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Embolotherapy for Neuroendocrine Tumor Hepatic Metastases 183
Fig. 14.3a−d. Fifty-six-year-old female with nonfunctioning rectal carcinoid tumor metastatic to liver, complained of upper
abdominal pain and hormonal symptoms. (a) Pre-embolization venous-phase CT image of the liver shows the largest metastasis
in the left lobe (arrow). (b) CT image without intravenous contrast injection, obtained immediately after LHA embolization
using 4.5 vials of tris-acryl gelatin microspheres, shows retained arterially injected contrast within the largest metastasis (arrow).
(c) Venous-phase CT image 3 days post-embolization shows decreased attenuation and a small amount of gas within the largest
metastasis, consistent with necrosis. (d) Venous phase CT image 3 months post-embolization shows a signifi cant decrease in
size of the largest metastasis, but growth of a new metastasis in the caudate lobe (arrow)
a b
c d
g h
184
K. T. Tan and J. R. Kachura
14. 4
Results
At present, there is no conclusive data regarding
the effectiveness of embolotherapy for liver metas-
tasis from neuroendocrine tumor in comparison
to other methods of treatment due to various rea-
sons. It is an uncommon condition with a wide
spectrum of clinical presentations and severity in
addition to multiple treatment options. Hence, it
is highly unlikely that randomized trials will ever
be conducted to investigate this matter. All results
for embolotherapy published so far are case series
involving small numbers of subjects ranging from
14 to 41 patients with a wide range of disease sever-
ity. Despite this, allowing for different stages of dis-
ease and method of treatments, these series show
a good clinical response rate (reduction of symp-
toms, somatostatin requirement, tumor size) of
between 50 to 100%, with symptom-free intervals
of 5–10 months in 90%–100% of patients [43, 47, 48,
61–75]. Interestingly, the reported 5-year survival
of 53% to 83% post-embolotherapy is superior in
comparison to historical controls receiving medical
treatment alone (0%–40%) [2, 3, 9, 10]. However,
there is no definitive evidence that any particular
embolic agent is more superior to others.
Our center recently prospectively evaluated
11 patients with metastatic neuroendocrine tumors
treated with 20 hepatic artery embolizations using
tris-acryl gelatin microspheres for pain, hormonal
symptoms, and/or rapid tumor growth. On follow-
up CT scanning, 90% of lesions showed reduction in
vascularity suggesting tumor necrosis. All patients
had amelioration of original pain and/or hormonal
symptoms (mean 31% decrease in pain score) lasting
3–15 months. There was one major complication:
encephalopathy for which no etiology was found and
which resulted in a prolonged hospital stay [70].
14. 5
Complications (Table 14.3)
Serious complications following embolization of
metastatic neuroendocrine tumor are uncommon
with careful patient selection, thorough pre-pro-
cedure preparation, and meticulous angiographic
technique [72]. Reported major complication rates
and death rates after embolotherapy for neuroen-
docrine tumor hepatic metastases range from 1% to
10%, and 0% to 3%, respectively.
14. 5.1
Angiographic Complications
Access site complications are unusual as a large-
diameter common femoral artery access is rarely
required for the embolization. Iatrogenic arterial
dissection occasionally occurs at the celiac artery
origin during difficult catheterization. In patients
with borderline hepatic or renal function, the risk
of contrast induced nephropathy and hepatorenal
syndrome can usually be prevented with optimal
hydration and by limiting the volume of liver embo-
lized.
14. 5.1.1
Nontarget Embolization
Inadvertent extrahepatic deposition of embolic
material is relatively common. Although any non-
target embolization is undesirable and may cause
complications, the frequency of significant clini-
cal sequela is low [72]. Asymptomatic deposition of
embolic material may be seen in the lung, stomach,
pancreas, duodenum, gallbladder, diaphragm, and
Table 14.3. Complications of embolotherapy for neuroendo-
crine tumor liver metastases
Angiographic complications
Access-related
Dissection / thrombosis
Distal embolization
Hemorrhage / hematoma / false aneurysm
Arteriovenous fistula
Nerve damage
– Contrast media
– Allergic / anaphylactoid
– Nephrotoxicity
– Catheter and general complications
– Air embolism / thromboembolism
– Fracture of guide wire or catheter
Nontarget embolization
Cholecystitis
Pancreatitis
Splenic infarct
Gastric or bowel infarction
Pulmonary embolism
Embolization complications
Severe/prolonged post-embolization syndrome
Carcinoid crisis
Anemia, neutropenia, and thrombocytopenia (due to cyto-
toxic agent)
– Liver abscess
– Liver failure
Embolotherapy for Neuroendocrine Tumor Hepatic Metastases 185
spleen. Some patients may develop significant com-
plications, however, from such deposition of embol ic
material. Acalculous cholecystitis, gangrenous cho-
lecystitis, acute pancreatitis, and splenic infarction
have all been reported. Fortunately, most of these
complications can be treated conservatively and
they rarely require surgical interventions.
14. 5.1. 2
Embolization complications
Although the main objective of embolotherapy is to
cause tumor cell death, this by itself may have unde-
sirable effects. Post-embolization syndrome (pain,
nausea, vomiting, pyrexia, and malaise) practically
occur in all patients and can last for 1 to 2 weeks.
Anemia, neutropenia, and thrombocytopenia are
invariable if a cytotoxic agent is used. Secondary
infection of the necrotic liver/tumor can occur and
may lead to the formation of liver abscess (Fig. 14.4),
which may require percutaneous drainage. Previous
biliary tract surgery such as enterobiliary anasto-
mosis or sphincterotomy is associated with a greater
incidence of liver abscess, and this is likely due to
the colonization of the biliary tree by gut organisms
[76 –78]. There is some evidence to suggest t hat bowel
preparation combined with tazobactam/piperacillin
given intravenously for 3 days reduces the incidence
of this complication in high risk patients [79].
Until the introduction of somatostatin analogues,
exacerbation of the symptoms of carcinoid or frank
carcinoid crisis was common with embolization of
carcinoid metastases. Now, with somatostatin ana-
logues used routinely for hormonally active tumors,
both during and after embolization, carcinoid crisis
occurs in only a small percentage of patients. Treat-
ment of these patients, who often have severe disease
of the pulmonary and tricuspid valves, is difficult
because there is little room for error when reducing
preload to treat pulmonary edema. Right atrial pres-
sure must be maintained to ensure adequate flow
through the diseased tricuspid valve. Maintenance
of right atrial pressure requires close collaboration
with an experienced anesthesiologist or cardiolo-
gist.
14. 6
Pitfalls
There are many potential variations of the anat-
omy of the arterial supply to the liver. Scrupulous
attention to hepatic arterial anatomy, variants, and
nontarget branches is necessary to avoid potentially
devastating complications. In addition, hypervascu-
lar metastases can create a sump effect, reversing
the flow in the gastroduodenal artery (GDA). Thus
a superior mesenteric artery injection may fill the
hepatic artery via an enlarged GDA, which could be
mistaken for a replaced right hepatic. Furthermore,
a celiac injection in such a case may fail to opacify
the GDA because of the flow reversal and may give
the impression of an occluded GDA. After emboliza-
tion of the tumor, the flow will revert to antegrade
Fig. 14.4a,b. Fifty-four-year-old male with metastatic neuroendocrine tumor of unknown primary. (a) Pre-embolization venous-
phase CT image of the liver shows the largest metastasis in the left lobe (arrow). (b) Venous-phase CT image of the liver
obtained 7 wks post-embolization of the LHA using 6 vials of tris-acryl gelatin microspheres shows that the largest metastasis
has decreased in size and enhancement, but contains a moderate amount of gas. The patient complained of fever and vomiting,
which resolved with antibiotic therapy. The lesion was not aspirated or drained. We suggest percutaneous drainage only if a
patient becomes septic or if there is no response to antibiotics. Arrowheads denote interval growth of a right lobe metastasis
a b
186
K. T. Tan and J. R. Kachura
in the GDA. Thus it is important to have the catheter
tip distal to the origin of the GDA to avoid nontarget
embolization.
Some advanced or superficial tumors may parasit-
ize a rterial supply from t he arteries of adjacent organs ,
especially after multiple prior embolization proce-
dures. Such parasitization may require embolization
of branches arising from such arteries as the right
renal, colonic, gastric, phrenic, internal thoracic, and
intercostal arteries. It is important to recognize that
not all such parasitized vessels can be safely treated
without risk to other important organs.
A patent portal venous system with hepatopedal
flow is essential to minimize the risk of possible
liver necrosis/failure post-embolization. In patients
with occluded or reversed flow (hepatofugal) portal
venous systems, embolization can still be performed
using a modified technique of superselective injec-
tion and reduced amounts of embolic material [71].
14. 7
Conclusion
Current management strategies for neuroendocrine
tumor hepatic metastases have relied on data from
anecdotal evidence and retrospective studies involv-
ing small numbers of patients. It is unlikely that
this situation will change in the near future, since
prospective studies are difficult to perform in such
a relatively rare and biologically heterogeneous dis-
ease. Embolotherapy is a widely accepted method
of treatment for nonresectable hepatic metastases
from neuroendocrine tumors. Long-term palliation
of pain and hormonal symptoms is possible using
repeated treat ment. Both bland hepatic ar tery embo-
lization and chemoembolization have been used,
and there is no conclusive data to indicate which
embolization method and which embolic agents are
most efficacious.
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Bone Metastases from Renal Cell Carcinoma: Preoperative Embolization 189
15 Bone Metastases from Renal Cell Carcinoma:
Preoperative Embolization
Shiliang Sun
S. Sun, MD
Associate Professor of Radiology, Department of Radiology,
University of Iowa, College of Medicine, 200 Hawkins Dr., 3955
JPP, Iowa City, IA 52242, USA
asymptomatic RCC is more frequently detected and
de te cted at l ower st ages o f d isea se, whe n t umors may
be re sected w ith curative intent or when a metast atic
lesion is in the early stage [7, 8]. As a result, fewer
than 20% of patients with RCC have overt metastasis
at the initial presentation [7].
Treatments for RCC includes radiation therapy,
chemotherapy, and surgical intervention. RCC is
relatively radioresistant. The response rate to radia-
tion therapy is 50% at best, and symptomatic recur-
rences are common [4–9]. Despite extensive evalu-
ation of many different treatment modalities, RCC
remains highly resistance to systemic therapy, and
the median survival of RCC patients is ~8 months.
About 10% to 20% of patients exhibit complete or
partial response to interferon and/or interleukin-2
with/without chemotherapy or each therapy alone,
with a durable response of >2 years in 5% or less [3].
In patients with localized disease, surgical resec-
tion of the primary tumor remains the mainstay of
therapy [7, 8].
Although metastasis to the bone represents an
advanced stage of underlying disease, it may be asso-
ciated with relatively prolonged survival. However,
reports of survival conflict in a range of less than
15% to more than 50% [4, 10]. Therefore, indications
for surgical intervention and the appropriate extent
of surgery remain controversial. Wide excision of
metastat ic lesions was advocated because of the un re-
sponsiveness of RCC to noninvasive measures, such
as chemotherapy and radiation therapy, and the pos-
sibility that survival may be relatively prolonged in
treated patients [10]. Existing reports on the surgical
management of metastatic RCC of bone have limited
value since they are based on only a small number of
patients or failed to mention the surgical technique
and its effect on local tumor control [10].
Most metastases from RCC are hypervascular
and tend to bleed massively during surgery [11].
Biopsies, open reductions, internal fixations, and
resections have been associated with an average
intraoperative blood loss of 1.5–3 L [12]. A blood loss
of 2000–18,500 ml (mean 6800 ml) was reported in
CONTENTS
15.1 Introduction 189
15.2 Clinical Features and Physiopathology 190
15.3 Angiography and Embolization Technique 190
15.3.1 Indications 190
15.3.2 Preprocedural Preparation 191
15.3.3 Angiographic Technique 191
15.3.4 Embolization Technique 191
15.4 Results 193
15.4.1 Obliteration of Tumor Blush / Estimated
Blood Loss 193
15.4.2 Osseous Healing and Survival 196
15.4.3 Complications 196
15.5 Conclusion 198
References 199
15.1
Introduction
The American Cancer Society estimates that there
w il l b e a pp ro x im at ely 36 ,16 0 n ew ca se s o f k i dn ey a nd
other urinary carcinomas in the U.S. in 2005. Renal
cell carcinoma (RCC) is the most common type of
kidney cancer in adults, accounting for 70% of the
tumors, i.e., approximately 25,312 new cases. Fur-
thermore, since the 1970s, incidence rates for RCC
have been increasing an average of 2% per year, but
recently this increase appears to be leveling off [1,
2]. Up to one-third of patients with RCC have metas-
tases at presentation [3]. Eighty percent of patients
with RCC eventually have metastases, and nearly
one-half of these patients have metastases to the
bone [4–6]. However, more recent reports indicated
that with the significant improvement of imaging
techniques, such as ultrasonography, computerized
tomography (CT), magnetic resonance imaging
(MRI), and positron emission tomography (PET),
190
S. Sun
20 patients operated on during the pre-emboliza-
tion era [13]. Preoperative embolization of these
lesions appears to be a safe and effective technique
to decrease intraoperative blood loss and the dura-
tio n of surger y, and thus r educe the s urgic al morbid-
ity/mortality and hospital stay [11–20]. Preoperative
embolization has become a standard measure for
this type of patient before surgical intervention.
15. 2
Clinical Features and Physiopathology
Due to its visceral location and the existence of a
second functional kidney, RCC is characterized by a
lack of early warning signs, resulting i n a high propor-
tion of patients with either locally advanced disease
or metastases already present at the time of diagnosis
[3, 21]. RCC metastases take place via the lymphatic
or venous routes. The lung parenchyma, bone, liver,
and brain are the most common sites of metastases
[3, 21, 22]. Although metastasis to the bone from RCC
ranks as approximately the sixth most common site,
compared to other tumors, this tumor has several
unique features that increase its significance: (1) the
metastases may occur many years (up to 10 years)
after the primary tumor has been treated surgically;
(2) the metastases may occur as a solitary lesion and
as such an en bloc surgical resection may render the
patient free of cancer and offer hope for a cure; (3)
even though the incidence of RCC is proportionally
small, the tumor has a high avidity for the skeletal
system and thus produces a relatively large number
of bone lesions; and (4) the bone lesions can be large,
with an average size of 7 cm in diameter, and have an
aggressive appearance [3, 19, 21, 22].
Pain is the most common presenting symptom.
Pathological fracture rarely occurs without a history
of a few weeks or months of increasingly severe pain.
S ys te mi c s ymp to ms m ay a ls o o cc u r, su c h a s hy po ca l -
caemia. Occasionally, patients may have hyperten-
sion from the tumor affecting the rennin-angioten-
sin pathway. RCC metastases most commonly affect
the spine, proximal long bone, pelvis, ribs, sternum,
and skull [3, 22, 23]. Since the kidney is comprised
of mostly blood vessels, RCC is normally a hyper-
vascular tumor. RCC metastases usually mimic the
primary tumor in vascularity, being hypervascular
in 65%–75% of patients, and bleeding extensively
(even audibly) after a simple biopsy [3, 8].
15. 3
Angiography and Embolization Technique
15. 3.1
Indications
Due to the fact that most embolization procedures
were performed preoperatively, surgical indications
dictate the number and extent of the procedures.
Indications for surgery are divided into two groups
according to signs of mechanical skeletal failure
(Table 15.1). For patients who required amputa-
tion or wide radical resection due to massive tumor
extension to the soft tissue with invasion of the major
neurovascular bundle of the extremity, preoperative
embolization may not be indicated [10]. Similarly, for
patient s wit h a sma ll, e asi ly acc ess ed lesion or wit h an
angiography-proven very hypovascular tumor, pre-
operative embolization may not be necessary [18].
Otherwise, all other patients should undergo preop-
erative embolization with the intent to obliterate all
tumor feeders and decrease intraoperative blood loss.
General indications for transcatheter embolization of
bone metastasis are listed in Table 15.2. Even though
listed, practically, the applications of this technique
in the indications other than preoperative emboliza-
Table 15.1. Indications for surgery
Without mechanical bone failure
• Solitary bone metastasis
• Intractable pain
With mechanical bone failure
• Impending or pathological fracture
Table 15.2. Indications for embolization of bone metastasis from RCC
Preoperative embolization (72%)
Control of hemorrhage
Inhibition of tumor growth
Reducing viable tumor volume to facilitate radiation or chemotherapy
Bone Metastases from Renal Cell Carcinoma: Preoperative Embolization 191
tion have been limited, with only sporadic reports in
the literature [11–20].
15. 3. 2
Preprocedural Preparation
Due to the preoperative nature of the procedure, the
orthopedic surgeon should do a complete work-up
of the patient to rule out all potential major medical
contraindications for surgery. Interventional radiol-
ogists should review every document available and
focus on issues related to the embolization proce-
dure. One should perform and document findings
of physical examination in terms of the patient’s
general condition, the status of affected limb, and
circulation of the extremities in order to set up a
baseline and compare with postembolization find-
ings later. For patients who have a history of contrast
allergy, premedication should be given according to
the institutional protocol. Routine preprocedure lab
tests include CBC, coagulation tests, and renal func-
tion tests. Patients may have impaired renal func-
tion due to previous nephrectomy for RCC. These
patients need to be sufficiently hydrated before the
embolization procedure. The amount of contrast
media given during the procedure should also be
limited if possible. For patients who have significant
coagulopathy, correction is necessary with Vitamin
K or transfusion of fresh frozen plasma or platelets.
Placing a Foley catheter may be helpful, as the embo-
lization procedure can be lengthy if multiple tumor
feeders need to be embolized, and since the patient
may have a pathological fracture, ambulation could
be difficult. Furthermore, for patients with a pend-
ing pathological fracture, early ambulation postem-
bolization may complicate the pathological fracture
[19]. A review of available imaging studies is impera-
tive for choosing a treatment plan. Consents for the
procedure and conscious sedation are obtained rou-
tinely. Whether or not one should give prophylactic
antibiotics routinely before the procedure is contro-
versial. Most authors do not prescribe antibiotics for
the purpose of prophylaxis [18–20].
15.3.3
Angiographic Technique
Most preoperative embolizations can be performed
under intravenous conscious sedation via a trans-
femoral approach. Lesions in the proximal femur are
treated from the contralateral approach. Lesions in
the distal femur may be accessed in an ipsilateral
antegrade fashion to facilitate catheter manipula-
tion [19]. For lesions located in the pelvis and upper
extremities, a right femoral approach is routinely
used. A 5-F sheath is used for most procedures. A 5-F
Davis catheter, JB-1 or Cobra visceral catheter is com-
monly used for selective catheterization. Microcath-
eters such as the 2.9-F Renegate Super-flow (Boston
Scientific) through a coaxial system are used for
superselective catheterization that allows a safe and
effective embolization of the tumor feeders.
The pre-embolization arteriogram should be
started at the main territory artery in order to cover
the entire area and identify all tumor feeders. For
example, a distal abdominal aortogram or common
iliac arteriogram should be performed when a
tumor is located in the proximal femur, because
the tumor may derive blood from superior/inferior
gluteal arteries, medial/lateral circumflex femoral
arteries, and descending muscular branches from
the profunda femoris artery. In rare situations, the
obturator and internal pudendal arteries from the
anterior group of the internal iliac artery may also
provide blood supply to the tumor. The postem-
bolization arteriogram should include all possible
collateral pathways, because untreated collater-
als may become more prominent after occlusion
of other feeders (Fig. 15.1a–c). The amount of con-
trast medium given during an arteriogram must be
sufficient to make all possible tumor feeders well-
opacified. Therefore, in addition to an appropriate
injection rate, the period of injection should also be
long enough (lasting more than 3 sec). The acqui-
sition should be long enough to cover all phases
of the arteriogram (arterial, capillary, and venous
phase) to document tumor vascularity and arterial
to venous shunting. Frequently, multiple selective
arteriograms in different projections may be neces-
sary in order to show the origin of a tumor feeder
in profile and facilitate superselective catheteriza-
tion. The fluoro-fade, or road mapping, technique is
available for use with most modern digital arterio-
graphic equipment. This is very helpful for superse-
lective catheterization, especially when a tumor is
located in the extremities (reduced artifacts caused
by movements of breathing and bowel peristalses).
15. 3.4
Embolization Technique
Thus far, there has been no single embolic agent
that is ideal for preoperative embolization of bone
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metastases from RCC. An ideal embolic agent should
be easily delivered through a microcatheter, should
reach and permanently occlude small blood ves-
sels deep within the tumor, and should be nontoxic
and easy to prepare and control during delivery.
Different embolic agents have been used for pre-
operative embolization of bone metastases from
RCC, including absolute alcohol, tissue adhesives,
coils, gelatin sponge, Embospheres, and polyvinyl
alcohol particles (PVA) [11–20, 24–31]. The use of
liquid embolic agents (e.g., ethanol, tissue adhesive)
was not advocated for preoperative embolization of
bone metastasis since they may be associated with
a high rate of complications (even in experienced
hands) such as tissue ischemia, skin necrosis, and
neurologic impairment when used for spinal metas-
tasis [13]. Coils are a permanent embolic agent, but
they induce relatively proximal occlusion of target
vessels, and thus are less effective for decreasing
estimated blood loss (EBL), because bone metastasis
from RCC shows angiomatous vascularization that
may reconstitute collaterals within hours. Practi-
cally, it is not uncommon to find new tumor feeders
that were not evident on the preembolization angio-
gram, immediately after the major feeders were
occluded. Coil embolization made no significant
difference in EBL compared with a control group
in hypervascular spinal lesions [13, 19]. The same
studies also suggested that the additional use of coils
after PVA particles provides no further benefit.
Gelfoam particles have been used in the early stage
of preoperative embolization of bone metastasis. Due
to the fact that it is biologically degradable and not
definite in size, Gelfoam pledge only creates proxi-
mal and temporary occlusion of target vessels. Early
recanalization and revascularization of embolized
vessels h ave been observed, wh ich resulted in u nfavor-
able outcomes regarding EBL. Therefore, compared
Fig. 15.1a–c. Collateral supply of tumor vessels. a Pre-embolization arte-
riogram. Tumor supply from branches of the right lateral femoral circum-
fl ex (large arrow), profunda (small arrow), and the superior gluteal (arrow
heads) arteries. b Superselective catheterization of the lateral femoral cir-
cumfl ex artery. Note that the descending branches do not supply the tumor
(arrow). c Arteriogram after embolization of the tumor with PVA. Note sub-
traction artifact from coil (large arrow) that was placed into the descending
branch of lateral femoral circumfl ex artery before PVA embolization. Also
note that gluteal supply is more obvious after embolization of the main
tumor feeders (small arrows)
a b
c
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