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AJR:190, January 2008 99

tastasis does occur, chemotherapeutic op-

tions are limited.

Hepatic arterial chemoembolization for the

management of hepatic metastasis of melano-

ma was first reported in 1988 [2]. Chemoem-

bolization achieves greater drug concentra-

tion within the tumor than does systemic che-

motherapy while decreasing systemic toxicitysuch as myelosuppression [5]. A retrospec-

tive analysis [6] showed that hepatic arterial

chemoembolization with a cisplatin-based

regimen was the only technique resulting in

improved survival compared with other treat-

ments, including systemic chemotherapy and

chemotherapy through a surgically implanted

arterial port. However, reports of outcomes

remain extremely limited. The primary goal

of hepatic arterial chemoembolization is to

Hepatic Arterial

Chemoembolizationfor Management ofMetastatic Melanoma

Karun V. Sharma1

Jennifer E. Gould1,2

J. William Harbour2, 3

Gerald P. Linet te2, 4

Thomas K. Pilgram1

Pouya N. Dayani3

Daniel B. Brown1,2,5

Sharma KV, Gould JE, Harbour JW, et al.

1Mallinckrodt Institute of Radiology, Washington

University School of Medicine.

2Siteman Comprehensive Cancer Center, Washington

University School of Medicine, St. Louis, MO.

3Department of Ophthalmology, Washington University

School of Medicine, St. Louis, MO.

4Division of Oncology, Department of Medicine,

Washington University School of Medicine, St. Louis, MO.

5Present address: Division of Cardiovascular and

Interventional Radiology, Thomas Jefferson University

Hospital, Suite 4200 Gibson Bldg., 111 S 11th St.,

Philadelphia, PA 19107. Address correspondence to

D. B. Brown.

Itervetio Rioogy • Origi Reerch

AJR 2008; 190:99–104

0361–803X/08/1901–99

© American Roentgen Ray Society

The overall incidence of liver-

dominant metastatic melanoma

is low, particularly in compari-

son with that of other primary

tumors, such as colon and breast cancer. Oc-

ular melanoma is the most common intraoc-

ular malignant tumor in adults [1–3]. Despite

undergoing apparently definitive manage-ment of the primary tumor with either enu-

cleation or plaque radiation therapy, many

patients eventually have a relapse, and dis-

tant metastatic lesions develop, most com-

monly in the liver. Once hepatic metastasis

occurs, the prognosis is extremely poor; the

mean survival period is approximately 4

months despite salvage chemotherapy [3, 4].

Cutaneous melanoma rarely results in liver-

dominant metastasis. When this type of me-

Keywords: hepatic arterial chemoembolization, liver,metastatic disease, metastasis, ocular melanoma

DOI:10.2214/AJR.07.2675

Received June 5, 200 7; accepted after revision

August 7, 2007.

OBJECTIVE. Hepatic arterial chemoembolization is an accepted therapy for stage 4 mela-

noma with liver-dominant metastasis. However, the reports of outcomes are limited. We present

our outcomes with hepatic arterial chemoembolization for metastasis of stage 4 melanoma.

MaTERIals and METHOds. Twenty patients with liver-dominant metastasis of

ocular or cutaneous melanoma were treated with hepatic arter ial chemoembolization. Overall

survival and progression-free survival rates were calculated from the first treatment. Patients

with intrahepatic tumor progression were treated with additional hepatic arterial chemoembo-lization. Both overall survival and progression-free survival were analyzed with the Kaplan-

Meier method. Tumor pattern on angiography was characterized as either nodular or infiltrative

on the basis of angiographic appearance.

REsUlTs. The 20 patients underwent 46 hepatic arterial chemoembolization sessions

(mean, 2.4 sessions; range, 1–5). The mean and median overall survival times were 334 ± 71

and 271 days, respectively. There were no deaths within 30 days of treatment. Thirteen of

the 20 patients had progression of disease. The mean and median progression-free survival

times for these patients were 231 ± 42 and 185 days, respectively. Patients with lesions that

had a nodular angiographic appearance had longer progression-free survival than patients

with lesions that had an infiltrative appearance (mean progression-free survival time, 249

vs 63 days). Patients with lesions that had a nodular angiographic appearance also survived

significantly longer than those with lesions that had an infiltrative angiographic pattern (mean

overall survival time, 621 vs 114 days; p = 0.0002).

COnClUsIOn. Hepatic arterial chemoembolization for liver-dominant metastasis ofstage 4 melanoma is a safe treatment that results in longer survival than has occurred among

historical controls. Patients with lesions that have a nodular tumor appearance on angiogra-

phy survive significantly longer than patients with lesions that have an infiltrative appearance

on angiography.

Sharma et al.Hepatic Arterial Chemoembolization of MelanomaInterventional RadiologyOriginal Research



100 AJR:190, January 2008

shrm et .

arrest progression of disease. A common

finding in existing studies is that a large num-

ber of patients experience disease progres-

sion despite treatment with hepatic arterial

chemoembolization, the reported response

rates being less than 50% [6, 7]. To date there

has been no method, to our knowledge, of pre-

dicting which patients will respond to therapy.The reported survival times among patients

who do respond to treatment range from 14 to

22 months [6, 7]. In this study, we evaluated

our institutional experience with a multidrug

hepatic arterial chemoembolization regimen

of cisplatin, doxorubicin, and mitomycin C

in the treatment of patients with liver-domi-

nant metastasis of melanoma. The principle

outcome investigated was overall survival in

a contemporary cohort. A secondary mea-

sure was angiographic findings, which sug-

gest there are two distinct forms of hepatic

metastatic disease that respond differently to

hepatic arterial chemoembolization and are

predictive of outcome.

Materials and Methods

This study was approved by our institutional

review board. All patients underwent cross-sec-

tional imaging with contrast-enhanced CT, PET/

CT, or both within 1 month before treatment.

Informed consent was obtained from all pa-

tients. On the day of treatment, laboratory data,

including complete blood cell count, complete

metabolic panel, and prothrombin time, were ob-

tained. Standard preprocedural medications (8

mg ondansetron, 10 mg dexamethasone, and 500mg metronidazole) were administered.

Local anesthesia was obtained with 1% buff-

ered lidocaine, and sedation was achieved with IV

midazolam and fentanyl. The Seldinger technique

was used to access the common femoral artery.

Superior mesenteric angiography was performed

though the portal venous phase to evaluate for

portal vein patency and flow direction and vari-

ant arterial anatomic features. Celiac artery an-

giography was followed by subselection of the

right or left hepatic artery with a microcatheter.

After confirmation of the appropriate position,

chemoembolization was performed with a mix-

ture of 50 mg cisplatin, 50 mg doxorubicin, and 10

mg mitomycin C dissolved in sterile contrast ma-

terial (ioversol, Optiray 350, Mallinckrodt Medi-

cal) and emulsified with ethiodized oil (Ethiodol,

Savage Laboratories). After infusion of the che-

motherapeutic agents under fluoroscopic monitor-

ing, embolization was performed with either ab-

sorbable gelatin sponge (Gelfoam, Upjohn) slurry

or 300–500 mm polyvinyl a lcohol (PVA) par ticles

mixed in contrast material until near stasis of flow

in tumor-feeding branches was achieved. Use of

PVA was reserved for cases in which feeding ar ter-

ies were severely pruned from previous treatment.

The decision to use PVA was made by the pr imary

operator at the time of the procedure. Use of PVA

did not limit further hepatic arterial chemoem-

bolization. Aliquots of 1–3-mL of 1% lidocaine

were intermittently administered intraarterially

during infusion of the chemotherapeutic mixture

[8]. Up to one lobe was treated per hepatic arterial

chemoembolization session; the contralateral lobe

was treated 4–6 weeks after the first procedure.

After the procedure, patients received main-

tenance IV antiemetics and antibiotics (8 mg on-

dansetron every 8 hours and 500 mg metronidazole

every 12 hours) until discharge from the hospital.

Pain control was achieved with hydromorphone hy-

drochloride delivered through a patient-controlled

anesthesia device. Patients were discharged from

the hospital when oral intake was adequate and

pain well controlled without IV narcotics. Follow-

up cross-sectional imaging (contrast-enhanced CT

or PET/CT) was performed approximately 4–6

weeks after treatment of all tumor-bearing branch-

es to evaluate response and determine the need

for additional hepatic arterial chemoembolization

treatments. If residual hepatic disease was pres-

ent or if there was evidence of intrahepatic disease

progression, additional chemoembolization proce-

dures were performed with repeated imaging after

repeated treatment of tumor-bearing vessels. Dis-

ease progression, response, and stability were de-

fined according to the Response Evaluation Criteria

in Solid Tumors [9]. Complications were evaluated

with the National Cancer Institute Common Toxic-

ity Criteria for Adverse Events (CTC) version 3.0,

which is the accepted measurement tool for toxic-

ity in oncologic studies [10]. Survival rates and

time to disease progression from the time of first

chemoembolization were calculated with Kaplan-

Meier analysis.

Results

Patient Characteristics and Survival

Between February 2004 and February 2007,

20 patients (14 men, six women; mean age, 62

years; range 31–81 years) underwent 46 hepatic

arterial chemoembolization procedures. Sev-

enteen patients had ocular and three had cuta-

neous melanoma. All patients except one pre-

1.0

0.9

P r o p o r t i o n o

f P a t i e n t s

S u r v i v i n g

Survival Period (d)

1,200

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1,0009008007006005004003002001000

0.0

Fig. 1—Graph shows resultsof Kaplan-Meier analysis ofoverall survival for entiregroup after hepatic arterialchemoembolization. Calcu-lated mean and median sur-vival times were 33 4 ± 71 and272 days, respectively.

1.0

0.9

P r o p o r t i o n

o f P a t i e n

t s

S u r v i v i n g

Time to Progression (d)

900

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

8007006005004003002001000

0.0

Fig. 2—Graph shows resultsof Kaplan-Meier analysis of

time to progression for entiregroup after hepatic arterialchemoembolization. Calcu-lated mean and median times

to progression were 231 ± 42and 185 days, respectively.



AJR:190 , January 200 8 101

Hepatic Arterial Chemoembolization of Melanoma

sented with bilobar disease with more than 10

tumors measurable on imaging. Most of the pa-

tients had too many tumors to count. The pa-

tient who was the exception had a solitary 8-cm

tumor in the right lobe of the liver and was

judged not a candidate for resection. One to five

hepatic arterial chemoembolization treatments

were performed per patient (mean, 2.4 treat-ments per patient). There were no deaths within

30 days of treatment and no complications ac-

cording to CTC version 3.0 criteria. Kaplan-

Meier analysis showed the mean and median

overall survival times for the group were

334 ± 71 and 271 days, respectively (range,

36–1,185 days) (Fig. 1). Six patients were alive

at the time of this writing, a median survival

time of 311 days (range, 141–1,185 days).

According to the Response Evaluation

Criteria in Solid Tumors, there were no com-

plete or partial responses. At initial follow-up,

13 (65%) of the patients had stable disease

and seven (35%) had progression. All seven

patients with progression at initial follow-up

died within 109 days. Of the 13 patients with

stable disease on initial imaging, six eventu-

ally had disease progression, for a total of 13

patients with progression of disease. The

mean and median progression-free survival

times for this group of patients were 231 ± 42and 185 days, respectively (Fig. 2).

Angiographic Appearance

Review of angiographic images showed

two distinct appearances of hepatic metastatic

lesions. In one subset of patients (n = 8),

large nodular well-defined tumor masses

were present (Fig. 3). In the other subset of

patients (n = 12), a diffuse infiltrative stain-

ing pattern without distinct nodularity was

seen (Fig. 4). The cross-sectional imaging

appearance was not predictive of the angio-

graphic appearance.

Kaplan-Meier analysis of the two distinct

angiographic subsets revealed that angio-

graphic appearance strongly correlated with

and was predictive of survival and disease

progression after hepatic arterial chemoem-

bolization. Overall survival among patients

with the nodular angiographic appearance

was significantly longer than among the groupwith infiltrative findings (621 ± 87 vs 115 ± 22

days; p = 0.0002) (Fig. 5). The median surviv-

al times for the nodular and infiltrative groups

were 750 and 109 days, respectively. All of the

35% of patients who had immediate disease

progression despite hepatic ar terial chemoem-

bolization had the infiltrative angiographic

pattern. The longest survival period of any

patient with the infiltrative angiographic pat-

tern was 271 days. Time to progression also

was longer for patients with the nodular an-

giographic pattern, although this value did not

reach statistical significance, likely because of

sample size (nodular, 250 ± 62 days; infiltra-

tive, 63 ± 8 days; p = 0.90) (Fig. 6).

dicuio

Ocular melanoma represents less than

5% of all reported cases of melanoma but is

the most common primary intraocular ma-

lignant tumor in adults and the second most

common site of primary melanoma after

cutaneous sources. Ocular and cutaneous

melanomas both arise from the same em-

bryologically derived dendritic melanocytes.

The incidence of ocular melanoma is ap-

proximately six cases per 1,000,000 personsin the United States, with approximately

1,200–1,500 cases diagnosed each year. The

average age at diagnosis is 55 years [3, 4].

More than one half of patients who undergo

apparently successful therapy for the primary

tumor eventually have distant hematogenous

metastasis. Cutaneous melanoma is far more

common than ocular melanoma, approxi-

mately 57,000 cases being diagnosed each

year. Unlike ocular melanoma, however, cu-

taneous melanoma metastasizes through the

lymphatic vessels to regional lymph nodes or

by hematogenous spread to almost any organ

[11–13]. The liver is the third most commonorgan involved. When they develop, hepatic

metastatic lesions are rarely isolated and

amenable to hepatic arterial chemoembo-

lization. Other investigators (Ahrar et al.,

presented at the 2007 annual meeting the

Society of Interventional Radiology) have

presented data showing that the outcomes of

hepatic arterial chemoembolization are com-

parable for ocular and cutaneous melanoma.

A

B C

Fig. 3— 51-year old woman with metastatic ocular melanoma.A, Angiogram shows nodular metastatic ocular melanoma before therapy.B, Pretreatment PET/CT scan shows hypermetabolic focus in right lobe of liver.C, PET/CT scan after hepatic arterial chemoembolization shows metabolic activity in dominant tumor hasbeen eliminated and replaced with dense uptake of iodized oil. Patient survived 42 7 days from first emboliza-

tion session .



102 AJR:19 0, January 200 8

shrm et .

Ocular melanoma has a high affinity for

metastasizing to the liver, which is usually

the first site of extraocular disease and is

involved in approximately 90% of patients.

In more than one half of patients with meta-

static disease, the liver may be the only or-

gan involved [14, 15]. The presence of he-

matogenous metastasis in the liver is a major

determinant of clinical course and patient

survival. Despite advances in the diagnosis

and management of primary uveal melano-ma, hepatic metastasis remains refractory to

standard oncologic therapies. Once hepatic

metastasis is diagnosed, the mean survival

time without treatment is only 2–3 months.

Treatment with systemic chemotherapy is

of limited value, the reported mean survival

time being approximately 4 months [16–18].

Surgical resection is rarely an option. Al-

though one study [19] showed an overall sur-

vival period of 27 months, less than 10% of

patients with hepatic metastasis in that study

were candidates for surgical resection.

In 1988, Mavligit et al. [2] first reported

management of ocular melanoma with he-patic arterial chemoembolization and cis-

platin and PVA particles. Those authors re-

ported a 46% radiologic response rate and

an 11-month median survival time for 30

patients with metastatic ocular melanoma. In

1995, the same group [6] reported their in-

stitutional experience comparing hepatic ar-

terial chemoembolization, systemic chemo-

therapy, and hepatic arterial chemotherapeu-

A B

Fig. 4—43-year-old man with metastatic ocular melanoma.A, Angiogram shows miliary pattern of contrast enhancement throughout liver without dominant nodules.

B, PET images 2 weeks before hepatic arterial chemoembolization suggest nodular appearance. This lack of correlation was common in patients with infiltrativeangiographic appearance. Patient survived 45 days from first embolization session.

1.0

0.9

P r o p o

r t i o n

o f P a t i e n t s

S u r v i v i n g

Survival Period (d)

1,200

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1,0009008007006005004003002001000

0.0

Fig. 5—Graph shows overallsurvival period after hepaticarterial chemoembolization issignificantly longer in patientswith nodular pattern (dashedline ) compared with patientswith infiltrative pattern (solidline ) of disease. Mean andmedian survival periods fornodular group were 621 ± 87and 750 days and for infiltra-

tive group were 115 ± 22 and109 days (p = 0.0002).

1.0

0.9

P r o p o r t i o n

o f P a t i e n

t s

S u r v i v i n g

Time to Progression (d)

900

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

8007006005004003002001000

0.0

Fig. 6—Graph shows resultsof Kaplan-Meier analysis of

time to disease progression.Mean time to progressionwas 250 days for patients withnodular angiographic pattern(dashed line ) and 63 days forpatients with infiltrative pat-

tern (solid line ) (p = 0.5).



AJR:190 , January 200 8 103

Hepatic Arterial Chemoembolization of Melanoma

tic infusion through a surgically implanted

port in the treatment of patients with meta-

static ocular melanoma. Only hepatic arterial

chemoembolization with the cisplatin-based

regimen produced a meaningful response

rate. Responders survived a median of 14.5

months; patients who underwent systemic

therapy survived 5 months. Not all patientsresponded to chemoembolization; that sub-

set survived a median of 5 months. This out-

come is similar to that among our group of

patients who did not respond to therapy.

Improved survival among patients with

metastatic uveal melanoma managed with

hepatic arterial chemoembolization and car-

mustine has been reported [7]. The overall

median survival time in that study was 5.2

months. However, patients with a radio-

graphic response had a median survival time

of nearly 22 months. Another treatment op-

tion attempted is direct hepatic arterial che-

motherapeutic infusion through a surgically

implanted port. Using fotemustine, Leyvraz

et al. [20] reported a response rate of 40%

and a median overall survival time of 14

months. Feldman et al. [21] and Grover and

Alexander [22] evaluated isolated hepatic

perfusion by infusing melphalan and captur-

ing the effluent from the hepatic vein. This

treatment led to a radiologic response in ap-

proximately 60% of patients and resulted in a

median survival period of 12 months. There

is much room for improvement in maximiz-

ing the percentage of patients who respond

and delaying the time to disease progressionand treatment failure. Other catheter-direct-

ed techniques, such as use of 90Y have not

been described but may be of value.

The results of the cur rent study show over-

all mean and median survival times of 271

and 334 ± 71 days among patients with liver-

dominant metastatic melanoma managed

with cisplatin–doxorubicin–mitomycin he-

patic arterial chemoembolization. We found

that compared with the findings in studies

of single-drug regimens, the multidrug regi-

men is extremely well tolerated without ad-

ditional toxicity. The survival period of our

group of patients is consistent with previ-ously reported median survival times of 5

and 11 months with carmustine and cisplatin

therapy, respectively.

An important finding of our study is rec-

ognition of two distinct angiographic pat-

terns of metastatic melanoma that appear to

be predictive of patient response and overall

survival after hepatic arterial chemoembo-

lization treatment. Patients with the nodu-

lar angiographic pattern were found to have

a favorable response to hepatic arterial

chemoembolization treatment, evidenced

by a median survival time of more than 2

years. Patients with the infiltrative angio-

graphic pattern, however, typically did not

have a favorable response to hepatic arterial

chemoembolization treatment, evidenced bya median survival time of only 115 days. We

believe that the strong correlation between

the observed angiographic pattern and sur-

vival benefit after hepatic arterial chemoem-

bolization may be valuable prognostic infor-

mation that can be used to help counsel and

guide the care of individual patients. Unfor-

tunately, the observed angiographic pattern

was not accurately predicted with pretreat-

ment contrast-enhanced CT or PET/CT.

Although it is possible that the nodular

pattern may represent an earlier pattern of

disease that eventually transforms into in-

filtrative disease, this evolution was not ob-

served in our cohort. The nodular and infil-

trative angiographic patterns may be related

to underlying differences in tumor genetics

that confer different biologic behavioral and

growth patterns that result in the observed

morphologic features. This hypothesis is

supported by results of gene expression pro-

file experiments showing that primary uveal

melanomas cluster into two distinct molecu-

lar classes. Results of this molecular classi-

fication into distinct low-grade (class 1) and

high-grade (class 2) groups are strongly pre-

dictive of metastatic death of patients withocular melanoma [4, 23–25]. It is tempting

to speculate that the differences in molecu-

lar class may be related to the differences in

angiographic pattern and response to hepatic

arterial chemoembolization treatment. To

further investigate this possibility, we are

obtaining hepatic arterial chemoemboliza-

tion before hepatic biopsy specimens for

gene profile analysis.

Deficiencies of this study were those in-

herent to a retrospective design and those re-

lated to small sample size. Our sample size,

however, was similar to those in other stud-

ies of hepatic arterial chemoembolization [2,7]. Given the size of the study group, we use

these findings as a way to counsel patients,

not to make decisions about whether therapy

should be offered. Our treatment group did

include two types of melanoma, but Ahrar et

al. (presented at the 2007 annual meeting the

Society of Interventional Radiology) found

similar survival data among patients with dif-

fering melanotic sources. The number of pa-

tients with cutaneous melanoma in our group

was too small for statistical comparison with

those with ocular melanoma. However, the

patients with cutaneous melanoma were not

outliers in median survival. The only two pa-

tients who survived more than 1,000 days in

our group had ocular melanoma.

Ocular melanoma is a rare tumor, and oncehepatic metastasis is diagnosed, patients are

faced with an extremely poor prognosis. He-

patic arterial chemoembolization of hepatic

metastatic lesions of melanoma was first re-

ported in the late 1980s and has been found

to be a safe, well-tolerated treatment option.

Unlike the well-reported outcome of hepatic

arterial chemoembolization for hepatocellu-

lar carcinoma, there is a relative lack of infor-

mation in the medical literature on outcome

after hepatic arterial chemoembolization

therapy for metastasis of hepatic melanoma.

In this study, we found improved survival

among patients with metastatic melanoma

managed with cisplatin–doxorubicin–mito-

mycin C hepatic arterial chemoembolization

compared with survival of historical controls

treated with systemic chemotherapy and sug-

gest that this outcome can be predicted on

the basis of angiographic pattern.

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Ha Tace for Mmlm 2008