overall objective response rate of 36%. In 48 pa-ients, the disease was stable for a median duration of.4 months. Median OS for the whole group was 15onths (95% confidence interval [CI], 12.1–17.6onths) with a 1-year survival rate of 67% (95% CI,
7%–75%). Twenty-nine percent of the patients werelive at 2 years and 12% at 3 years.
Another study conducted by Siegel et al confirmedhe potential efficacy of hepatic arterial infusion withotemustine for the treatment of hepatic metastasisrom uveal as well as cutaneous melanoma.65 Thereere nine PRs and 10 patients with SD in 30 treatedatients without a significant difference in responsemong cutaneous or uveal melanoma patients. Beckert al reported the superiority of fotemustine hepaticrterial infusion over intravenous injection.66 In theirrial, 100 mg/m2 of fotemustine over 60 minuteshrough the hepatic artery was administered to patientsith disease confined to the liver. Fotemustine was
iven intravenously over 15 minutes to patients withxtrahepatic disease. All patients were subsequentlyiven immunotherapy with interleukin-2 and interfer-n-alpha administered subcutaneously. The hepatic re-ponse rate in patients who received fotemustine intra-rterially was higher than in those who receivedntravenous therapy, 22% versus 8%, respectively. How-ver, the median survival of each group was similar at69 and 349 days, respectively.
Cantore et al administered 300 mg/m2 carboplatinnce every 2 weeks through the hepatic artery in eightatients with uveal melanoma metastatic to the liver.67
hey observed responses in three (38%) of eight pa-
ResponsesOverall
Survival (mo) Comments
4 CR, 8 PR,15 SD
14 LDH was a significant prognostic factor.
15 CR, 21PR, 48 SD
15 Catheter-related complications occurredin 23% of patients.
9 PR, 10 SD 14 No difference in response betweenocular and skin melanomas.
HAI, 5 PR; IV,1 CR, 1 PR
12.1 vs. 11.5
3 PR, 1 SD 152 PR, 10 SD 1 PR, cisplatin � DTIC � hydroxyurea �
dactinomycin; 1 PR, IL-23 CR, 15 PR 12.1 Transient grade 3/4 hepatic toxicity in
19 patients (65%).4 responses 9.94 PR, 6 SD 10 Veno-occlusive disease in 4 patients2 CR, 3 PR N/A A phase III study in progress
patic perfusion; PHP, peripheral hepatic perfusion; PR, partial
tients
12 skin
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Locoregional management of hepatic metastasis 135
ients. The median OS was 15 months (range, 8–29onths). Treatment-related morbidity was low; the
nly limiting toxicity observed was thrombocytopenia.n the other hand, the results of intra-arterial therapy
rials at the M.D. Anderson Cancer Center are ratherisappointing, including only two PRs observed in 38atients.9 One PR was observed after intra-arterial infu-ion of cisplatin combined with DTIC, hydroxyurea,nd dactinomycin; the other after administration ofntra-arterial interleukin-2.
EPATIC ARTERIAL PERFUSION
The goal of isolated hepatic perfusion (IHP) is toxpose the liver containing metastatic melanoma toigh doses of chemotherapy to achieve maximal tumorhrinkage but not to cause fatal hepatotoxicity. Seminalork on IHP for hepatic metastases from uveal mela-oma was done by Alexander’s group at the Nationalancer Institute.68–71 They initially reported their re-ults with IHP using melphalan with or without tumorecrosis factor (TNF) in 22 patients with uveal mela-oma metastatic to the liver and observed an overallesponse rate of 62% with a median duration of hepa-ic response of 9 months.68 However, a number ofreatment variables confounded outcome assessment.hese included two doses of melphalan (1.5 and 2g/kg), 1 mg of TNF in 11 patients, and perfusion via
he hepatic artery and portal vein in five patients. Thesenvestigators subsequently reported on the outcome of9 consecutive patients treated with a 60-minute hy-erthermic IHP using 1.5 mg/kg melphalan alone witherfusion inflow via the hepatic artery.69 Twenty-nineatients (14 males and 15 females; mean age, 49 years)ith unresectable liver metastases from uveal mela-oma were treated (mean total dose of melphalan 105g). There was no treatment-related mortality. Tran-
ient grade 3/4 hepatic toxicity was observed in 19atients (65%). Mean lengths of operation and hospitaltay were 8.3 hours and 10 days, respectively. Thereere three (10%) CRs (12, 14�, and 15 months dura-
ion) and 15 PRs (52%; mean duration, 10 months). Atmedian follow-up of 30.7 months, the median actu-
rial progression-free survival (PFS) and OS were 8 and2.1 months, respectively. The median PFS in the liveras 12 months. The initial site of disease progression
ncluded the liver in 17 of 25 patients (68%). Prognosticactors predicting survival by univariate analysis in-luded the number of metastases, size of the largestetastasis, percent of hepatic replacement, and base-
ine LDH level. At the Leiden University Medical Cen-er, 18 patients with unresectable liver metastases fromvariety of tumors (13 uveal melanomas, two neuroen-ocrine carcinomas, two gastrointestinal stromal tu-ors, and one renal cell carcinoma) and one HCCatient were treated with a 60-minute IHP using 200
g melphalan.72 There was no treatment-related mor- tality. Reversible grade 3/4 hepatotoxicity occurred in0 patients, while veno-occlusive disease occurred inour patients. Of the 12 uveal melanoma patients whoere perfused, there were four PRs (33.3%) and sixatients with SD (50%). The median disease-free sur-ival was 6.6 months with a median OS of 10 months.n another small study by Noter et al, eight patientsith metastatic uveal melanoma confined to the liverere treated with IHP of high-dose melphalan.73 Four
50%) of the patients responded. The median PFS andS were 6.7 and 9.9 months, respectively. Two-year
urvival was 37%.While administration of high doses of melphalan
sing IHP yields beneficial effects, the fact that a sur-ical procedure is required and only one treatment isossible makes IHP less desirable for conventional use.o overcome this limitation, the feasibility of percutane-us hepatic perfusion (PHP) with melphalan using a Del-ath double-balloon inferior vena cava catheter (Delcathystems, New York, NY) has been investigated.74 Variousoses of melphalan were infused over 30 minuteshrough the hepatic artery with subsequent venousemofiltration. Fifty-one patients, including 12 withveal melanoma, were treated. In the preliminary anal-sis, two CRs and three PRs were seen among the 10atients with uveal melanoma metastatic to the liver.hree of five responses lasted 1 year or longer.75 Aandomized phase III trial comparing PHP and the bestvailable treatment is currently ongoing.
UMMARY AND FUTURE PROSPECTIVE
Various locoregional treatments have been devel-ped for the treatment of uveal melanoma metastatic to
igure 2. Decision-making process for locoregional treat-ent of hepatic metastasis from uveal melanoma. DEB,
rug-eluting beads; IHA, intra-hepatic arterial infusion; IHP,solated hepatic perfusion; PHP, pericutaneous hepatic per-usion; RFA, radiofrequency ablation; TACE, transarterialhemoembolization; TAIE, transarterial immunoemboliza-
ion.
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136 T. Sato
he liver. Since there has been no prospective random-zed trial to compare the efficacy of individual treat-
ents, current choice of treatment in uveal melanomaatients with hepatic metastasis depends on the avail-bility of treatment modalities and the experience atndividual institutions. Figure 2 shows the flowchart forhe selection of treatment for individual patients athomas Jefferson University Hospital. The choice of
ocoregional treatments based on the amount of he-atic metastasis is also shown in Table 3. Patients withsmall number of metastases in the liver can be suc-
essfully treated by various modalities. The major chal-enge for the current locoregional treatment of hepatic
etastases from uveal melanoma is advanced hepaticetastases involving more than 50% of the liver. In this
egard, comprehensive follow-up of high-risk patientsith imaging tests of the liver is critically important in
dentifying a hepatic metastasis in its early stage. De-elopment and progression of extrahepatic systemicetastasis after successful control of hepatic metastasis
s another challenge for the management of metastaticveal melanoma. Establishment of an effective systemicreatment should be explored with priority.
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Table 3. Selection of Locoregional Treatment
Treatment Modality
Solitary Metastasis,Time to Systemic
Metastasis>5 Years
Surgical resection, RFA ��
Chemoembolization *Immunoembolization *HAI *PHP, IHP *Radiosphere *Drug-eluting beads *HAI, hepatic arterial infusion; IHP, isolated hepatic perfusion; PH*Appropriate; **most appropriate; xnot indicated.
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iple Tumorsmall Volume20% liverolvement)
Medium TumorVolume
(20–50% liverinvolvement)
Large TumorVolume
(>50% liverinvolvement)
* x x** ** *** ** x** ** *** * *** ** x** ** *
taneous hepatic perfusion; RFA, radiofrequency ablation.
Multbut S
(<inv
P, percu
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