STANDARDS OF PRACTICE

Radioembolization of Hepatic Malignancies:

Background, Quality Improvement
Guidelines, and Future Directions
Siddharth A. Padia, MD, Robert J. Lewandowski, MD, Guy E. Johnson, MD, Daniel Y. Sze, MD,
PhD, Thomas J. Ward, MD, Ron C. Gaba, MD, Mark O. Baerlocher, MD, Vanessa L. Gates, MS,
Ahsun Riaz, MD, Daniel B. Brown, MD, Nasir H. Siddiqi, MD, T. Gregory Walker, MD,
James E. Silberzweig, MD, Jason W. Mitchell, MD, MPH, MBA, Boris Nikolic, MD, MBA, and
Riad Salem, MD, MBA, for the Society of Interventional Radiology Standards of Practice Committee

ABBREVIATIONS

AFP = α-fetoprotein, ECOG = Eastern Cooperative Oncology Group, EASL = European Association for Study of the Liver, FDA =
Food and Drug Administration, FDG = fluorodeoxyglucose, HCC = hepatocellular carcinoma, MAA = macroaggregated albumin,
mRECIST = modified Response Evaluation Criteria In Solid Tumors, QI = quality improvement, RECIST = Response Evaluation
Criteria In Solid Tumors, REILD = radioembolization-induced liver disease, SPECT = single-photon emission computed
tomography, 3D = three-dimensional

PREAMBLE
The mission of the Society of Interventional Radiology (SIR) is to
improve patient care through image-guided therapy. The Society was
founded in 1973, and is recognized today as the primary specialty
society for physicians who provide minimally invasive image-guided
therapies. The Standards Division of SIR writes a number of different
types of standards documents to reflect the current clinical paradigm
and evolution in the treatment of a specific disease state or a procedure.
The Standards Division currently produces four different types of
documents. A Position Statement document reflects the viewpoints of
SIR on a specific disease state or procedure. A Reporting Standards
document attempts to codify the key elements required for future
research on a specific procedure or disease process. A Quality
Improvement (QI) Guideline attempts to provide clinical guidelines
on the application of a specific procedure or treatment of a disease
process when a significant body of literature is available. A Credentialing
document describes the knowledge base, technical skills, and experience
required to perform a specific procedure.
A QI Guideline is produced by the Standards of Practice
Committee. The membership of the SIR Standards of Practice
Committee represents experts in a broad spectrum of interventional
procedures from the private and academic sectors of medicine.
Generally, Standards of Practice Committee members dedicate the
vast majority of their professional time to performing interventional
procedures; as such, they represent a valid broad expert constituency of
the subject matter under consideration for standards production.
DOCUMENT METHODOLOGY
SIR produces its QI Guidelines documents by using the following
process. Topics of relevance and timeliness are conceptualized by the
Standards of Practice Committee members, Service Lines, SIR

From the Division of Interventional Radiology (S.A.P.), Department of Radi-
ology, David Geffen School of Medicine at University of California, Los
Angeles, Los Angeles, California; Division of Interventional Radiology (D.Y.S.),
Stanford University School of Medicine, Stanford, California; Section of Inter-
ventional Radiology, Department of Radiology (R.J.L., V.L.G., A.R., R.S.),
Robert H. Lurie Comprehensive Cancer Center, Northwestern University,
Chicago, Illinois; Department of Radiology, Division of Interventional Radiology
(R.C.G.), University of Illinois Hospital and Health Sciences System, Chicago,
Illinois; Section of Interventional Radiology, Department of Radiology (G.E.J.),
University of Washington, Seattle, Washington; Section of Interventional
Radiology, Department of Radiology (T.J.W.), Florida Hospital, Orlando,
Florida; Department of Radiology, Vanderbilt University School of Medicine
(D.B.B.), Nashville, Tennessee; Division of Interventional Radiology (T.G.W.),
Massachusetts General Hospital, Boston, Massachusetts; Interventional
Radiology, P.C. (J.E.S.), New York, New York; Department of Radiology
(B.N.), Stratton Medical Center, Albany, New York; Department of Diagnostic
Radiology and Nuclear Medicine (J.W.M.), Division of Vascular & Interven-
tional Radiology, University of Maryland School of Medicine, Baltimore,
Maryland; Department of Medical Imaging, Royal Victoria Hospital (M.O.B.),
Barrie, Ontario Canada; and Department of Radiology, King Faisal Specialist
Hospital & Research Center (N.H.S.), Riyadh, Saudi Arabia. Received August
16, 2016; final revision received September 18, 2016; accepted September
20, 2016. Address correspondence to S.A.P., c/o Debbie Katsarelis,
SIR, 3975 Fair Ridge Dr., Suite 400 N., Fairfax, VA 22033; E-mail: spadia@
gmail.com
S.A.P. is a paid consultant for and serves on the advisory board of BTG
International (Ottawa, Ontario, Canada) and Guerbet (Roissy, France). R.J.L.
serves on the advisory boards for BTG International and Boston Scientific
(Marlborough, Massachusetts) and is a paid consultant for Cook (Blooming-
ton, Indiana). D.Y.S. receives personal fees from BTG International, Sirtex
(North Sydney, Australia), Boston Scientific, EmbolX (Los Altos, California),
Cook, Covidien (Dublin, Ireland), Amgen (Thousand Oaks, California), and
Codman (Raynham, Massachusetts). M.O.B. is a paid consultant for Boston
Scientific. D.B.B. is a paid consultant for Cook, Vascular Solutions
(Minneapolis, Minnesota), and Onyx Pharmaceuticals (South San Francisco,
California). R.S. receives grants and personal fees from BTG International and
personal fees from Boston Scientific, Merit Medical (South Jordan, Utah),
Terumo (Tokyo, Japan), Siemens (Munich, Germany), and Bayer (Leverkusen,
Germany). None of the other authors have identified a conflict of interest.
& SIR, 2016
J Vasc Interv Radiol 2017; 28:1–15
http://dx.doi.org/10.1016/j.jvir.2016.09.024
2 ’ Quality Improvement Guidelines for Hepatic Radioembolization
members, or the Executive Council. A recognized expert or group of
experts is identified to serve as the principal author or writing group for
the document. Additional authors or societies may be sought to
increase the scope, depth, and quality of the document depending on
the magnitude of the project.
An in-depth literature search is performed by using electronic
medical literature databases. Then, a critical review of peer-reviewed
articles is performed with regard to the study methodology, results, and
conclusions. The qualitative weight of these articles is assembled into
an evidence table, which is used to write the document such that it
contains evidence-based data with respect to content, rates, and
thresholds. Threshold values are determined by calculating the stand-
ard deviation of the weighted mean success and adverse event reported
in all relevant trials with a sample size of approximately 50 patients or
greater. Calculated threshold values represent two standard deviations
above or below the mean for adverse event and success rates,
respectively.
When the evidence of literature is weak, conflicting, or contra-
dictory, consensus for the parameter is reached by a minimum of 12
Standards of Practice Committee members by using a modified Delphi
consensus method (Appendix A). For purposes of these documents,
consensus is defined as 80% Delphi participant agreement on a value or
parameter.
The draft document is critically reviewed by the writing group
and Standards of Practice Committee members by telephone confer-
ence calling or face-to-face meeting. The finalized draft from the
Committee is sent to the SIR Operations Committee for approval. The
document is then posted on the SIR Web site for SIR membership to
provide further input/criticism during a 30-day comment period. These
comments are discussed by the Standards of Practice Committee, and
appropriate revisions are made to create the finished standards docu-
ment before its publication.
INTRODUCTION
Locoregional therapies have an important role in the management of
hepatic malignancies. Percutaneous ablation and transarterial therapies
are the two main tools available to interventional radiologists for the
treatment of liver tumors. Yttrium-90 (90Y) radioembolization is a
transarterial catheter-based technique that is increasingly being used in
the management of primary and secondary liver malignancies.
This document serves as a guide on hepatic artery radioemboliza-
tion for the treatment of primary and secondary liver malignancies.
The readers are also referred to the Research Reporting Standards for
Radioembolization of Hepatic Malignancies (1) with recommendations
on presenting data regarding radioembolization.
Throughout this document, the procedure under discussion will be
referred to as “radioembolization.” Many other terms have been used
to describe the same procedure in the literature, including selective
internal radiation therapy (or “SIRT”) and transarterial radioemboli-
zation (or “TARE”).
PRIMARY HEPATIC MALIGNANCIES
There were an estimated 782,500 new primary liver cancer cases and
645,500 liver cancer–related deaths globally in 2008 (2). Hepatocellular
carcinoma (HCC) constitutes approximately 85%–90% of all primary
hepatic malignancies (2–4). Liver resection, liver transplantation, and
ablation are considered potentially curative therapies in select patients
with HCC (5,6). Systemic therapy, including the use of sorafenib, has
had a limited impact in the management of HCC, and is primarily
indicated in patients with advanced or metastatic disease (7,8).
Transarterial-based therapies such as bland embolization, chemoembo-
lization, and radioembolization have an established role in the manage-
ment of HCC (9,10). Radioembolization has an accepted role in the
treatment of HCC in several scenarios, and is endorsed by national
guidelines for hepatobiliary malignancies (11). This includes “bridging”
patients to liver transplantation by delaying disease progression,
Padia et al ’ JVIR
downstaging disease to meet transplantation criteria, controlling
disease while simultaneously inducing hypertrophy of the future liver
remnant before surgical resection, and treating patients with
macrovascular invasion, and as primary/definitive therapy in patients
with tumors located within a single liver segment (10,12–17).
Several prospective and retrospective studies have demonstrated
the safety and efficacy of radioembolization in patients with primary
hepatic malignancies (Table 1) (10,13–25). Studies comparing radio-
embolization versus surgery and percutaneous ablation techniques have
not been performed because these procedures are typically done in
different patient populations. Several studies comparing chemoembo-
lization versus radioembolization in HCC demonstrated longer times to
progression, better quality of life, slightly improved toxicity profiles,
and fewer days of hospitalization among patients treated with radio-
embolization compared with patients treated with chemoembolization
(26–29). However, a significant survival benefit has not been demon-
strated. Multiple prospective studies are under way comparing radio-
embolization versus systemic chemotherapy in advanced-stage hepatic
malignancy.
Cholangiocarcinoma represents the other subset of primary
hepatic malignancy. The accepted systemic chemotherapy regimen
for unresectable cholangiocarcinoma has a limited survival benefit
(30). Radioembolization has demonstrated efficacy in the setting of
intrahepatic cholangiocarcinoma (Table 1), and can therefore play a
role in improving long-term survival. In survival assessments, several
factors were found to be good prognostic indicators, specifically patient
performance status, tumor burden, and peripheral tumor type. Con-
versely, factors deemed to be poor prognostic indicators were multi-
focal tumor, infiltrative tumor, and higher tumor burden (18–20).
SECONDARY (METASTATIC) HEPATIC
MALIGNANCIES
The treatment of cancers metastatic to the liver includes surgical
resection and/or systemic chemotherapy. Radioembolization has been
shown to be safe and effective in patients with liver metastases from
primary cancers such as colorectal carcinoma and neuroendocrine
tumors.
Radioembolization for the treatment of metastatic cancer to the
liver has been evaluated primarily in the setting of colorectal cancer
metastases, often for chemotherapy-refractory disease (ie, “salvage
therapy”). Several studies have evaluated the efficacy of radioemboli-
zation for this indication (Table 2) (31–50). In a multicenter prospective
randomized phase III trial, the addition of radioembolization to
salvage chemotherapy showed a trend toward prolonged overall
survival compared with chemotherapy alone (10.0 vs 7.3 mo; P = .8)
(36). Radioembolization as first-line therapy for colorectal metastases
has recently been evaluated, with preliminary results showing no
significant improvement in progression-free survival when radioembo-
lization is added to systemic chemotherapy compared with systemic
chemotherapy alone (37). However, an advantage in hepatic
progression-free survival was identified in the radioembolization arm.
Prospective trials assessing the effectiveness of radioembolization in the
second-line setting are currently under way.
Radioembolization for neuroendocrine tumors metastatic to the
liver has repeatedly shown excellent tumor response rates with
significant improvement in survival. A retrospective study of 148
patients demonstrated a median survival of 70 months (32). In the
setting of multifocal disease, bland embolization and chemo-
embolization have also shown efficacy with acceptable safety profiles.
A systematic review of chemoembolization and radioembolization for
the treatment of neuroendocrine metastases demonstrated similar
response rates and survival (51). However, the heterogeneity of the
study populations makes this comparison challenging to draw firm
conclusions. Debate therefore continues as to the optimal transarterial
treatment regimen for this indication.
Radioembolization has also been studied for several other meta-
static tumors, including breast cancer, uveal melanoma, renal-cell
 Volume 28
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Table 1 . Outcomes of Radioembolization for Primary Liver Cancer ([10,13–25)

90
Study, Year Y Device No. of Pts. CTP Score (No. of Pts.) BCLC Stage (No. of Pts.) OR (%) Median (95% CI) TTP* Survival

’
2017
Hepatocellular carcinoma
Carr, 2004 (13) Glass 65 NR NR NR NR 649 d (Okuda I), 302 d
(Okuda II)
Lewandowski et al, 2009 (14) Glass 43 A (24), B (19), C (0) A (0), B (34), C (9), D (0) 61 33.3 mo (17.8– 33.8 mo) 35.7 mo
Riaz et al, 2011 (15) Glass 84 A (41), B (42), C (1) A (27), B (25), C (31), D (1) 81 13.6 mo (9.3–18.7 mo) 26.9 mo
Salem et al, 2010 (10) Glass 291 A (131), B (152), C (8) A (48), B (83), C (152), D (8) 57 7.9 mo (6–10.3 mo) 17.2 mo (Child–Pugh class A),
7.7 mo (Child–Pugh class B)
Sangro et al, 2011 (23) Resin 325 A (268), B (57), C (0) A (52), B (87), C (183), D (3) NR NR 12.8 mo
Padia et al, 2014 (16) Glass 20 A (11), B (8), C (1) A (2), B (2), C (15), D (1) 95 319 d 90% at 1 y
Mazzaferro et al, 2013 (22) Glass 52 A (43), B (9), C (0) A (0), B (17), C (35), D (0) 40 11 mo 15 mo
Kokabi et al, 2015 (24) Glass 30 A (20), B (10), C (0) A (0), B (0), C (30), D (0) NR 9 mo (6.2–13.1 mo) 13 mo
Saxena et al, 2014 (25) Resin 40 A (30), B (10), C (1), NR 48 NR 27.7 mo
unknown (4)
Gramenzi et al, 2015 (21) Resin 63 A (58), B (5), C (0) A (0), B (26), C (37), D (0) 73 5 mo 13.2 mo
Cholangiocarcinoma
Saxena et al, 2010 (18) Resin 25 NR NR 24 NR 9.3 mo
Hoffman et al, 2012 (19) Resin 33 NR NR 36 9.8 mo 22 mo
Mouli et al, 2013 (20) Glass 46 NR NR 73 NR 14.6 mo

BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; CTP ¼ Child–Turcotte–Pugh; NR ¼ not reported; OR ¼ objective response; TTP ¼ time to progression.
*TTP is presented as overall time to progression unless otherwise stated.

3
4 ’ Quality Improvement Guidelines for Hepatic Radioembolization Padia et al ’ JVIR

Table 2 . Outcomes of Radioembolization for Metastatic Disease to the Liver (31,33–50)

90
Study, Year Y Regimen Previous Chemotherapy No. of Pts. Objective Response Survival
Colorectal cancer metastases
van Hazel et al, 2016 (37) Resin þ FOLFOX No 267 76.4% 10.7 mo (PFS)
Gray et al, 2001 (31) Resin þ chemotherapy No 35 44% 72% (1 y)
Sharma et al, 2007 (33) Resin þ FOLFOX No 20 90% 9.3 mo (PFS)
Mulcahy et al, 2009 (34) Glass Yes 72 40% 14.5 mo
Van Hazel et al, 2004 (35) Resin þ 5-FU No 11 91% 29.4 mo
Murthy et al, 2005 (39) Resin Yes 12 0% 4.5 mo
Abbott et al, 2015 (40) Glass Yes 68 NR 11.6 mo
Hendlisz et al, 2010 (36) Resin Yes 21 9.5% 10 mo
Kalva et al, 2014 (41) Resin Yes 45 2% 186 d
Saxena et al, 2015 (42) Resin Yes 302 39% 10.5 mo
Kennedy et al, 2015 (43) Resin Yes 606 NR 9.6 mo
Lewandowski et al, 2014 (44) Glass Yes 214 NR 10.6 mo
Neuroendocrine metastases
Rhee et al, 2008 (45) Resin or glass No 42 52% 25 mo
King et al, 2008 (46) Resin þ 5-FU 15% of patients 34 50% 24.2 mo
Kennedy et al, 2008 (32) Resin NR 148 63.2% 70 mo
Saxena et al, 2010 (47) Resin 52% of patients 48 54% 35 mo
Breast cancer metastases
Gordon et al, 2014 (48) Glass Yes 75 35% 6.6 mo
Saxena et al, 2014 (49) Resin Yes 40 31% 13.6 mo
Uveal melanoma
Gonsalves et al, 2011 (38) Resin No 32 6% 10 mo
Klingenstein et al, 2013 (50) Resin 77% of patients 13 62% 7 mo

5-FU ¼ 5-fluorouracil; FOLFOX ¼ leucovorin/5-fluorouracil/oxaliplatin; NR ¼ not reported; PFS ¼ progression-free survival.

carcinoma, and sarcoma (38,48–50,52,53). Current evidence supports
consideration of the use of radioembolization for these malignancies in
the salvage setting. The incidence of liver-dominant metastases is
relatively low with these cancers; therefore, large-scale prospective
randomized trials are not feasible.
DEFINITIONS/TERMINOLOGY
Although practicing physicians should strive to achieve perfect out-
comes (eg, 100% success, 0% adverse events), all physicians will fall
short of this ideal to a variable extent. Therefore, indicator thresholds
may be used to assess the efficacy of ongoing QI programs. For the
purposes of these guidelines, a threshold is a specific level of an
indicator that should prompt an internal review. “Procedure thresh-
olds” or “overall thresholds” reference a group of indicators for a
procedure, eg, major adverse events. Individual adverse events may
also be associated with adverse events–specific thresholds. When
measures such as indications or success rates fall below a (minimum)
threshold, or when adverse event rates exceed a (maximum) threshold,
a review should be performed to determine causes and to implement
changes, if necessary. For example, if the incidence of gastrointestinal
ulceration is one measure of the quality of radioembolization, values in
excess of the defined threshold (in this case 3%) should trigger a review
of policies and procedures within the department to determine the
causes and to implement changes to lower the incidence of the adverse
events. Thresholds may vary from those listed; for example, patient
referral patterns and selection factors may dictate a different threshold
value for a particular indicator at a particular institution. Thus, setting
universal thresholds is very difficult, and each department is urged to
alter the thresholds as needed to higher or lower values to meet its own
QI program needs.
Primary liver cancers are those malignancies that originate from
the hepatic tissue. These include HCC and cholangiocarcinoma.
Cholangiocarcinoma can present initially as intrahepatic or extrahe-
patic. Radioembolization has been studied for HCC and intrahepatic
cholangiocarcinoma.
Secondary liver cancers are those malignancies that originate at an
extrahepatic site and then metastasize to the liver. Examples include
metastases from colorectal cancer, neuroendocrine tumors, breast
cancer, lung cancer, uveal melanoma, other gastrointestinal carcino-
mas, renal-cell carcinoma, and sarcoma.
Activity is the amount of radiation that is emitted per unit time.
The SI unit for activity is the becquerel, which is one nuclear
disintegration per second.
Absorbed dose refers to the amount of energy deposited (in Joules
per kilogram) in matter by radiation, and should not be confused with
the unit of radioactive activity (becquerels) of the radiation source.
Exposure to radiation will result in a radiation absorbed dose, which is
dependent on many factors, such as the activity of the source, volume
of exposed tissue, duration of exposure, energy of the emitted
radiation, and distance from the source. The SI unit for absorbed
radiation dose is the Gray.
C-arm computed tomography (CT; also commonly referred to as
cone-beam CT) is a three-dimensional (3D) CT-like filtered back-
projection reconstruction after a rotational angiogram is obtained with
the use of a flat-panel detector. Potential advantages of c-arm CT
include improved tumor detection and extrahepatic perfusion detec-
tion, 3D vascular mapping, and real-time 3D guidance during angio-
graphic procedures (54).
Nontarget embolization is defined as the unintended delivery of an
embolic agent to a vascular territory outside the target region. In the
liver, this includes portions of the liver, possibly free of disease, that
were not the intended target. Gallbladder, duodenum, stomach,
anterior abdominal wall, and lungs are examples of extrahepatic
nontarget regions. Nontarget embolization can result in radiation-
induced damage to these areas and produce symptoms of abdominal
Volume 28 ’ Number 1 ’ January ’ 2017
pain, bleeding, or dyspnea with the possibility of temporary or
permanent disability. It should be recognized that, depending on the
angiographic anatomy, gallbladder, anterior abdominal wall, and lung
deposition within limits may be clinically acceptable. However, non-
target deposition involving the duodenum and stomach are never
clinically acceptable.
Postembolization syndrome is the occurrence of abdominal pain,
low-grade fever, nausea, vomiting, loss of appetite, and/or malaise in
the first few days after radioembolization. Although this is an expected
part of recovery, its frequency and severity may be lower than seen with
chemoembolization. This process should not be considered an adverse
event of radioembolization unless unplanned medical therapy or
hospitalization is required.
Technical success is the administration of 90Y microspheres into
the target artery supplying the intended region of treatment. On
occasion, a patient may not be a candidate for 90Y infusion based on
nonsuitable vasculature identified on the mapping angiogram or
because of a high lung shunt fraction. This should not be considered
a technical failure because the treatment plan changed before the
infusion procedure.
Radioembolization-induced liver disease (REILD; often described
as “radiation-induced liver disease” because of subtle differences
caused by external-beam irradiation) consists of a constellation of
symptoms related to radiation-induced liver dysfunction in the absence
of objective tumor progression. These include jaundice and/or ascites,
usually with associated increases in serum alkaline phosphatase and
bilirubin levels (unlike radiation-induced liver disease from conven-
tional external-beam radiation, which is often associated with normal
bilirubin levels). REILD usually occurs 1–2 months after radioembo-
lization, but its onset is highly variable, making the diagnosis often
challenging (55).
PATIENT SELECTION
A comprehensive understanding of the patient’s oncologic stage,
performance status, laboratory test results, treatment history, and
potential future treatment options is critical in patient selection.
Interventional radiologists should be aware of (i) clinical parameters
such as the Eastern Cooperative Oncology Group (ECOG) perform-
ance status; (ii) laboratory assessment of liver function, coagulation
status, renal function, and tumor markers; and (iii) radiologic staging
of disease, including distribution, number, and size of tumors and the
presence of vascular invasion or extrahepatic metastases. The Coui-
naud liver segment classification system is preferred for describing the
anatomic location of hepatic tumors.
A thorough clinical history, including previous therapies (surgical/
medical/interventional), should be obtained. The previous administra-
tion of certain systemic chemotherapy agents (especially patients
receiving biologic agents such as bevacizumab) is relevant because of
the association with hepatic vasculature adverse events, such as vaso-
spasm, dissection, or inability to deliver the microspheres. Other
systemic agents may cause subclinical hepatic toxicity and compromise
liver reserve. Finally, the interventional radiologist should decide
whether to proceed with radioembolization in the context of other
available therapies (eg, surgical resection, ablation, external-beam
radiation, systemic chemotherapy, chemoembolization). In patients
who are already receiving systemic chemotherapy, the interventional
radiologist should also assess whether radioembolization should be
performed concurrently or during a chemotherapy “holiday” (56).
Disease Staging
Oncologic staging should be performed by using accepted staging
systems for the particular malignancy. In the case of HCC, in which
there is often coexisting liver cirrhosis, assessment of liver function with
the Child–Turcotte–Pugh score should be calculated. Some commonly
used staging systems for HCC include the Barcelona Clinic Liver
Cancer, Cancer of the Liver Italian Program, Okuda, United Network
5
for Organ Sharing tumor/node/metastasis, and Hong Kong staging
systems. Although one study suggested that the Cancer of the Liver
Italian Program system outperformed other staging systems in HCC,
no single staging system can be recommended in view of the limited
data comparing the various staging systems (57–59).
Given the numerous types of liver metastases that may be treated
with radioembolization, it is impractical to mandate a specific staging
system based on all tumor types (eg, Dukes/tumor/node/metastasis
staging for colorectal cancer). However, baseline data regarding
presence of extrahepatic metastases should be obtained.
Indications and Contraindications
If feasible, therapy selection is recommended by consensus in a
multidisciplinary team, for example, including hepatologists (in the
case of primary liver cancer), medical oncologists, radiation oncolo-
gists, surgeons, and interventional radiologists.
For HCC, size, number, and distribution of tumors play pivotal
roles in patient selection. Other locoregional options should also be
considered, including transarterial chemoembolization and ablation.
There is considerable overlap in the indications and patient selection of
each treatment modality. The choice of therapy must take multiple
factors into consideration, such as best potential tumor response,
lowest degree of toxicity, patient preference, and availability of local
expertise. Degree of cirrhosis (measured by Child–Turcotte–Pugh class)
must be considered, as well as trends in patients’ liver function over
time. The albumin-bilirubin grade is being investigated as an adjunct to
the Child–Pugh score (60). In general, radioembolization may be safely
offered to patients with borderline liver function if performed in a more
selective (ie, segmental) fashion, even though this depends on stability
of the patient’s liver function over time, goals of treatment (eg,
palliation vs downstaging to transplantation), and the expertise and
experience of the performing interventional radiologist.
For intrahepatic cholangiocarcinoma, patients should have sur-
gically unresectable disease at the time of treatment. Presence of
extrahepatic metastases should not be considered an absolute contra-
indication, as several studies have shown promising overall survival in
this scenario (18,20). Rather, efforts at combining radioembolization
with systemic chemotherapy should be considered in this situation.
Caution should be taken in patients with biliary obstruction or in
patients with a history of biliary manipulation, even though this does
not represent an absolute contraindication and is associated with a
lower risk for hepatic abscess formation than seen with chemoembo-
lization (61). There is currently no role for radioembolization in the
setting of hilar/extrahepatic cholangiocarcinoma.
In the setting of hepatic metastases, indications vary widely and
are often institution-dependent. For colorectal cancer metastases, the
metastases should be considered unresectable and not amenable to
ablation. However, the timing of radioembolization with regard to a
patient’s chemotherapy regimen remains controversial. Most centers do
not perform radioembolization as first-line therapy, but rather in a
salvage setting. It is unclear when the maximum benefit from radio-
embolization may be derived, such as after failure of first-line or second
line chemotherapy. Although survival times tend to be longer in
patients receiving radioembolization earlier in the disease course, this
may reflect selection and lead-time bias. In certain situations when a
patient has exhibited toxicity from systemic chemotherapy, radio-
embolization can allow for a chemotherapy holiday while controlling
tumor growth.
Patients with metastatic disease to the liver should have accept-
able performance status, ie, ECOG performance status 0 or 1. Poor
performance status should be addressed before treatment, as this may
reflect a patient whose condition is rapidly declining. In these cases,
radioembolization would be of no benefit, and could even be poten-
tially harmful by accelerating the decline in performance status.
Hepatic function should be within normal limits, and any liver function
abnormality before treatment must be addressed and managed. Abnormal
liver function is often a sign of toxicity from systemic chemotherapy or
6 ’ Quality Improvement Guidelines for Hepatic Radioembolization
rapid tumor infiltration. In these situations, radioembolization would be
contraindicated. This is in contrast to patients with HCC, who usually
have underlying cirrhosis, typically resulting in some baseline decline in
performance status and/or hepatic function abnormality. Furthermore,
trends in hepatic function should be reviewed if available, as patients with
declining liver function may still have laboratory values that are
considered within normal limits. Isolated elevation of alkaline phosphatase
is typically not of concern and is more a marker of metastatic foci in the
liver rather than hepatic dysfunction.
The absolute contraindications to radioembolization for any
malignancy include severely compromised hepatic function, poor
performance status (ECOG 4 2), active hepatic infection, significant
extrahepatic metastases, and pregnancy. After mapping angiography,
the inability to administer 90Y microspheres without nontarget embo-
lization to the bowel is also considered an absolute contraindication. A
high lung shunt fraction (LSF) that would lead to a greater than 30-Gy
dose to the lungs with a single treatment is an absolute contraindication
for radioembolization.
Relative contraindications to radioembolization include uncorrect-
able coagulopathy, severe radiographic contrast medium allergy, and
renal impairment, all of which can often be medically addressed. Increased
bilirubin level and significant ascites are relative contraindications;
individualized patient decision-making is recommended in these settings.
DEVICES
There are two types of 90Y microspheres commercially available.
TheraSphere (BTG International, Ottawa, Ontario, Canada) consists
of 20–30-mm-diameter glass microspheres with 90Y integrated into the
glass structure. This device received US Food and Drug Administra-
tion (FDA) approval in 1999 under a Humanitarian Device Exemption
as radiation treatment or as a neoadjuvant therapy to surgery or
transplantation in patients with unresectable HCC who can have
placement of appropriately positioned hepatic arterial catheters, or in
patients with HCC with partial or branch portal vein thrombosis/
occlusion, when clinical evaluation warrants the treatment. In the
European Union and Canada, it is approved for the treatment of
hepatic neoplasia in patients who have appropriately positioned
arterial catheters. SIR-Spheres (Sirtex, North Sydney, Australia) are
biodegradable resin 20–60-mm-diameter microspheres onto which 90Y
is adsorbed to the surface. This device received FDA approval in 2002
for the treatment of metastatic colorectal cancer with concomitant use
of intraarterial floxuridine. In the European Union, SIR-Spheres are
indicated for the treatment of patients with inoperable liver tumors.
Despite the relatively narrow FDA-approved indications for both
devices, both are often used on an off-label basis based on several
medical practice guidelines (62,63). There are other radiopharmaceut-
ical agents (ie, radionuclide/carrier combinations) available, but there
are limited data available on their safety and efficacy (64–67).
TECHNIQUE
Multiple factors may influence technique of radioembolization, such as
tumor distribution, choice of 90Y device, and goals of therapy.
Preprocedure Angiography
Pretreatment (ie, planning) angiography is an integral step before
radioembolization (68–72). Meticulous mapping of the vascular anat-
omy allows the interventional radiologist to (i) identify the vascular
supply of the liver and the tumor, (ii) identify and embolize vessels that
may lead to nontarget deposition of the radioembolic material, and (iii)
to quantify LSF. The choice to perform prophylactic embolization of
extrahepatic vessels (eg, gastroduodenal artery, right gastric artery) is
largely operator-dependent and varies considerably across institutions.
It is recommended that new users have a low threshold to perform
prophylactic embolization of extrahepatic vessels before radioemboli-
zation. However, many experienced, high-volume centers have moved
Padia et al ’ JVIR
away from routine prophylactic embolization of the gastroduodenal
artery and right gastric artery (73). Many cases of collateral vessel
formation have been observed following gastroduodenal and right
gastric artery embolization, and these collateral vessels are exceedingly
difficult to embolize (74,75). The degree of anticipated arterial stasis
during radioembolization is an important consideration when deciding
if prophylactic embolization is necessary.
Several techniques (in addition to coil embolization) have been
used to decrease the incidence of extrahepatic microsphere deposition.
A thorough evaluation of the technetium-99m (99mTc) macroaggre-
gated albumin (MAA) images should be performed to assess for
extrahepatic uptake. Free technetium should be excluded as a cause
of uptake in the stomach. In certain cases, a second mapping angio-
gram may be necessary if scintigraphic findings are concerning. The
concept of vascular redistribution (ie, occluding intrahepatic vessels
before radioembolization to induce redistribution of flow) has been
developed to simplify treatment and potentially avoid gastric vessels
(76,77). For example, in the case of a replaced left hepatic artery
originating from a left gastric artery, the gastrohepatic trunk is
embolized to redistribute flow to the left from the right hepatic artery.
This is commonly done for radioembolization with higher particle
loads. Finally, antireflux catheters (eg, Surefire, Surefire, Westminster,
Colorado) have played an increasing role in preventing reflux of
particles.
C-arm cone-beam CT is now routinely used intraprocedurally in
addition to digital subtraction angiography to determine vascular
supply to the tumor and detect potential extrahepatic vessels (78–82).
It allows for visualization of tumors as well as intraprocedural
guidance to position microcatheters in the appropriate vessels for
targeting (54). This intraprocedural imaging technique is strongly
recommended and may become the standard of care, but is currently
not mandated as a result of the lack of universal availability.
99m
Imaging with Tc MAA
Technetium-99m MAA scintigraphy is performed at the time of the
pretreatment angiography to quantify the LSF and identify nontarget
flow. It is important to recognize that the gold standard for assessment
of extrahepatic arterial flow is angiography (with or without cone-beam
CT) and not 99mTc-MAA scintigraphy. However, improved imaging
protocols and implementation of single-photon emission CT (SPECT)
will continue to play a role in confirming the lack of extrahepatic
deposition of 99mTc-MAA (83).
Choosing Hepatic Target Volume
The decision to use whole-liver, lobar, or selective (ie, two or fewer
hepatic segments perfused) approaches is dependent on the patient’s
baseline laboratory values, clinical characteristics, tumor distribution,
and vascular anatomy. In general, patients with better performance
status, adequate liver function, and lack of previous treatment tend to
tolerate treatment of larger hepatic target volumes. Targeting is
principally accomplished with angiography, use of c-arm cone-beam
CT, and correlation with preprocedural imaging. This allows an
appropriate level of vessel selection.
Lobar infusion is the most common approach for multifocal
disease. For whole-liver therapy, sequential lobar injections (typically
separated by 4–8 wk) are the most common method. In select
situations, especially in the setting of metastatic liver tumors in which
no underlying liver disease is present, whole-liver infusion can be
performed (via separate lobar injections in a single session). Selective
multivessel infusions can potentially avoid nontarget deposition in
proximal extrahepatic vessels (eg, cystic artery, supraduodenal artery).
Segmental radioembolization, whereby one or two hepatic segments
are treated, can be considered in patients with isolated tumor burden,
and may allow higher administered dose because most segments of the
liver would remain unaffected by treatment (15,16,84).
Volume 28 ’ Number 1 ’ January ’ 2017
DOSIMETRY
Standard dosimetric formulas are presented as follows:
Dose Calculation for Glass Microspheres
Dose calculations require the use of 3D-reconstructed cross-sectional
imaging to calculate the volume of the targeted liver tissue to be
infused. The volume (in milliliters) is then used to calculate the mass (in
grams) by multiplying it by a factor of 1.03 (conversion factor that
represents liver parenchymal density). The activity (A in Equation 1) in
gigabecquerels administered to the target area of the liver, assuming
uniform distribution of microspheres, is calculated using the following
the Medical Internal Radiation Dose formula as follows:
A¼D  m=50 [Eq 1]
Where D is the dose administered in Grays and m is the mass in
kilograms of the perfused tumor-bearing liver tissue. The dose delivered
to the treated mass also depends on the percent residual activity (R in
Eq 2) in the vial and tubing after treatment and the LSF, which is
calculated beforehand by using 99mTc-MAA scintigraphy. These
factors are accounted for in the following formula:
D¼A  50  ð1LSFÞ  ð1RÞ=m [Eq 2]
Although it is noted that this dosimetry model is independent of
tumor burden, for a given dose, different number of microspheres can
be administered to account for larger tumor size.
Dose Calculation for Resin Microspheres
The model of dosimetry for SIR-Spheres is based on whole-liver
infusion. The calculated activity of the whole liver is multiplied by
the percentage of the target site as a proportion of the whole liver. The
formula for dosimetry of SIR-Spheres is as follows:

of AFP trends can help direct future therapy. In cases of solitary HCC
A¼body surface area–0:2 þ % tumor burden=100
Where A is the activity in gigabecquerels, body surface area is
measured in meters squared, and “% tumor burden” is the percentage
of the liver that is involved by tumor. For treatment of less than the
whole liver, the dose is adjusted according to the proportion of liver
treated. A lower number of microspheres per activity can now be
administered when infused 1 day early relative to its calibration date.
Several drawbacks to both dosimetry models exist, leading many
experienced users to modify their approach to dosimetry with the intent
of maximizing tumor response and minimizing liver toxicity (85). For
example, many centers have adopted partition modeling for resin
microsphere dosimetry, which involves calculating tumor versus
nontumor distribution of dose (86,87). Other centers have adopted
quantitative SPECT/CT after 99mTc-MAA injection to adjust dosim-
etry for glass microspheres (88–90). This area is still under
investigation.
FOLLOW-UP AND OUTCOME ASSESSMENT
The response to radioembolization may be evaluated by using (i)
imaging findings, (ii) changes in tumor markers, and (iii) pathologic
findings (91–93). The clinical impact should be assessed as well, such as
change in energy levels and pain palliation. A clinic visit is recom-
mended with laboratory workup (including liver function tests) within
1 month of treatment. Radiologic evaluation is recommended at 1–3
months following treatment and at 3–6-month intervals thereafter.
Although early follow-up imaging at 1 month is often performed, one
should interpret tumor response with caution at such an early time
period, as the effects of radioembolization occur over several months.
Radiologic Response
The imaging modality (ie, CT vs magnetic resonance imaging) should
be consistent throughout the patient’s care to best assess response to
therapy. It may be difficult in some situations to have patients receive
7
the same imaging modality and temporal follow-up; if possible,
standardization is recommended.
Radiologic response has been shown to correlate with survival
(94). Tumor response can be measured strictly based on size by using
the World Health Organization criteria and Response Evaluation
Criteria In Solid Tumors (RECIST). In cases of enhancing tumors
(ie, HCC), the European Association for Study of the Liver (EASL)
and modified RECIST (mRECIST) guidelines (measuring change in
the amount of enhancing, ie, viable, tumor only) are commonly used
(95,96). The use of EASL guidelines and mRECIST for HCC has
numerous advantages over conventional size measurements, and has
been shown in multiple studies to be a better predictor of progression
and survival (97–99). Combining size and enhancement criteria has
been shown to improve the prediction of complete pathologic necrosis
at explant (100). Recently, use of the “primary index tumor” to assess
response following locoregional therapy in HCC has been reported,
thereby simplifying and standardizing response evaluation
methodology in HCC (101). The use of quantitative 3D imaging
assessment is a developing tool that may prove to have better accuracy
and correlation with outcomes (102,103).
Fluorodeoxyglucose (FDG) positron emission tomography is a
metabolic imaging technique that has a role in response assessment
following radioembolization of some metastatic hepatic tumors, but is
rarely used in the setting of HCC because HCC is not typically FDG-
avid (104–108).
Changes in Tumor Markers
Posttreatment changes in tumor markers, such as α-fetoprotein (AFP)
in HCC and carcinoembryonic antigen in colorectal metastases,
correlate to response to treatment. Recent studies support the use of
tumor markers following locoregional therapies (92). In many cases in
which response for HCC is challenging to assess with imaging, the use
and elevated baseline AFP level (4 200 ng/mL), AFP assessment may
outperform imaging in predicting long-term outcomes (109).
Tumor Progression
It is important to be able to recognize progression following treatment.
RECIST, mRECIST, World Health Organization, and EASL guide-
lines define progression distinctly. Progression should incorporate
development of new tumor, development or expansion of vascular
invasion, and development of extrahepatic metastases. As staged
therapy has become more accepted for liver malignancy, the differ-
entiation of local tumor progression and overall tumor progression is
vital in defining treatment success. In addition, the pattern of extra-
hepatic disease should be well-understood, particularly in HCC, to
avoid premature discontinuation of effective treatment (110).
Patient Mortality
Patient mortality unrelated to the intervention is expected as a result of
(i) cancer, (ii) progression of underlying liver disease (particularly in the
case of HCC), and (iii) other comorbidities. Mortality rates should not
be confused with survival. Mortality rates are represented by the
percentage of patients who have died at a specific time, whereas
survival data represent extrapolated medians calculated by using the
Kaplan–Meier method.
ADVERSE EVENTS
Published rates for individual types of adverse events (Appendix B) are
highly dependent on patient selection and may be based on series
comprising several hundred patients, which is a volume larger than
most individual practitioners are likely to treat. Generally, the adverse
event–specific thresholds should therefore be set higher than the
adverse event–specific reported rates listed here earlier. It is also
recognized that a single adverse event can cause a rate to cross
above an adverse event–specific threshold when the adverse event
8 ’ Quality Improvement Guidelines for Hepatic Radioembolization
occurs within a small patient volume, (eg, early in a QI program). In
this situation, the overall procedure threshold is more appropriate for
use in a QI program. All values in Table 3 were supported by the
weight of literature evidence and panel consensus.
Adverse events following radioembolization may occur as a result
of (i) a toxic dose to normal hepatic parenchyma, (ii) a toxic dose to
extrahepatic tissue, (iii) adverse events of angiography (eg, puncture
site adverse events, vessel dissection), and (iv) systemic side effects. It is
recommend to actively track additional clinical and biochemical
toxicities representing liver function abnormalities, such as bilirubin
toxicity and ascites.
Adverse events secondary to treatment delivery should be defined
by using the National Cancer Institute Common Terminology Criteria
for Adverse Events, version 4.03 (111). These criteria are designed to be
applied to all treatment modalities.
Hepatic Adverse Events
Hepatic adverse events include liver failure, portal hypertension
(caused by hepatic fibrosis), liver abscess, intrahepatic bilomas, and
liver infarction (112–117). Worsening ascites, jaundice, and laboratory
test results (eg, elevated total bilirubin) may indicate postprocedural
liver dysfunction.
The incidence of hepatic adverse events in the literature is highly
variable as a result of diverse patient selection, duration of patient
follow-up to assess for toxicities, and definitions for grading toxicities.
The presence of underlying cirrhosis (in the case of HCC) further
complicates this picture, as the natural history of cirrhosis progression
may be confounded with liver toxicity from radioembolization. This is
especially the case in patients with Child–Pugh class B and C disease,
as well as patients with rapidly deteriorating liver function before
treatment.
Multiple factors have been identified that place patients at
increased risk of hepatic dysfunction, especially the presence of
preexisting liver disease. For this reason, patients with Child–Pugh
class C disease are at markedly increased risk of further hepatic
toxicity, and radioembolization should be performed with extreme
caution. Patients with elevated baseline bilirubin levels, low albumin
levels, or the presence of ascites are not ideal candidates for radio-
embolization. Patients with metastatic liver tumors should have normal
background hepatic parenchyma, and therefore any hepatic laboratory
abnormality should raise concern. This often occurs when patients have
received numerous lines of systemic chemotherapy, some of which may
be hepatotoxic. Although several guidelines on absolute values of
acceptable liver function are available, one must also assess trends in a
patient’s liver function tests over time to assess their candidacy for
radioembolization.
REILD can present at any time after radioembolization, but
usually occurs at least 1 month after treatment. REILD is characterized
by abnormal liver function test results (including elevated alkaline
Table 3 . Adverse Events
Adverse Event
Radiation-induced liver disease
Biloma requiring percutaneous drainage
Abscess with functional sphincter of Oddi
Postembolization syndrome requiring extended stay or readmission
GI ulceration
Radiation-induced skin injury
Radiation-induced cholecystitis
Radiation pneumonitis
Radiation-induced pulmonary fibrosis
Iatrogenic dissection preventing treatment
Death within 30 d
Padia et al ’ JVIR
phosphatase and bilirubin levels), ascites, and fatigue in the absence of
tumor progression. Although the incidence of REILD is relatively low
(typically less than 4%), it can progress to liver failure and death (114).
Previous radioembolization, multiple lines of chemotherapy, abnormal
baseline liver function, single-session whole-liver therapy, and empiric
model dosimetry with resin microspheres have been identified as risk
factors for the development of REILD (55,114).
Biliary adverse events from radioembolization have been
reported, but are relatively uncommon compared with other intra-
arterial therapies, likely because of the minimally embolic effect of
radioembolization (112). Patients with biliary stents, obstructed bile
ducts, or previous manipulation of the ampulla of Vater are at
increased risk of cholangitis and bilomas. Such a history tends to be
more prevalent in the setting of intrahepatic cholangiocarcinoma, as
many of these patients initially present with biliary obstruction.
However, these should not be considered an absolute contraindi-
cation to radioembolization. Instead, a thorough assessment of
competing therapies and discussion with the patient regarding risks
should be undertaken. The use of prophylactic antibiotic agents, as per
the SIR antibiotics guidelines (116), may lower the rate of infection and
should be considered.
Hepatic abscess is a known adverse event associated with all
intraarterial therapies, including radioembolization. Its incidence is
relatively low, likely because of the minimally embolic effect of 90Y
microspheres. Management is usually conservative, but percutaneous
drainage may be required occasionally.
Hepatic fibrosis can be observed months to years after radio-
embolization, and may manifest clinically as portal hypertension.
Several case series demonstrating hepatic volume reduction and splenic
enlargement after radioembolization have been published (118–120).
Repeat treatments have been associated with an increased incidence of
fibrosis, and, in these cases, alternative therapies should again be
evaluated. Refinements in dosimetry may help to reduce the incidence
in the future, as the fibrosis likely occurs from microsphere deposition
into the normal hepatic parenchyma. In some scenarios, the develop-
ment of fibrosis in a treated lobe may be beneficial, as contralateral
lobar hypertrophy may occur, facilitating an eventual surgical resection
(119).
Extrahepatic Adverse Events
Extrahepatic adverse events can be separated into adverse events
resulting from systemic effects of radioembolization (eg, lymphopenia)
and extrahepatic deposition of injected material (ie, nontarget embo-
lization). The latter includes radiation pneumonitis and radiation-
induced pulmonary fibrosis, radiation cholecystitis, and gastrointestinal
ulcers. When these adverse events occur, reevaluation of relevant
details of the vascular anatomy from angiography and 99mTc-MAA
is recommended for QI purposes.
Reported Rate (%) Suggested Threshold (%)
1–4 5
o1 2
o1 2
1–2 4
0–5 3
o1 4
2 5
o1 1
o1 1
1 5
0–2 4
Volume 28 ’ Number 1 ’ January ’ 2017
Gastrointestinal ulceration remains one of the most concerning
sequela of extrahepatic deposition of 90Y microspheres. This occurs
from unintentional 90Y embolization to arteries supplying the stomach
or duodenum, such as the gastroduodenal artery, right gastric artery,
supraduodenal artery, left gastric artery, or accessory left gastric artery.
The consequences of gastrointestinal ulceration are potentially severe.
In the setting of metastatic disease, the use of biologic agents is not
recommended if gastrointestinal ulceration occurs. In addition, it may
be necessary to withhold systemic chemotherapy agents to allow for
healing. Because patients may have difficulty eating, weight loss and
poor nutritional status become a major concern, which may lead to
fatigue and decrease in performance status. Many patients may require
long-term proton pump inhibitors, intravenous nutrition, and narcotic
pain control. Overall quality of life is markedly affected in patients with
gastrointestinal ulceration, and symptoms may last for years.
In some cases, it may not be technically possible to safely
administer 90Y without a significant risk of nontarget embolization to
the bowel. In such cases, alternative therapies (eg, systemic chemo-
therapy, chemoembolization, bland particle embolization) should be
considered.
A recent series (121) has shown that stasis during injection of resin
microspheres, a proximal injection location, and a distal origin of the
gastroduodenal artery (even if coil embolization has been performed)
are the greatest risk factors for ulceration. Infusion should never be
performed from the region of the common or proper hepatic artery,
and, at the very least, lobar (eg, right hepatic artery) injections should
be performed. In the case of whole-liver infusions, a multivessel 90Y
approach to cover the entire liver should be chosen instead of infusion
from a proximal position.
Radiation-induced skin injury has been reported from micro-
sphere deposition in the falciform artery (122,123). Severe cases can
manifest in dermatitis or even skin ulceration. Many patients report
symptoms of superficial abdominal pain, which is thought to result
from falciform artery deposition. Because of the exceedingly low
incidence of severe adverse events from falciform artery uptake of
90
Y, it may not routinely require prophylactic embolization. In many
cases, the origin of the falciform artery is in a distal second- or third-
order left hepatic artery branch, and attempted catheterization may
cause spasm or dissection of the left hepatic artery. Therefore, risks of
coil embolization in these instances may exceed the potential benefits.
Inclusion of the falciform artery in the treated distribution is not an
absolute contraindication to radioembolization.
Radiation-induced cholecystitis is a well-known adverse event
when infusion is performed proximal to the cystic artery, and occurs in
as many as 2% of cases. Not uncommonly, the gallbladder wall may
enhance at follow-up imaging as a result of exposure to 90Y. This
finding is most commonly clinically innocuous. Several studies have
assessed the impact of prophylactic embolization (eg, gelatin, coils) of
the cystic artery, but a decrease in the rate of cholecystitis has not been
observed with these maneuvers (124). It is likely that cases of
cholecystitis after prophylactic embolization may be ischemic in
nature. Most instances of radiation-induced cholecystitis can be
managed conservatively with hydration, pain control, and antibiotic
therapy. In rare cases, cholecystectomy or percutaneous cholecystos-
tomy may be required; however, these measures should be reserved as a
last option (125). Prevention by administration of microspheres distal
to the cystic artery should be attempted whenever feasible.
Radiation pneumonitis is rare and likely occurs from hepatic
arterial–hepatic venous shunting, resulting in particle deposition to the
lungs. Its incidence can be controlled by appropriate dose reduction in
cases of elevated LSF. Elevated lung shunting is often seen with
infiltrative disease, high tumor burden, and portal vein invasion (126).
However, the presence of these factors should not preclude mapping
angiography, as many tumors with these features do not exhibit a high
degree of lung shunting. For glass microspheres, dose should be
reduced to keep a single-session pulmonary dose under 30 Gy (in a
patient with normal pulmonary function). Resin microspheres may be
dose-modified in the same manner, or can be reduced based on shunt
9
fractions exceeding 10% as recommend by the manufacturer. Interest-
ingly, a recent study of resin microspheres for HCC (21) reported two
deaths (among a total of 63 patients) secondary to radiation-induced
lung injury. In both these cases, large tumors with arterial–venous
fistulae were prophylactically embolized to lower the shunt fractions to
less than 20%, but were hypothesized to reform fistulae by the time of
treatment. Although chemotherapy was not administered in these two
cases, systemic chemotherapy may also play a role in predisposing
patients to radiation pneumonitis (127).
Vascular Adverse Events
Systemic chemotherapeutic agents may render blood vessels fragile.
Hence, vascular adverse events may occur more often following
systemic chemotherapy for secondary liver tumors. Biologic agents
have been widely known to cause vascular adverse events during
arteriography. The most common agent associated with vascular
adverse events is bevacizumab, a monoclonal antibody to vascular
endothelial growth factor commonly used in metastatic colon and
breast cancer. Arterial dissection, vasoconstriction, and poor vascular
flow have been reported (128,129). Therefore, it is recommended that
radioembolization proceed at least 4–6 weeks after the last dose of
bevacizumab. Careful selection and manipulation of microcatheters
and wires are mandatory in these situations.
Systemic Side Effects
Systemic side effects are frequent consequences of radioembolization,
but rarely result in substantial morbidity. The most common side effect
is a postradioembolization syndrome that consists of a combination of
fatigue and anorexia, occasionally with nausea, vomiting, fever, and
abdominal discomfort. Analgesic agents with or without oral steroids
may be considered. Patients may be given antiemetic agents such as
ondansetron on the day of treatment. Gastrointestinal prophylaxis with
H2 receptor blockers or proton pump inhibitors and may be consid-
ered. Postradioembolization syndrome is less severe than that observed
after other embolic therapies (such as chemoembolization) in which
fatigue and constitutional symptoms predominate (39,130,131).
Mild abdominal pain may be experienced following radioembo-
lization. Rare cases of significant pain during infusion have been
reported. This is often accompanied by nausea and diaphoresis,
occasionally with alterations in blood pressure and heart rate. It has
been attributed to an idiosyncratic reaction, often to resin microspheres
(39).
FUTURE DIRECTIONS
Future developments in radioembolization will continue to refine the
therapy, with the goal of expanding appropriate indications, improving
tumor response (and hence survival), and minimizing adverse events.
It is imperative that robust data be obtained for new indications
of radioembolization. For example, further research is needed to
appropriately define its role in the treatment of hepatic metastases
from uveal melanoma, sarcoma, renal-cell carcinoma, lung cancer,
pancreatic cancer, and prostate cancer. The challenge in obtaining data
is the relatively low incidence of liver-only or liver-dominant metastases
in these situations. For example, patients with liver metastases from
renal-cell carcinoma often present with concurrent pulmonary and
osseous metastases. Although radioembolization is not commonly
recommended in this setting, there may be instances in which extra-
hepatic metastases are being well-controlled by systemic chemotherapy.
This is especially true in breast cancer. In this scenario, radioemboliza-
tion may result in improved time to progression and patient survival. It
is widely believed that hepatic tumor progression in many of these
cancers represents the limiting factor in patients’ survival.
Comparative data of radioembolization versus other locoregional
therapies are important to collect, especially for primary liver cancer.
Several studies comparing chemoembolization and radioembolization
have shown no significant superiority of any one therapy in overall
10 ’ Quality Improvement Guidelines for Hepatic Radioembolization
survival (26–28,132). However, many of these studies had broad
inclusion criteria and included patients across the spectrum of Barce-
lona Clinic Liver Cancer staging. In several studies, even within the
same tumor stage, radioembolization was often offered to patients who
were not candidates for chemoembolization. Further work is needed to
compare these therapies based on tumor stage. For example, compar-
ing chemoembolization and radioembolization when performed in a
segmental fashion would be a fair comparison. Finally, many of the
previously published studies compared radioembolization versus che-
moembolization when the authors were experienced with chemoembo-
lization but were early in their experience with radioembolization. As
the radioembolization technique continues to be refined and improved,
comparative studies may indeed reveal differences in the future.
The combination of systemic chemotherapy and radioemboliza-
tion continues to be debated for primary and metastatic disease. In the
case of HCC, patients with certain features that portend a high
likelihood of future metastatic disease (eg, high AFP level, vascular
invasion) may benefit from the addition of a systemic agent in addition
to local arterial-based therapy. In the case of metastatic disease, the
safety of systemic agents may be potentially compromised by the
addition of radioembolization. Future studies should continue to focus
on the safety and efficacy of combined strategies, as this will likely
become the new paradigm for liver cancer treatment.
With further evolution and refinement of technology and techni-
ques, the efficacy of radioembolization will continue to improve for
primary and secondary hepatic malignancy. A wide range of tumor
response rates following radioembolization has been published. Further
research is needed to identify factors that could result in higher tumor
response rates without raising rates of hepatic toxicity. For example,
there has been significant work in improving dosimetry models for resin
and glass microspheres, acknowledging the limitations of the currently
accepted dosimetry formulas. Several publications on non–FDG
positron emission tomography–based dosimetry and quantified single
photon-emission CT dosimetry may help to create threshold doses to
achieve higher tumor response rates (133,134).
Further studies are needed to assess factors that result in hepatic
toxicity, especially radiation-induced liver disease. Refinements in
dosimetry can play a large role in reducing hepatic toxicity. In many
cases, this is unavoidable, especially when multifocal tumor is present.
However, refinements in dosimetry, use of segmental infusions, and use
of ancillary devices may help to improve rates of hepatic toxicity.
Several series have shown extraordinarily low rates of hepatic toxicity
from segmental radioembolization (15,16), as most of the hepatic
parenchyma is spared exposure to radiation. Future directions in
dosimetric quantification from the mapping 99mTc-MAA study may
further help to refine the dosimetry model.
Nontarget embolization of microspheres to the gastrointestinal
tract must be minimized, as radiation-induced ulcers represent a
significant cause of patient morbidity and can severely limit quality
of life. Future studies looking at various techniques to minimize
nontarget deposition are needed.
Finally, cost–benefit analyses are lacking in this arena. This is
becoming increasingly important as the trend to reduce overall health
care expenditures continues. Although many believe radioembolization
can be a costly procedure, cost–benefit comparisons of radioemboliza-
tion versus other techniques must take into account costs over specified
time periods (ie, cost per patient year of survival) as well as quality of
life (eg, number of days of hospitalization, days of work lost) (135).
CONCLUSIONS
Radioembolization has an established role in the management of
hepatic malignancies. Ongoing research will help to refine the technol-
ogy and techniques, further validate indications, and help determine its
exact place among other therapies for primary and secondary liver
cancer.
Padia et al ’ JVIR
APPENDIX A. CONSENSUS METHODOLOGY
Reported adverse event–specific rates in some cases reflect the aggre-
gate of adverse events of varying severities. Thresholds are derived
from critical evaluation of the literature, evaluation of empirical data
from Standards of Practice Committee members, and, when available,
the National Benchmarks from the National Quality Registry for
Interventional Radiology. Modified Delphi technique may be used to
enhance effective decision-making (136,137).
APPENDIX B. ADVERSE EVENT CLASSIFICATION
Adverse Event Description
A. Description narrative of adverse event (including sedation and
anesthesia)
B. Adverse event severity assessment*: escalation of level of care.
1. Mild adverse event: No therapy or nominal (non-substantial)
therapy (post-procedural imaging performed and fails to show
manifestation of adverse event); near miss (e.g., wrong site of
patient prepped, recognized and corrected prior to procedure,
wrong patient information entered for procedure, etc.);
2. Moderate adverse event: moderate escalation of care, requiring
substantial treatment, e.g., intervention (description of interven-
tion and result of intervention) under conscious sedation, blood
product administration, extremely prolonged outpatient obser-
vation or overnight admission post outpatient procedure not
typical for the procedure (excludes admission or hospital days
unrelated to adverse event);
3. Severe adverse event: marked escalation of care, i.e. hospital
admission or prolongation of existing hospital admission for >
24 h hospital admission that is atypical for the procedure,
inpatient transfer from regular floor/telemetry to ICU or com-
plex intervention performed requiring general anesthesia in
previously non-intubated patient (generally excludes pediatrics
or in circumstances where GA would primarily be used in lieu of
conscious sedation, e.g., in mentally challenged or severely
uncooperative patients);
4. Life-threatening or disabling event, e.g. cardiopulmonary arrest,
shock, organ failure, unanticipated dialysis, paralysis, loss of
limb or organ;
5. Patient death or unexpected pregnancy abortion
n
The SIR Adverse event Severity Scale is intended to approximate
the surgical Clavien-Dingo scale and the NCI CTCAE scale. The SIR
scale is tailored towards the procedures and adverse events encountered
in IR practices. The grading of interventional oncology adverse events
can selectively incorporate relevant adverse event grading definitions
published in the current CTCAE for oncological interventions, which
may be particularly relevant in the context of research publications. All
adverse events occurring within 30 days of a procedure should be
included in the adverse event description and analysis, regardless of
causality, in the interest of objectivity. The adverse event scale itself
does not assess operator performance.
Modifier:
M = multiple adverse events, each of which is counted and
evaluated separately if possible;
The preceding part refers to adverse event description and severity
characterization. It is suitable for scientific use (presentations, publica-
tions etc.) as well as for adverse event reviews within a practice,
practice group, facility or specialty.
The following part pertains to adverse event analysis. It is designed to
enable a confidential and constructive review of any adverse event
within an IR practice or practice group. Applicability for scientific
publications is limited and there is none for other public use. The
following content is meant to provide a strictly confidential, legally
Volume 28 ’ Number 1 ’ January ’ 2017 11

non-discoverable, non-punitive, objective, consistent and clinically ACKNOWLEDGMENTS

constructive analytic guide that may result in quality improvement
measures to advance the quality of patient care in interventional Siddharth A. Padia, MD, authored the first draft of this document and
radiology. served as topic leader during the subsequent revisions of the draft.
T. Gregory Walker, MD, and James E. Silberzweig, MD, are co-chairs
of the SIR Standards of Practice Committee. Boris Nikolic, MD,
Adverse Event Analysis MBA, is Councilor of the SIR Standards Division. All other authors
A. Causality are listed alphabetically. Other members of the Standards of Practice
Category 1. Adverse event not caused by the procedure Committee and SIR who participated in the development of this
Category 2. Unknown whether adverse event was caused by the guideline are (listed alphabetically): J. Fritz Angle, MD, Bulent Arslan,
procedure MD, Stephen Balter, PhD, Kevin Baskin, MD, Olga Brook, MD,
Category 3. Adverse event caused by the procedure Drew Caplin, MD, Michael Censullo, MD, Abbas Chamsuddin, MD,
B. Patient and procedural risk modifier: Christine Chao, MD, Marco Cura, MD, Mandeep S. Dagli, MD, Sean
R, Dariushnia, MD, Jon Davidson, MD, A. Michael Devane, MD,
Risk modifier: Eduardo Eyheremendy, MD, Florian Fintelmann, MD, Suvranu
Category 1. High risk patient AND technically challenging Ganguli, MD, Joseph J. Gemmete, MD, Vyacheslav Gendel, MD,
procedure Kirk Giesbrandt, MD, Jennifer Gould, MD, Tara Graham, MD, John
Category 2. High risk patient (e.g. ASA 4, uncorrectable coagul- Hancock, MD, Mark Hogan, MD, Bertrand Janne d’Othee, MD,
opathy, poor functional status (ECOG 3 & 4), poly- MPH, Ahmed Kamel Abdel Aal, MD, MSc, PhD, Sanjeeva Kalva,
pharmacy/polyintravenous therapy and transfusion, MD, Baljendra Kapoor, MD, Maureen P. Kohi, MD, Naganathan B.
septicemia, hemodynamic instability, recent cata- Mani, MD, Gloria Martinez‑Salazar, MD, Mehran Midia, MD,
strophic event/ICU admission/major surgery or inter- Donald L. Miller, MD, John Moriarty, MD, Christopher Morris,
ventions) etc. OR low risk patient and technically MD, Waleska Pabon‑Ramos, MD, MPH, Indravadan Patel, MD, Anil
challenging procedure (e.g. TIPS with occluded portal Pillai, MD, Uei Pua, MD, Ellen Redstone, MD, Anne C. Roberts,
vein, percutaneous biliary drain placement in non- MD, Tarun Sabharwal, MD, Cindy K. Saiter, NP, Marc Sapoval,
dilated biliary system, etc.) MD, PhD, Brian J. Schiro, MD, Samir Shah, MD, Paul Shyn, MD,
Category 3. No modifier Nasir Siddiqi, MD, LeAnn Stokes, MD, Rajeev Suri, MD, Timothy L.
C. Adverse event preventability Swan, MD, Naciye Turan, MD, Ulku Turba, MD, Aradhana
Category 1: Rarely preventable: i.e. well described and “typical” for Venkatesan, MD, Jeffrey L. Weinstein, MD, and Joan C. Wojak, MD.
the procedure and occurring despite adequate precau-
tionary and preventive measures
Category 2: Potentially preventable
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Volume 28 ’ Number 1 ’ January ’ 2017 15

SIR DISCLAIMER
The clinical guidelines of the Society of Interventional Radiology attempt to define principles that generally should
assist in producing high quality medical care. These guidelines are voluntary and are not rules. A physician may
deviate from these guidelines, as necessitated by the individual patient and available resources. These guidelines
should not be deemed inclusive of all proper methods of care or exclusive of other methods of care that are
reasonably directed towards the same result. Other sources of information may be used in conjunction with these
principles to produce a process leading to high quality medical care. The ultimate judgment regarding the conduct of
any specific procedure or course of management must be made by the physician, who should consider all
circumstances relevant to the individual clinical situation. Adherence to the SIR Quality Improvement Program will
not assure a successful outcome in every situation. It is prudent to document the rationale for any deviation from the
suggested guidelines in the department policies and procedure manual or in the patient’s medical record.