REVIEW/STATE OF THE ART

Radioembolization with 90Y Microspheres: Angiographic andTechnical Considerations

Robert J. Lewandowski Æ Kent T. Sato Æ Bassel Atassi Æ Robert K. Ryu ÆAlbert A. Nemcek Jr. Æ Laura Kulik Æ Jean-Francois Geschwind ÆRavi Murthy Æ William Rilling Æ David Liu Æ Lourens Bester ÆJose Ignacio Bilbao Æ Andrew S. Kennedy Æ Reed A. Omary Æ Riad Salem

Received: 26 March 2007 / Revised: 26 March 2007 / Accepted: 1 April 2007

� Springer Science+Business Media, LLC 2007

Abstract The anatomy of the mesenteric system and the

hepatic arterial bed has been demonstrated to have a high

degree of variation. This is important when considering

pre-surgical planning, catheterization, and trans-arterial

hepatic therapies. Although anatomical variants have been

well described, the characterization and understanding of

regional hepatic perfusion in the context of radioemboli-

zation have not been studied with great depth. The purpose

of this review is to provide a thorough discussion and

detailed presentation of the angiographic and technical

aspects of radioembolization. Normal vascular anatomy,

commonly encountered variants, and factors involved in

changes to regional perfusion in the presence of liver tu-

mors are discussed. Furthermore, the principles described

here apply to all liver-directed transarterial therapies.

Keywords Brachytherapy � Radioembolization �Yttrium-90 � Liver cancer � Embolization � SIR-Spheres �TheraSphere � Selective internal radiation

Introduction

As the incidence of primary and metastatic liver cancer

continues to increase [1, 2], the use of minimally invasive

techniques as a treatment option is becoming more com-

D. Liu

Inland Imaging LLC, Angio/Interventional Section Providence/

Sacred Heart Medical Center, Spokane, WA, USA

L. Bester

Department of Interventional Radiology, University of New

South Wales, Sydney, Australia

J. I. Bilbao

Departamento de Radiologia, Clinica Universitaria de Navarra,

Pamplona, Navarra, Spain

A. S. Kennedy

Wake Radiology Oncology, Cary, NC, USA

R. Salem (&)

Department of Radiology, 676 North St. Claire, Suite 800,

Chicago, IL 60611, USA

e-mail: r-salem@northwestern.edu

R.S. and J.-F.G. are consultants for MDS Nordion. R.M., D.L., L.B.,

and J.I.B. are proctors for Sirtex Medical. A.S.K. has received

honoraria from MDS Nordion and Sirtex Medical. This work was not

funded.

R. J. Lewandowski � K. T. Sato � B. Atassi �R. K. Ryu � A. A. Nemcek Jr. � R. A. Omary �R. Salem

Department of Radiology, Section of Interventional Radiology,

Northwestern Memorial Hospital, Robert H. Lurie

Comprehensive Cancer Center, Chicago, IL, USA

L. Kulik

Department of Hepatology, Northwestern University, Chicago,

IL, USA

J.-F. Geschwind

Department of Radiology, Section of Interventional Radiology,

The Johns Hopkins Hospital, Baltimore, MD, USA

R. Murthy

Department of Radiology, Section of Interventional Radiology,

MD Anderson Cancer Center, University of Texas, Houston, TX,

USA

W. Rilling

Department of Radiology, Section of Interventional Radiology,

Medical College of Wisconsin, Milwaukee, WI, USA

123

Cardiovasc Intervent Radiol

DOI 10.1007/s00270-007-9064-z

mon. Percutaneous interventions such as radiofrequency

ablation, cryoablation, and percutaneous ethanol ablation

have been shown to be effective for the treatment of small

liver tumors [3–5]. Similarly, endovascular techniques such

as transcatheter arterial chemoembolization (TACE) and

transcatheter arterial embolization (TAE) have shown

clinical benefit in selected patients [6–8].

Recently a new form of transarterial therapy involving

infusion of radioactive microparticles has been developed,

and has shown promise for the treatment of patients with

liver tumors. Radioembolization, a form of intra-arterial

brachytherapy, is a technique where particles of glass or

resin, impregnated with the isotope yttrium-90 (90Y), are

infused through a catheter directly into the hepatic arteries.90Y is a pure b emitter and decays to stable Zr-90 with a

physical half-life of 64.1 h. The average energy of the bparticles is 0.9367 MeV, has a mean tissue penetration of

2.5 mm, and has a maximum penetration of 10 mm. There

are currently two commercially available agents: SIR-

Spheres (Sirtex Medical Ltd., Lane Cove, Australia), and

TheraSphere (MDS Nordion, Ottawa, Canada). Radio-

embolization refers to the use of TheraSphere, SIR-

Spheres, or other microsphere agents that have the emis-

sion of radiation as their primary and microembolization as

their secondary modes of action. For the purposes of this

review, unless otherwise specified, radioembolization re-

fers to all such devices.

TheraSphere was approved by the U.S. Food and Drug

Administration (FDA) in 1999 under a humanitarian device

exemption, defined as safe and probably beneficial for the

approved indication. The approval was for treatment of

unresectable hepatocellular carcinoma (HCC), with or

without portal vein thrombosis, or as a bridge to trans-

plantation in patients who could have appropriately posi-

tioned catheters. This device is also approved for the

treatment of liver neoplasia in Europe. Its composition is

that of nonbiodegradable glass microspheres where 90Y is

an integral constituent of the glass and, therefore, cannot

leach. Ninety-five percent of the particles are between 15

and 35 lm in diameter. Each microsphere contains 2500

Bq of activity at the time of calibration. Available activity

vials are 3, 5, 7, 10, 15, and 20 GBq, corresponding to 1.2

million, 2 million, 2.8 million, 4 million, 6 million, and 8

million microspheres per activity vial, respectively [9]. As

opposed to SIR-Spheres, the vial cannot be split, and

hence, the entire vial of TheraSphere must be injected

during the administration.

SIR-Spheres were granted premarket approval by the

FDA in 2002, defined as safe and effective for the approved

indication. The indication is for the treatment of metastatic

colorectal cancer to the liver with concomitant use of

floxuridine (FUDR). This device is also approved in Eur-

ope, Australia, and various Asian countries for liver neo-

plasia. SIR-Spheres are resin-based particles,

approximately 29–35 lm in diameter, in which the 90Y and

resin are intimately bound. The standard activity vial is 3

GBq, of which a predetermined amount is decanted in the

nuclear medicine pharmacy from the vial for injection into

the patient. A 3-GBq activity vial contains between 40

million and 80 million microspheres [10]. Each micro-

sphere contains 50 Bq of activity at the time of calibration.

Once the particles are infused through the catheter into

the hepatic artery, they travel to the distal arterioles within

the tumors, where the b-emissions from the isotope irra-

diate the tumor. With traditional external beam radiation to

the liver, doses are limited to 30–40 Gray (Gy) due to the

risk of radiation-induced liver disease (radiation hepatitis)

that may occur with higher doses [11, 12]. With radio-

embolization, tumors receive a much higher dose of radi-

ation given the direct arterial deliver of the microspheres,

as well as the hypervascularity of the tumors and target

tissue. Hence, radiation doses that are significantly higher

can be delivered directly to the tumor with minimal irra-

diation of normal liver tissue. This has been shown to be

effective for both primary and metastatic tumors [13–18].

Radioembolization is defined as the injection of embolic

particles loaded with a radioisotope using percutaneous

transarterial techniques. There are two distinct aspects to

the procedure: the first being the injection of embolic

particles (‘‘embolization’’) as the vehicle and the second

being the delivery and administration, via this embolic

vehicle, of radiation (‘‘radio’’). Fluoroscopic guidance,

angiographic end points of embolization and stasis, and the

need to modify this based on angiographic findings make

this treatment a true embolization procedure. Furthermore,

the administration and delivery of radiation, modification

of dose based on tumor and hepatic volume, and required

knowledge of radiation effects on tissue make this a

brachytherapy procedure as well. There is a spectrum of

radioembolic effect that exists with this therapy: with

TheraSphere, there is high specific activity and a small

number of microspheres (mild radioembolic effect); with

SIR-Spheres, there is low specific activity and a large

number of microspheres (moderate/high radioembolic ef-

fect). It is this varying number of microspheres, embolic

effect, and possible vascular saturation that makes fluoro-

scopic observation necessary.

These technical aspects of radioembolization are an in-

terventional radiology procedure almost in its entirety.

Given this, it is important that interventional radiologists

play a leading role in the future evolution of this technol-

ogy, including angiographic delivery, dosimetry, and

overall technical enhancements in radioembolization.

Depending on institutional policies and hospital radiation

safety committees, interventional radiologists (IRs) should

function in a collegial manner with other authorized users

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

of brachytherapy devices such as radiation oncologists and

nuclear medicine physicians. Although local regulatory

bodies may impose some hurdles that limit the ability of

IRs from performing radioembolization independently, this

model should not be discouraged. Many successful radio-

embolization practices involving the interventional radiol-

ogists as authorized user have been established, supporting

this practice model [19, 20]. IRs receive formal didactic

training in radiation biology, radiation physics, and radia-

tion safety, making them fully able to undertake roles and

responsibilities of authorized users. In most clinical or

hospital settings, radiologists, radiation oncologists and

nuclear medicine physicians are the most knowledgeable in

matters regarding radiation and radiation safety. Interven-

tional radiologists also provide the full spectrum of patient

clinical care services—from consultation and initial patient

evaluation to actual performance of the procedure, post-

operative care, and follow-up care. Hence, IRs (as well as

nuclear medicine and radiation oncology physicians) are

ideally suited to be authorized users for this therapy.

The principles described in this review represent the

international collective angiographic experience of the

authors accumulated over 2000 90Y infusions in over 1000

patients at eight major internationally renowned cancer

centers. They are meant to provide an in-depth review and

stimulate dialogue in the interventional radiology com-

munity on optimizing and improving the techniques used

for radioembolization. Also, the angiographic techniques

described herein may be applied to radioembolization

using radioisotopes other than 90Y (holmium, rhenium).

Finally, although the focus of this article is radioemboli-

zation with 90Y, the angiographic concepts described

herein apply to all transarterial therapies, including TACE,

TAE, and drug-eluting microspheres.

Patient Selection

With both devices, patient selection criteria are similar.

Patients should have a reasonable performance status.

Using the Eastern Cooperative Oncology Group (ECOG)

criteria, a score of 0–2 is acceptable. If Karnofsky perfor-

mance status is used, a score of at least 60 (requires

occasional assistance, but is able to care for most personal

needs) is necessary. In general, patients must have non-

compromised pulmonary function, be able to undergo

angiography and selective visceral catheterization, have

adequate hematology (platelet count >75 · 109/L [unless

closure devices are used]), serum creatinine <2.0 mg/dl,

and adequate liver function. An in-depth discussion of

patient selection criteria has been published previously

[21].

The optimal selection criteria for patients with HCC

have been described previously [22, 23]. For patients with

HCC, the tumor volume should be less than 70% of the

total liver volume, not have infiltrative disease or main

portal vein thrombosis, and have alanine or aspartate

aminotransferase levels less than five times the upper-

normal limit. Radioembolization may be undertaken in the

setting of abnormal/elevated liver function if a segmental

infusion can be performed, without significant impact on

liver functions [24, 25]. Patients with metastatic liver dis-

ease should have normal liver function tests and acceptable

performance status.

Portal vein thrombosis has been seen as a relative con-

traindication for such treatments as TACE; however, it is

not necessarily a contraindication for radioembolization.

TheraSphere is indicated for patients with PVT and has

been shown to be safe in this setting, even when the portal

vein has been invaded by tumor [9, 26]. SIR-Spheres are

contraindicated in the setting of portal vein thrombosis, as

the number of particles in a typical vial may result in

embolic occlusion of the parent vessel [27]. Hence, if SIR-

Spheres are to be used in the setting of PVT, dose frac-

tionation should be considered.

Other exclusionary criteria include immediate life-

threatening extrahepatic disease, uncorrectable flow to the

gastrointestinal (GI) tract, and hepatopulmonary lung

shunting. For TheraSphere, the limitation of what can be

administered to the lungs is based on cumulative dose,

irrespective of lung shunt [9]. Although the literature

supports the safety of a 50-Gy cumulative lung dose, cer-

tain centers use the more conservative 30 Gy (16.5 mCi).

For SIR-Spheres, infusion is limited by the lung shunt

fraction (20%). Activity of SIR-Spheres infused is adjusted

based on tumor volume and lung shunt fraction [10].

Dosimetric and device-specific technical considerations are

not addressed in this article, as these have been discussed

in depth by previous authors [13, 16, 17, 21, 28–30].

Technical Considerations

Angiographic Evaluation

Once a patient has been selected as a candidate for radio-

embolization, an initial angiographic evaluation is per-

formed. The proper sequence of vessels to be addressed

and evaluated has been published previously [31]. This is

done primarily to document the visceral anatomy, identify

anatomic variants, and isolate the hepatic circulation by

occluding extrahepatic vessels [32]. The technique includes

standard visceral angiography using a hooked catheter such

as a Cobra-2 (Boston Scientific, Natick, MA), Sos Omni

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

select (Angiodynamics, Queensbury, NY), or a Simmons-

1/2/3 (Cook, Bloomington, IN). Once an abdominal

aortogram has been performed, a superior mesenteric

arteriogram is performed to assess for the presence of

accessory or replaced hepatic arteries arising from the

superior mesenteric artery (SMA). A venous phase is also

obtained to evaluate the status/patency of the portal vein.

Next, the celiac trunk is selectively catheterized to evaluate

the hepatic arterial supply. Subsequent to celiac injection, it

is imperative that selective right and left hepatic angiog-

raphy with power injection angiography be performed,

usually with 3-French microcatheter systems (Renegade

High-Flow; Boston Scientific, Natick, MA, or Progreat,

Somerset, NJ). This will allow for the identification of

variant mesenteric anatomy and subsequent prophylactic

embolization of extrahepatic vessels such as the right

gastric, gastroduodenal, or falciform artery. Other vessels

that may be identified and may require prophylactic

embolization include the supraduodenal, retroduodenal,

left inferior phrenic, accessory left gastric, and inferior

esophageal. Care should be taken when considering

embolization of the gastroduodenal artery (GDA), as

accessory hepatic vessels feeding tumor may arise from

this artery [31].

The following is the technical protocol for mapping

mesenteric angiography that is recommended prior to ra-

dioembolization. This is meant as guidance and should be

modified accordingly based on institutional standards. The

particular rationale for each step is described in detail.

Following radiation safety, optimization of imaging (fil-

tering) and power injection (not hand injection) are highly

recommended.

Abdominal aorta: injection of 15 ml/s for 30 ml. The

reasons for this step include identification of patent celiac,

SMA, and aortic tortuosity, as well as guiding proper vis-

ceral catheter selection. For example, SMA and celiac

vessels that have acute angles are best catheterized by re-

verse curve catheters such as the Sos-Omni (Angiody-

namics, Queensbury, NY) and Simmons (Cook,

Bloomington, IN). Otherwise, C-shaped catheters may be

used routinely.

Fig. 1 A Selective SMA

injection shows a common

hepatic artery (C) arising from

it, with the right hepatic (R) and

left hepatic (L) arteries

branching in standard fashion. BReplaced common hepatic

artery. C Celiacomesenteric

trunk seen on aortography. DAccessory right hepatic arising

off the SMA perfusing segments

6/7

Fig. 2 HCC causing parasitization from the SMA

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

Superior mesenteric artery : injection of 3 ml/s for 30

ml. Although several institutions use rates such as 6–7 ml/s

for 60–70 ml, we use a more conservative approach. Using

a 3 ml/s for 30 ml injection allows for the identification of a

replaced right hepatic, replaced proper hepatic (Fig. 1a),

replaced common hepatic (Fig. 1b) celiacomesenteric

trunk (Fig. 1c), accessory right hepatic (Fig. 1d), patency

of the portal vein, and the rare parasitization of blood flow

from the SMA to the liver (Fig. 2). Furthermore, contrast

use is preserved and not refluxed into the aorta, which

usually occurs with injection rates that are higher than

those advocated herein. Retrograde flow (from tumor

sumping, or celiac occlusion/stenosis) into the GDA is also

assessed. Finally, contrast is preserved for injections that

matter most, such as may be required during angiography

and embolization of the hepatic and extrahepatic vessels.

Celiac artery: injection of 3–4 ml/s for 12–15 ml.

Classic branches of the celiac artery include the splenic,

common hepatic, and left gastric arteries. Interrogation of

the celiac trunk allows for assessment of the celiac anat-

omy and identifies the presence of any possible variants,

including a replaced left hepatic artery arising off the left

gastric (gastrohepatic trunk) as well as the right and left

inferior phrenic arteries. In the presence of such variants,

selective catheterization of these vessels should be per-

formed. Catheterization of the replaced left hepatic artery

Fig. 3 A Common hepatic arteriogram demonstrates small extrahe-

patic perforating branches (arrows). Reflux into the common hepatic

artery may result in inadvertent gastritis, duodenitis, and pancreatitis.

B Common hepatic angiogram demonstrates a trifurcation into a

GDA and right and left hepatic arteries. C Injection with reflux

demonstrates the patient to have the ‘‘double hepatic’’ artery variant

Fig. 4 A Triphasic CT

demonstrates right lobe lesions.

Lesions (arrows) did not

respond to right lobe treatment,

while response and tumor

shrinkage were seen in the third

and smaller lesion (arrowhead).

B CT angiogram via the right

hepatic artery demonstrates lack

of opacification of the two

tumors (arrows), but

opacification of the more

posterior lesion that did respond

to Y90 (arrowhead). C GDA

angiogram demonstrates a

hypertrophied epiploic vessel

(arrows) providing flow to the

medial tumor. D Epiploic artery

catheterization. E Injection of

epiploic artery demonstrates

opacification of the medial

tumor. F CT angiogram via the

hypertrophied epiploic artery

provides flow to the medial

tumor (arrow). The patient

underwent successful Y90

treatment from this location. GRight inferior phrenic

arteriogram demonstrates

parasitization of flow to the

lateral tumor, successfully

treated

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

should be performed and an injection rate selected that

would not result in gastric/esophageal artery reflux. If re-

flux is a possibility depending on the radioembolic device

used, prophylactic embolization of the left gastric should

be undertaken. In the presence of a gastrohepatic trunk, it is

quite common for several small esophageal, phrenic, and

gastric perforators to be present, particularly at the hori-

zontal portion of the left hepatic artery variant. Consider-

ation of embolization of these vessels should be made,

functionally converting the gastrohepatic trunk into a left

hepatic artery. In the presence of large hepatic tumors,

particularly in the dome of the liver, the right inferior

phrenic may be a source of parasitization of blood flow.

Although this occurs in patients with metastases, it is more

common in cases of HCC. Injection of this vessel will

result in the proper outlining of blood flow to tumor and

will allow for optimization of transarterial therapy. Finally,

the dorsal pancreatic artery may arise off the celiac. Its

presence should be recognized and the possibility of reflux

into this vessel should be recognized if excessive micro-

spheres are injected within the hepatic circulation.

Common hepatic artery (CHA): injection rate of 3 ml/s

for 12 ml. The use of the same injection rate as the celiac

artery allows for the ‘‘flooding’’ of the hepatic circulation,

optimizing the likelihood that extrahepatic vessels will be

identified. Vessels of note that may require embolization

arising off the common hepatic include the right gastric,

dorsal pancreatic, and gastroduodenal (Fig. 3a). Other

complex variants exist. (1) A replaced right hepatic artery

off the SMA with a trifurcation from the CHA into a GDA

and left hepatic arteries (possibly also a middle hepatic). In

such cases, a right gastric is often seen, and unless seg-

mental infusions of radioembolization are planned, the

GDA/right gastric should be embolized. This functionally

converts the CHA (in the presence of a replaced right he-

patic) into a left hepatic artery. (2) Trifurcation of the CHA

into a GDA, right, and left hepatic arteries. Given the low

margin of error if reflux occurs from a lobar or segmental

infusion, the GDA should be embolized in this case. (3)

‘‘Double hepatic’’ artery: a very early takeoff of the right

hepatic artery. Unless sufficient contrast is injected and

refluxed to the origin of the celiac, this vessel may be

missed (Figs. 3b and c). Finally, in some cases, the dorsal

pancreatic artery arising off the CHA may be large enough

that prophylactic embolization may be considered. Given

the rich collaterals to the pancreas, embolization of the

dorsal pancreatic is safe, since this would result in

recruitment of flow from the pancreatica magna and the

Fig. 5 A Left hepatic

arteriogram demonstrates a

vessel clearly coursing outside

the expected confines of the left

lobe of the liver (arrow). BCatheterization confirms that

this is the left inferior phrenic

artery. C Coil embolization of

this vessel. D Left hepatic

arteriogram demonstrates three

vessels. Arrow points to

extrahepatic vessel. A

hypervascular tumor is seen. EInjection of this vessel confirms

that it is the left inferior phrenic

artery (arrows). F Left hepatic

arteriogram demonstrates a

vessel clearly coursing outside

the expected location of the left

lobe of the liver (arrows). GInterrogation of this vessel

confirms that it is the inferior

esophageal artery. Note

opacification of the stomach and

esophagus, as well as the

coronary vein. HPostembolization of the inferior

esophageal demonstrates

complete coil occlusion (arrow)

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

caudal pancreatic arteries. Nontarget radioembolization of

the pancreatic vessels may result in pancreatitis [31].

Gastroduodenal artery: injection rate of 2 ml/s for 8 ml.

Vessels sought include the (accessory) cystic artery,

superior pancreaticoduodenal, and parasitization of flow to

the liver from the GDA or from its branches (right gas-

troepiploic, omental/epiploic branches) (Fig. 4), as well as

accessory hepatic arteries (usually providing flow to seg-

ment 5 or 6) [31]. Given the clinically inconsequential

effects, prophylactic embolization of the GDA is recom-

mended if a highly radioembolic device is to be considered.

Settings where the GDA might not be embolized include

where there is parasitization of flow to liver that may re-

quire future catheterization and radioembolization, where

there is retrograde flow from the SMA from either hyper-

dynamic flow or celiac stenosis, or a minimally embolic

device is considered. In cases of GDA parasitization to

segments 5/6, embolization of all distal vessels except the

one feeding the liver tumors is recommended if possible,

essentially converting the GDA into an accessory hepatic

vessel feeding the tumor vasculature. Otherwise, if com-

plete embolization of the GDA is undertaken, it should be

embolized to the origin of the vessel, as small, very

proximal GDA branches may hypertrophy in response to

incomplete embolization.

Proper hepatic angiogram: 3 ml/s for 12 ml. Injection of

this vessel at this rate will often result in supraphysiolog-

ical flow rates and reflux but will opacify small and often

overlooked vessels. The vessel most commonly of interest

upon assessment of this vessel is the right gastric artery. At

times, the right gastric artery may have two parallel bran-

ches, both of which may require prophylactic embolization.

Left hepatic angiogram: injection of 2 ml/s for 8 ml.

Vessels of interest here include the left inferior phrenic

artery, accessory left gastric artery, inferior esophageal

artery, right gastric artery, and falciform artery (Figs. 5 and

6) [33]. Prophylactic embolization of these vessels may

decrease adverse events following radioembolization, such

as abdominal pain, gastritis, and ulceration. Furthermore,

delayed imaging of the left hepatic angiogram is recom-

mended in order to confirm the lack of opacification of the

coronary vein. Finally, injection of the left hepatic artery

Fig. 6 A Left hepatic

arteriogram demonstrates a

falciform artery (arrows). BSelective catheterization of the

falciform artery (arrow). CSuccessful embolization of the

falciform artery (arrow). DCeliac angiogram demonstrates

patent GDA, right and left

hepatic arteries. E Left hepatic

angiogram demonstrates a

patent falciform artery (arrow).

F Arrow points to the

‘‘falciform artery complex’’. GSuccessful embolization of the

GDA and falciform artery

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

should outline where there is flow to segment 4 via the

medial branch. If the medial branch is absent, a separate

middle hepatic artery should be sought, usually off the

right hepatic artery.

Right hepatic angiogram: injection of 2 ml/s for 10–12

ml. Vessels of interest include the middle hepatic artery,

supraduodenal, and cystic artery. In some cases of (large)

HCCs, a hypertrophied caudate artery may require angio-

graphic interrogation (Fig. 7). Also, selective injection may

identify the vascular dynamics that may be underappreci-

ated using cross-sectional imaging. For example, although

metastatic colorectal cancer carries the label of ‘‘hypo-

vascular,’’ selective injection often demonstrates the

opposite (Fig. 8). Finally, in rare instances, the right he-

patic artery may arise directly from the aorta (Fig. 9).

Phrenic arteries (right and left): injection of 1–2 ml/s

for 4–6 ml. Depending on the findings of the hepatic

angiogram, if a portion of the liver tumor (especially HCC)

is not visualized angiographically, interrogating this vessel

may identify the remainder of the flow to the tumor

(Fig. 10) [31]. Interrogating the right inferior phrenic and

other extrahepatic vessel parasitizing to liver tumors

(omental, intercostals, internal mammary) should be sus-

pected when tumors in the same vascular distribution re-

spond differently (Fig. 4). Tumors in the dome of the right

lobe may have parasitization from this vessel.

As can be noted from the above protocol, complete

mesenteric angiography and embolization can be per-

formed with 150 ml of contrast or less. Prophylactic

embolization of the above-mentioned vessels essentially

functions to convert the hepatic blood flow into one that is

analogous to surgically placed hepatic arterial ports. Usu-

ally, in surgical port placement, the CHA is skeletonized,

the GDA and right gastric are ligated, and any other he-

patic-mesenteric or extrahepatic vessels are ligated. This is

identical to what is accomplished with the above-described

angiographic technique. Furthermore, it is important that

all hepatic vessels be interrogated during the initial

angiographic assessment of the patient. Given the pro-

pensity of tumors to parasitize blood flow from vessels

other than the actual tumor location, only such direct

catheterization and interrogation of all vessels would

demonstrate this phenomenon (Fig. 11). The lack of rec-

ognition of this phenomenon may result in incomplete

treatment of the target tumor bed irrespective of the tran-

sarterial treatment modality that is used.

Once the anatomy has been established, selective arte-

riography is performed in the expected location of the 90Y

treatment. Microcatheters should be used, particularly if

the vessels are small in caliber or demonstrate significant

tortuosity (Renegade Hi-flow [Boston Scientific, Natick,

MA], Progreat [Terumo, Somerset, NJ], or 2.3-French

Prowler Plus [Cordis, Miami, FL]). Once a catheter has

been placed into the appropriate location, the presence of

any lung shunting through the tumor must be determined.

The lung-shunt fraction, F (fraction of Tc-99m macroag-

gregated albumin [MAA] observed in the lungs relative to

the total Tc-99m MAA activity observed), can be deter-

mined by infusing 4 mCi of Tc-99m labeled MAA particles

through the catheter into the desired liver distribution.

MAA particles range in size from 10 to 60 lm, with a mean

diameter of 35 lm. The same technique is used for both

SIR-Spheres and TheraSphere and gives an accurate esti-

mate of distribution of 90Y microspheres. The Tc-99m

MAA scan can also demonstrate the presence of any GI

flow. The shunting evaluation allows the physician to plan

Fig. 7 A Pretreatment MRI of a

caudate lobe (segment 1) HCC

(arrows). B Common hepatic

arteriogram demonstrates a

hypertrophied caudate artery

(arrows). C Selective

catheterization with a Prowler

Plus (Cordis, Miami, FL)

demonstrates tumor

hypervascularity. D One-year-

posttreatment MRI

demonstrates necrosis and near-

complete involution of the

caudate HCC

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for radioembolization therapy and minimize any uncer-

tainty in microspheres distribution at the time of treatment.

It is recommended that MAA injection be performed

once all vessels of concern have been embolized. In all

cases of metastases, injection is performed in the proper

hepatic artery, given the low incidence of lung shunting in

patients with metastatic disease to the liver (unless very

high tumor burden is present) [21]. In contrast, the ap-

proach to MAA injection in patients with HCC is slightly

different. If the patient has bilobar HCC, proper hepatic

artery injection of MAA is performed unless gross vascular

shunting into the hepatic or portal vein is seen. The

shunting fraction obtained is assumed to be representative

of the tumors in both lobes of the liver. In cases of bilobar

disease where angiographic shunting is seen, a unilobar

injection of MAA is performed and only one lobe is as-

sessed at any one time. A repeat MAA injection is per-

formed at a later date when the second treatment site

requires treatment.

It is important to note that in cases where variant arterial

anatomy exists, the MAA should be fractionated in order to

cover the entire liver in one setting if possible, saving the

patient an unnecessary catheterization. For example, in

cases where there is a replaced right hepatic artery, 2–3

mCi of MAA is given in that vessel, while the remaining

1–2 mCi is given in the left hepatic. In cases of a gastro-

Fig. 8 A Proper hepatic

angiogram clearly demonstrates

hypervascular tumors that were

described as ‘‘hypovascular’’

on cross-sectional imaging (CT)

(arrows). B ‘‘Hypovascular’’

metastases from colon

metastases. C Hepatic

angiogram does not demonstrate

hypervascularity on

fluoroscopy. D CT angiography

confirms hypervascularity of

tumors. E Six-month follow-up

after radioembolization

confirms excellent response.

F Bilobar ‘‘hypovascular’’

colorectal metastases. GHepatic angiography (left)

confirms the metastases are in

fact ‘‘hypervascular’’

Fig. 9 A Reflux of contrast into

aorta from an SMA injection

shows an unusual branch arising

from the right side (arrow). BSelective injection of this vessel

shows it to be a right hepatic

artery arising directly from the

aorta

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

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hepatic trunk, 1–2 mCi of MAA is injected in the left

hepatic, while the remainder is injected in the right hepatic

artery.

Variant Mesenteric Anatomy

In 55% to 65% of cases [34], the celiac artery gives rise to

the splenic artery, left gastric artery, and CHA. The dorsal

pancreatic artery commonly arises from the celiac origin,

although it may also arise off the CHA or splenic [31]. The

CHA then gives rise to the GDA and becomes the proper

hepatic artery, which divides into the right and left hepatic

arteries. When a distinct vessel arising from the right he-

patic artery provides flow to segment IV, it is referred to as

the middle hepatic artery (Fig. 11). In more than 40% of

cases, the origin and course of the hepatic arteries vary, as

does the vascular distribution of the vessel irrespective of

its anticipated course [34]. Vessels supplying one segment

may be recruited to provide flow to other anatomic seg-

ments (Fig. 11). The most common variants include a re-

placed right hepatic artery which arises from the SMA, a

replaced CHA (Fig. 1) arising from the SMA, and bifur-

cation of a short CHA into right and left hepatic arteries.

The right and left hepatic arteries may arise separately

from the celiac trunk, or directly from the aorta (Fig. 9).

The caudate lobe most commonly receives its blood supply

from a small branch off the left or right hepatic artery. This

caudate artery is normally rather diminutive; however, it

may become quite prominent in the setting of tumor,

thereby allowing selective catheterization and treatment

(Fig. 7). Given that traditional TACE and other large-par-

ticle-type therapy involves a high-viscosity chemothera-

peutic agent as well as embolic particles (300–700 lm), the

use of significantly smaller 90Y microspheres (20–60 lm)

are particularly advantageous in the setting of diminutive

vasculature (Fig. 7).

Extrahepatic Vasculature

The identification and isolation of the hepatic vasculature

are critical when performing radioembolization. One dev-

astating complication is extrahepatic delivery of 90Y par-

ticles, most commonly to the GI tract, invariably leading to

severe gastritis and possibly even ulceration [35, 36]. Al-

though some gastric and duodenal ulcers can be treated

medically, it is also possible for surgical intervention to be

required. In cases where GI ulceration or radiation gastritis

is suspected as an adverse event, patients should undergo

endoscopy for confirmation of ulceration and location of

injury, as well as to assess the size of the ulcer. Giant (>3-

cm) ulcers are at times unlikely to heal using medical

therapy [37, 38]. Also, as opposed to standard GI ulcers,

radioembolization-induced ulceration is caused from the

serosal surface, possibly decreasing the ability for the ulcer

to heal or be seen using endoscopy. Hence, every effort

should be made to minimize the risk of nontarget 90Y

administration.

The largest extrahepatic vessel is the GDA. Normally,

this vessel provides branches to the duodenum, pancreas,

and stomach. Angiographic assessment of this vessel is

important not only prior to embolization, but also to assessFig. 10 Right inferior phrenic arteriogram demonstrating significant

parasitization of blood flow to hepatic tumors (arrows)

Fig. 11 Proper hepatic

angiogram demonstrates tumor

blush in the right lobe. B Middle

hepatic artery injection

demonstrates parasitization of

flow across hepatic lobes.

Treatment of the right lobe

tumor via the middle hepatic

artery was performed

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

for (1) variant cystic artery origin, (2) presence of acces-

sory right hepatic artery, and (3) presence of parasitization

of flow from the GDA or other branches to the liver

(Fig. 4).

The next most important vessel to identify is the right

gastric artery (Fig. 12). The origin of this vessel is variable,

arising from any site from the hepatic artery, and usually

anastamoses via an arterial arcade to the left gastric artery.

In some cases of a continuous anastomosis with the left

gastric artery, catheterization can be accomplished from

the left gastric artery if antegrade catheterization of the

right gastric cannot be performed (Fig. 13).

There are many other arterial variants and accessory

vessels that deserve special mention [31]. The falciform

artery is one such vessel that is occasionally identified

angiographically. This vessel runs in the double fold of

peritoneum that is the falciform ligament and anastomoses

with the vasculature from the anterior abdominal wall,

usually the terminal vessels of the internal mammary and

inferior epigastric arteries (musculophrenic and superior

epigastric). Failure to identify and prophylactically occlude

this vessel may result in delivery of 90Y particles to the

anterior abdominal wall, which may result in adverse

events in the form of severe abdominal pain, skin necrosis,

and rash (Fig. 14) [39]. Another branch includes the

supraduodenal artery, which provides blood supply to the

upper portion of the duodenum and pylorus [31]. The ori-

gin of this vessel is also variable, and it communicates with

the pancreaticoduodenal arcade as well as right gastric

branches [40].

The cystic artery deserves special discussion. Although

the usual origin of this vessel is the right hepatic artery, it

may also arise from the left hepatic, middle hepatic, gas-

troduodenal, or replaced (accessory) right hepatic arteries

[31]. Furthermore, the blood supply to the gallbladder

comes not only from the cystic artery, but also from per-

forators to the body of the gallbladder from the hepatic

parenchyma and the GDA (Fig. 15) [31]. The gallbladder

may therefore be assumed to have redundant blood supply.

In the context of radioembolization, although infusion of90Y distal to the cystic artery is ideal, it is often not pos-

sible. This is because 90Y microspheres should be infused

at a location that will allow admixture of microspheres with

flowing blood, resulting in even and flow-dependent

microsphere distribution. The cystic artery often arises

deep within the right hepatic artery near its bifurcation into

anterior (segments 5/8) and posterior (segments 6/7) sec-

toral vessels. When this is the case and the cystic artery

arises distal to the ideal location for 90Y infusion, avoiding

microsphere flow into the gallbladder becomes impossible.

Although the incidence of radiation-induced cholecystitis

is very low, prophylactic embolization may be considered.

The technical approach to cystic artery embolization

should be addressed. At all times during 90Y infusion, the

treating physician should balance the risks of (1) infusion

proximal to the cystic artery with potential radiation

Fig. 12 A Celiac arteriogram

shows the right gastric artery

(arrow) arising from the

common hepatic artery.

B Selective right gastric artery

angiogram shows the

communication with the left

gastric artery (arrow)

Fig. 13 A Left gastric artery

injection demonstrates flow

through the lesser curve arcade

to the right gastric artery

(arrows). B Retrograde

catheterization complete.

C Successful right gastric artery

coil embolization from the left

gastric artery (arrows)

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

cholecystitis; (2) infusion distal to the cystic artery but with

suboptimal microsphere distribution; and (3) infusion

proximal to the cystic following prophylactic embolization

of cystic artery, resulting in optimal microsphere distribu-

tion but with a risk of ischemic cholecystitis. First, for all

cases of 90Y radioembolization, if the cystic artery is large

and appears to represent the dominant blood supply to the

gallbladder, prophylactic embolization should be avoided,

as the risk of ischemic cholecystitis may outweigh the risk

of radiation cholecystitis if infused proximally. However, if

the cystic artery is small, then the redundant blood supply

to the gallbladder may be assumed to be present and pro-

phylactic occlusion may be considered. The approach to

this differs between radioembolic devices. The risk of

radiation-induced cholecystitis is sufficiently low with

TheraSphere (low radioembolic load) that infusion proxi-

mal to the cystic artery may be preferable to the potential

benefits of advancing the catheter distal and risking inad-

equate microsphere distribution. However, given the higher

radioembolic load of SIR-Spheres, it is suggested that

treating physicians have a lower threshold for prophylactic

embolization of the cystic artery with the latter device.

Gelfoam torpedoes or microcoils may be used to provide

cystic artery blockade. Prophylactic antibiotics are also

advocated in such cases.

The above-described approach to cystic artery is a result

of two cases of radiation cholecystitis (one case with each

type of 90Y microsphere) and two cases of ischemic cho-

lecystitis we have encountered. All four patients required

surgery. Although a previous report had suggested that the

incidence of radiation cholecystitis without coil emboli-

zation of the vessel is clinically acceptable, we have

adopted this enhanced approach when necessary [41].

Another possible strategy to deal with the cystic artery,

should embolization be essential for proper 90Y infusion,

relates to the approach to the GDA. Since the blood supply

to the gallbladder may also come from the perforators from

the liver parenchyma or GDA, a modified GDA emboli-

zation technique may be considered, where embolization

with as few coils as possible very close to the origin of the

Fig. 14 A Left hepatic artery

injection shows a distal vessel

(arrows) traveling in a divergent

course from the other hepatic

vessels. Its course parallels the

falciform ligament. B Following

coil embolization, there is no

flow in this vessel (arrow).

C Left hepatic arteriogram in a

different patient demonstrates a

falciform artery (arrows).

D Falciform arteriogram

demonstrates retrograde anterior

abdominal wall flow into the

superior epigastric and

musculophrenic arteries

(arrows). E Postembolization of

the falciform artery

demonstrates no flow. F CT

scan confirms coils within the

falciform artery (arrow)

Fig. 15 A The right hepatic artery is very tortuous, with a cystic

artery (white arrow) arising from the apex of a bend. The optimal

catheter position for treatment (black arrow) would be directed at the

origin of the cystic artery. B Coil embolization minimizes the risk of a

radiation cholecystitis (arrow). C Injection of the cystic arrow

demonstrates flow to the body of the gallbladder (large arrow). There

is trans-cystic flow to the hepatic parenchyma (small arrow),

confirming a redundant blood supply

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

GDA may be in order. This may permit branches from the

GDA distal to the coils to receive retrograde blood from the

gastroepiploic artery and provide flow to the gallbladder

once the cystic artery is embolized. Finally, it should be

stated that the long-term consequences of this approach

have not been formally studied (Fig. 15).

The occlusion of extrahepatic vessels (excluding the

above discussion on cystic artery) is best accomplished by

superselective microcoil embolization. Due to the redun-

dant vasculature in this area, embolization of these vis-

ceral vessels can be performed safely, similar to treating

acute upper GI bleeding [42]. Larger vessels such as the

GDA can sometimes be catheterized by 4-French cathe-

ters (e.g., glide or C-shaped catheters) and embolized with

0.035- or 0.038-in. coils, such as Nester Coils (Cook,

Bloomington, IN). In the event that the GDA is not

accessible with a standard catheter due to size or vessel

course, a microcatheter can be used to select the vessel,

and embolization performed with 0.018-in. microcoils.

Catheterization of small vessels such as the falciform

artery is best accomplished using 2.3-French systems such

as the Prowler Plus (Cordis, Miami, FL). Coils can be

deployed with the use of a coil pusher, or by saline flush,

and should be deployed well within the vessel being

embolized as close to the origin as possible. Completion

angiography should demonstrate no further flow in the

occluded vessels. It should be stated that prophylactic

embolization of vessels is not without pitfalls. For

example, embolization of the GDA may induce redistri-

bution/parasitization of blood flow by normal tissue.

Small, previously unseen vessels can become more

prominent after embolization of the GDA and right gastric

artery. If this redistribution phenomenon is not recognized

at the time of treatment, complications may ensue

(Fig. 16).

It should finally be noted that the area most likely to

have aberrant vasculature and contain unrecognized

extrahepatic flow is the left hepatic artery/lobe. Variants

described above flowing to the esophagus, stomach, or

diaphragm may result in adverse events and toxicities. For

this reason, it is recommended that immediately prior to

performing the mapping angiogram in preparation for ra-

dioembolization, two anatomic observations be made: (1)

identification of any vessel in the ligamentum venosum on

CT/MRI and (2) extension and size of the left lobe of the

liver. A vessel coursing through the ligamentum venosum

represents an accessory left gastric, inferior esophageal, or

gastrohepatic trunk. The course and lateral extension of the

left lobe of the liver should also be appreciated, as any

vessel extending beyond the expected confines upon he-

patic artery injection should raise suspicion for extrahe-

patic flow (Figs. 16c–g).

Fig. 16 A Hepatic arteriogram

immediately following GDA

embolization shows no evidence

of extrahepatic flow. BArteriogram performed at the

time of treatment 2 weeks

postembolization now shows

duodenal branches (arrow) as a

result of GDA embolization.

This was not recognized at the

time of radioembolization. The

patient developed an ulcer and

required months of proton pump

inhibition for healing. C Arrow

demonstrates the border of the

left lobe of the liver in line with

the aorta. D Vessel off the left

hepatic artery extends

significantly beyond the left

lobe and aorta, suggesting the

possibility of extrahepatic flow.

E Injection of this vessel

confirms it to be an accessory

left gastric. Note contrast

outlining the gastric fundus and

coronary vein. F Following

embolization of this vessel,

nontarget embolization to the

stomach and esophagus has

been mitigated. G Coils

identified in the fissure for

ligamentum venosum (arrow)

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Lobar Versus Whole-Liver Injection

Although much of the early clinical experience with 90Y

involved whole-liver infusion, this treatment paradigm is

no longer recommended. Whole-liver treatment was

undertaken given limitations in microcatheters and imag-

ing, as well as in patients who underwent treatment using

surgically placed intrahepatic pumps. Enhancements in

microcatheter technology have decreased the use of sur-

gically implanted pumps for the treatment of liver tumors.

Furthermore, there exists significant extrahepatic flow,

described throughout this article, through small vessels that

can only be avoided using lobar/segmental infusions. For

radioembolization, a treatment paradigm that parallels

TACE is recommended, i.e., lobar or sub-/segmental

infusions. If a treating physician insists on treatment to the

entire liver at once, then a ‘‘bilobar lobar’’ infusion is

recommended. This involves placement of the catheter in

one, followed by the other, hepatic artery where infusion is

performed. Infusion of 90Y via the proper or common he-

patic arteries should be avoided, despite prophylactic

embolization of extrahepatic vessels.

Difficult Scenarios

It is not uncommon to observe anatomic abnormalities

other than the common variants described above. One

condition encountered is a stenotic or occluded celiac ar-

tery. This is usually evident on the initial SMA arterio-

gram, where a hypertrophied pancreaticoduodenal arcade is

visualized (Fig. 17). To continue with radioembolization,

there are two options available: (1) recanalize or stent the

celiac artery occlusion and proceed as usual, or (2) traverse

the pancreaticoduodenal vessel with a microcatheter and

proceed to the liver from the SMA.

Stenting a stenotic or occluded celiac origin can be

difficult. The various techniques available have been

described elsewhere and are not discussed in depth here

[43–46]. This technique is appropriate in the setting of

atherosclerotic disease of the celiac origin; however,

median arcuate ligament compression of the celiac artery

creates more difficulty. From a long-term patency stand-

point, any stent placed in the celiac will undoubtedly fail

over time due to the continued extrinsic stresses and

pressure on the vessel. However, the primary purpose of

stenting the vessel in the case of radioembolization is for

access to the hepatic arteries in patients who will require

repeated transarterial therapy for liver cancer. In our

experience, we have resorted to stenting a compressed

celiac artery when all other options were exhausted.

A less invasive, but equally challenging and time-con-

suming method is to try to navigate the pancreaticoduo-

denal arcade with a microcatheter and access the hepatic

arteries through the SMA. The route is almost always cir-

cuitous and will require a flexible microcatheter such as a

Prowler Plus (Cordis) and a maneuverable wire, such as a

Headliner (Boston Scientific) or Glidewire GT (Terumo)

(Fig. 18). If successful, it will allow the physician to per-

form radioembolization safely from the SMA.

Although stenotic celiac arteries can result in flow

limitations when delivering microspheres, other medical

conditions or previous procedures may do the same. Pa-

tients undergoing 90Y radioembolization following TACE

to the vascular bed invariably display angiographic hall-

marks of vascular injury such as sluggish flow, limited

tumor enhancement, and hypervascularity. Sluggish flow

may result in patients who have been treated with growth-

factor inhibitors (e.g., bevacizumab, cetuximab), compro-

mised cardiac output, and spasm induced when large

catheters are used in smaller vessels. Despite the ability of

most experienced interventional radiologists to be able to

advance 4- or 5-French catheters distal within the liver, this

approach is highly discouraged at the time of radioembo-

lization. This may be performed at the time of mesenteric

angiography and prophylactic embolization of collateral

vessels. However, on the day of radioembolization, given

that 90Y microspheres rely principally on blood flow

dynamics and hypervascularity, catheterization and infu-

sion should be performed at enough distance from the

vessel of interest to allow proper admixing of the micro-

spheres with flowing blood. For example, in a patient

where a right lobe infusion is intended, catheter position

should be such that enough distance exists to allow inter-

mixing of the microspheres with blood, allowing flow

dynamics and hypervascularity of the tumor to absorb the

microspheres. If the catheter is too close to the bifurcation

into the anterior and posterior branches, flow of micro-

spheres will preferentially be in the more dependent pos-

terior branch (segment 6/7) and will result in suboptimal

Fig. 17 Superior mesenteric arteriogram demonstrates hypertrophied

GDA (arrow) and pancreaticoduodenal arcade with opacification of

the hepatic artery. These are secondary findings suggesting the

presence of a celiac origin stenosis or occlusion

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

Fig. 18 A Selective

catheterization of a

pancreaticoduodenal branch of

the SMA shows a hypertrophied

and tortuous route to the hepatic

circulation. B Circuitous

microcatheter placement

through the vessel into the

hepatic circulation. C Injection

through the microcatheter

confirming catheter placement

prior to radioembolization

Fig. 19 A Posterior segment exophytic right lobe tumor. B Right

renal artery arteriogram demonstrates both adrenal artery branches

(arrows) providing blood flow to the tumor. C Transrenal parasiti-

zation of flow to the HCC. D Right lobe HCC which appears to be

perfused by an extrahepatic vessel (arrow). E Axial CT demonstrates

a vessel crossing the abdomen anterior to the liver (arrow). F Splenic

angiogram demonstrates a vessel from the splenic hilum crossing the

abdomen to the right upper quadrant (arrow). G Microcatheterization

of this vessel confirms that this is a splenic vessel providing blood

flow to the right lobe HCC (arrows)

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

flow to the lesions located anteriorly (segment 5/8). Be-

cause of this flow dependence, described above, the tech-

nique of balloon occlusion for microsphere injection is

highly discouraged. Balloon occlusion eliminates hyper-

vascularity dynamics and creates dependent layering of

microspheres that are ‘‘pushed’’ into the target tissue by

injected fluid, rather than being ‘‘absorbed’’ by the hy-

perdynamics of tumor flow.

Exophytic tumors can present a challenge due to the

complex vascular supply. Vascular tumors, especially HCC,

can parasitize blood flow from many other sources, such as

intercostal arteries, renal, adrenal, and splenic (Fig. 19).

Treatment through these vessels should only be performed

when a thorough evaluation has been performed to confirm

that the vessel only perfuses the tumor. A transcatheter CT

angiogram can be performed with the catheter in the vessel

in question. Contrast is injected directly into the catheter

while CT images of the liver are acquired, giving an ex-

tremely accurate view of contrast distribution. If no extra-

tumoral blood flow is seen, one can use this vessel to deliver

the 90Y microspheres. In other instances, tumors that appear

hypovascular on conventional contrast-enhanced CT scans

may in fact be shown to be hypervascular when the artery is

directly injected under CT. This can help predict the dis-

tribution as well as the concentration of the microspheres at

the time of therapy (Fig. 20) [24]. Hence, tumors should not

be assumed to be hypovascular without proper angiographic

and CT assessment.

One of the most difficult scenarios to deal with involves

tumor masses (either solitary or as part of multifocal dis-

ease) that are at angiographic watershed zones of the liver.

Although several scenarios exist, only the most common

are reviewed here. However, readers are directed to an

excellent review of these anatomic scenarios published

recently [47]. The first involves disease dominance in the

center of the liver, by either one or several large centrally

located masses, occupying segments 4A, 4B, 1, 5, and 8.

By virtue of this location, both right and left hepatic

arteries will require attention and infusion in order to

completely treat this disease presentation. Careful and

meticulous angiographic technique is required to ensure

that all portions of the tumor are covered by microspheres

while minimizing the risk of nontarget embolization

(Fig. 21). A second watershed area is that near or adjacent

to the gallbladder. Lesions near or adjacent to the gall-

bladder may derive their blood supply from the right, left,

or even proper hepatic arteries. Treatment using a lobar

approach where the catheter is placed well into the lobar

artery may result in inadequate microsphere coverage. A

third watershed area is that of the dome of the liver (seg-

ment 4A/8). In some cases, it can be quite difficult to

definitively assess whether a vessel will perfuse a certain

segmental territory of the liver. The blood supply to that

area may be from the anterior branch of the right hepatic

artery, the cranial portion of the middle hepatic artery

(segment 4A), the right inferior phrenic artery, the internal

mammary artery, or the cranial portions of the medial he-

patic artery. Parasitization of blood flow from the lateral

segment left hepatic artery to the dome of the liver may

also occur. A fourth watershed area is that of the tip of the

right lobe (segment 5/6). Treating this area may result in

inadequate tumor coverage since some of this territory may

be supplied by the right inferior phrenic, the right adrenal,

an intercostal/lumbar artery, a renal capsular branch, chest

wall vessels (thoracodorsal, lateral thoracic artery), or even

colic branches off the SMA (Figs. 2, 4, 10, 19). Given the

difficulties that may arise in difficult cases of blood supply,

the use of CT angiography is recommended (Fig. 22) [24].

Also, it is important when imaging response is being

evaluated that the location of the tumor be taken into

consideration, especially if in a watershed area. The 90Y

microspheres may be declared ineffective for a particular

tumor when, in fact, the microspheres were suboptimally

delivered given the lack of recognition of the exact blood

supply.

Another difficult scenario involves the management of

the gastrohepatic trunk. As the name implies, this repre-

sents blood supply to the left lobe of the liver as well as the

Fig. 20 A Conventional contrast-enhanced CT shows multiple ‘‘hyp-

ovascular’’ lesions in the liver (arrows). B Hepatic arteriogram shows

multiple areas of enhancement (arrows) consistent with the lesions seen

on CT. C Transcatheter CT arteriography shows the lesions to be

extremely vascular relative to the hepatic parenchyma, justifying the

use of radioembolization or other arterial therapies in this case

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

stomach from a common trunk. The presence of this vessel

can often be prospectively identified on cross-sectional

imaging, where the vessel is seen to provide flow to the

liver as it traverses the fissure for ligamentum venosum

(Fig. 23). The left hepatic lobe supplied by this vessel is

most commonly to segments 2 and 3 but may also supply

segment 4. The difficulty arises when trying to delineate

the extrahepatic blood supply from the gastrohepatic trunk.

It is not uncommon for branches such as the inferior

phrenic, inferior esophageal, and accessory left gastric as

well as the left gastric proper to arise from the gastrohe-

patic trunk. Radioembolization in the left hepatic artery

arising off a gastrohepatic trunk carries a risk of nontarget

embolization to the extrahepatic vessels described above.

Given this, the proper identification and embolization of

these vessels are critical during the angiographic evaluation

of patients. The selective catheterization of each of the

vessels arising off the gastrohepatic trunk is advocated.

Admittedly, it may be difficult to confirm whether a vessel

is a hepatic or an extrahepatic branch. CT Angiography can

aid in the defining of the vascular bed being perfused

(Fig. 22). Alternatively, we strongly advocate the use of a

consistently identified secondary sign of extrahepatic flow

when the gastrohepatic trunk is injected: opacification of

the coronary vein. This vein represents the venous drainage

of the body and fundus of the stomach, as well as the distal

Fig. 21 A Celiac injection demonstrates patent common hepatic

and splenic artery. No right hepatic artery is seen, given the

previously documented replaced right hepatic artery. B Selective

injection of the left hepatic artery following embolization of the

GDA demonstrates an inferior esophageal artery (top arrow), as

well as two other vessels (lower arrows: falciform and right gastric

arteries) in the area of the abdominal wall and right gastric

distribution that require interrogation. C The top arrow represents

the inferior esophageal artery. Inferior esophageal arteriogram prior

to embolization demonstrates flow to the esophagus and stomach.

D Injection of a vessel heading toward the stomach suggests

anterior abdominal wall flow. E Prolonged injection in the

anteroposterior plane confirms that this is flow into the anterior

abdominal (superior epigastric and musculophrenic arteries) wall via

the falciform artery. F Interrogation of the right gastric artery prior

to embolization. G, H Completion injection of the left and common

hepatic arteries, respectively, demonstrates embolization of all

extrahepatic vessels. Compared to B, more pronounced flow into the

tumors is noted and there is no extrahepatic flow, allowing for safe

radioembolization

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

esophagus. Opacification of this vessel confirms extrahe-

patic flow. Figure 24 demonstrates a case where complex

arterial anatomy is demonstrated and each extrahepatic

vessel is interrogated. Once all vessels have been embol-

ized, coronary venous flow has been obliterated, making

radioembolization feasible.

Radiation segmentectomy is a technique that has been

described in which the dose of 90Y is delivered superse-

lectively into a branch of the hepatic artery. This results in

a higher dose of radiation delivered to a smaller area and is

useful for focal lesions. The information obtained from CT

angiography can be helpful in better delineating tumor

location, tumor volume, and blood distribution pattern

(Fig. 22). Because this technique can accurately demon-

strate tumor volume within the hepatic lobe, more accurate

dose calculations can be performed, potentially resulting in

more effective treatments [24].

Idiosyncratic Reaction

During the immediate postprocedural time following ra-

dioembolization, patients may experience a rare and unu-

sual reaction. Just as penicillin and sulfa may cause

Stevens-Johnson syndrome, radioembolization with 90Y

may cause a short-lived idiosyncratic reaction. This reac-

tion is nearly identical to that obtained in patients receiving

urokinase, with clinical symptoms of shakes, chills, and

alterations in hemodynamics and vital signs [48]. Just as

with a urokinase reaction, management is supportive,

including fluids if hypotensive, as well as diphendydramine

and meperidine. This reaction is short-lived, usually lasting

less than 1 h. Both the onset of symptoms and their reso-

lution are quite rapid. Although it is difficult to predict

which patients will have this reaction, it has been seen

commonly in patients with arterioportal shunting who un-

dergo radioembolization (Fig. 25). In our series, we have

observed this reaction in 10 patients. All patients had re-

ceived TheraSphere and all had arterioportal shunting from

HCC. When we first observed this phenomenon, we

admitted all patients for possible fever and sepsis, includ-

ing chest x-ray, urinalysis, and blood cultures. Prophylactic

broad-spectrum antibiotics were given. In no case were any

of the tests or cultures positive. The diagnosis of 90Y-re-

lated idiosyncratic reaction was made in all cases.

Postprocedure Management and Follow-up

Radioembolization is performed on an outpatient basis.

Following the procedure, the arterial puncture is closed

with the assistance of a closure device or with manual

compression. After the appropriate recovery time, patients

are discharged home (2 h with closure devices, 6 h with

manual compression). Nondiabetic patients receive a Me-

drol DosePak for 6 days as directed to help combat the

fatigue that invariably ensues in most patients [21]. Patients

may receive 7–10 days of a fluoroquinolone if the entire

right lobe is to be treated and the cystic artery was perfused

with microspheres. All patients are placed on a proton

pump inhibitor for 7–10 days following treatment. Tumor

markers (AFP, CEA, CA-19-9, chromogranin A, CA-125),

complete blood count, liver function tests, and general

chemistries are obtained 4–6 weeks postprocedure. Cross-

sectional (triphasic CT, dynamic gadolinium-enhanced

MRI, perfusion imaging) and functional imaging (PET)

tests are obtained at that time to assess the results of

therapy. The opposite lobe is usually treated shortly fol-

lowing assessment of response and the demonstration of

lack of diffuse progression. Completion evaluation and

assessment of response (CT/PET/MR/tumor markers) are

usually performed once both lobes have been treated and

30–60 days have elapsed since last treatment.

Fig. 22 A CT demonstrates a

lesion in segment 3 of the liver.

B Selective arteriogram of the

segment 3 vessel does not

convincingly demonstrate the

lesion. C Direct CT

arteriography through the

microcatheter shows the area of

distribution encompasses the

lesion in question

Fig. 23 Gastrohepatic trunk coursing through the fissure for the

ligamentum venosum (arrow)

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

Conclusion

Radioembolization has been shown to be an effective

treatment for patients with either primary liver cancer or

metastatic liver disease [14, 36, 49]. Unlike other locore-

gional therapies, the preprocedure planning and meticulous

mesenteric angiography are of paramount importance in

order to determine the safest and most effective treatment

strategy. Identifying anatomic variants, isolating the he-

patic circulation and prophylactic embolization requires

attention to detail that is usually not necessary with treat-

ments such as TACE or TAE. Extrahepatic blood vessels

may occasionally be used to deliver the 90Y microspheres

as well if flow is confined to the tumor. Given the need for

in-depth comprehension of hepatic and extrahepatic vas-

culature to liver tumors, investigators are strongly urged to

Fig. 24 A Injection of the gastrohepatic trunk demonstrates complex

vascularity to the left lobe and hypervascular tumors. B Delayed

imaging illustrates a prominent coronary vein (arrows). C Injection of

the inferior esophageal artery clearly shows flow to the fundus of the

stomach and lower esophagus (arrows). D Left gastric artery injection

prior to embolization. E Injection of the gastrohepatic trunk following

embolization of the inferior esophageal and right and left gastric

arteries demonstrate persistent opacification of the coronary vein,

implying flow to the gastric circulation. F Retrospective evaluation of

the gastrohepatic trunk demonstrates an accessory left gastric artery

that was not recognized (arrow). G Injection of the accessory left

gastric artery demonstrates flow into the coronary vein. H Completion

injection following embolization of the accessory left gastric artery. IDelayed injection demonstrates no flow into the coronary vein,

implying that all vessels with gastric contribution have been

successfully embolized

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

review the available literature on angiographic anatomy, in

particular, three recent angiographic reviews [31, 32, 47].

Despite the in-depth review presented, it should be no-

ted that the prophylactic embolization of vessels during

mapping angiography is not being advocated for all cases.

Rather, investigators and treating physicians should rec-

ognize that the delivery of 90Y microspheres requires a

higher level of awareness of vascular anatomy, dosimetry,

and risks of nontarget administration compared to other

embolic therapies. The degree of pretreatment emboliza-

tion should be tailored based on the treating physicians’

experience, vessel size, planned treatment location, and

radioembolic device being considered. For example, the

prophylactic embolization of vessels is not necessary in all

cases of patients being treated with TheraSphere, given its

lower radioembolic load. IRs should make this decision

based on anatomy, experience, blood flow dynamics, and

planned injection site. However, this is not true of SIR-

Spheres; all patients receiving this therapy should undergo

prophylactic embolization (i.e., GDA, right gastric and

other vessels described herein) given the high radioembolic

mechanism of action and risks of nontarget administration.

Advancements in microcatheter technology now allow

access into vessels that were previously out of reach of

transvascular techniques (Fig. 26). Techniques such as

Fig. 25 Image demonstrating arterioportal shunting (arrow) in a

patient treated with Y90 radioembolization who experienced an

idiosyncratic reaction. Follow-up evaluation demonstrated a response,

with reduction in tumor size and portal vein retraction

Fig. 26 A Hepatic arteriogram

in a patient with a ligated

common hepatic from surgical

exploration demonstrates

alternate flow through the

pancreas to the proper hepatic

artery. B Transpancreatic

microcatheterization of the

hepatic artery. CTranspancreatic right hepatic

arteriogram

Fig. 27 A Patient with a large HCC treated with radioembolization.

Blood supply to the tumor was from the right, middle, and left

hepatic artery. B Pretreatment gastrohepatic trunk angiogram

demonstrates tumor hypervascularity from the medial branch left

hepatic artery. C Tumor has decreased in size on MR, with

significant necrosis 10 months following treatment. D Follow-up

angiogram 10 months after radioembolization demonstrates com-

plete obliteration of flow to tumor and preserved normal paren-

chyma: the angiographic ‘‘complete’’ response. A hemangioma is

noted in the lateral segment

R. J. Lewandowski et al.: Radioembolization with 90Y Microspheres

123

radiation segmentectomy allow for more focused delivery

of radiation to a much smaller area, thus reducing the

amount of normal liver parenchyma exposed to radiation.

Taking advantage of tumor hypervascularity as well as the

controlled embolic burden of radioembolization can result

in the ‘‘angiographic’’ complete response (Fig. 27). That

is, the microspheres preferentially accumulate in the tumor

vasculature, spare normal parenchyma, and obliterate the

tumor from an angiographic standpoint, removing all dis-

cernible flow to the tumor. Ultimately, this technique is one

that is well tolerated by the patient, may be as effective as

other alternatives available, and may have more wide-

spread adoption once additional studies have been per-

formed [14–17, 24, 26, 27, 49]. Finally, we believe that the

toxicity profile of all hepatic embolization therapies, irre-

spective of their nature (embolic, radiation, drug-eluting),

can be improved significantly by applying the principles

described in this comprehensive review article.

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