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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
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
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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
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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
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0.6
0.5
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8007006005004003002001000
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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.
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-
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-