Vanden Hoven

Radioembolization of liver tumors
Andor Franciscus van den Hoven

PhD dissertation, Utrecht University, The Netherlands
Copyright © A.F. van den Hoven 2016

All rights reserved. No part of this publication may be reproduced or transmitted
in any form or by any means without permission from the author. The copyright of
articles that have been published or accepted for publication has been transferred
to the respective journals.
Financial support for the publication of this thesis was generously provided by:
Surefire Medical, Quirem Medical, TD Medical, Terumo Europe, Sirtex Medical.
Cover: iStock
Lay out: Roy Sanders
Print: GVO drukkers en vormgevers B.V.
ISBN: 978-94-6332-003-0
Radioembolisatie behandeling van lever tumoren

(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht

op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen op donderdag 21 april 2016
des middags te 4.15 uur
door
Andor Franciscus van den Hoven

geboren op 19 september 1988
te Bonn, Duitsland
Promotoren: Prof. dr. M.A.A.J. van den Bosch
Prof. dr. M.G.E.H. Lam

Copromotoren: Dr. M.S. van Leeuwen
Aan mijn zus
TABLE OF CONTENTS
Chapter 1. General introduction and outline 9
Part I: Overview
Chapter 2. Introduction to hepatic radioembolization 17
Part II: Treatment planning
Chapter 3. Hepatic arterial configuration in relation to the 59

segmental anatomy of the liver; observations on MDCT
and DSA relevant to radioembolization treatment
Chapter 4. Identifying aberrant hepatic arteries prior to intra- 81

arterial radioembolization
Chapter 5. The caudate lobe – the blind spot in radioembolization 105

or an overlooked opportunity?
Chapter 6. Arterial liver anatomy – introducing functional concepts 121

and terminology to break down the complexity
Chapter 7. Liver CT during radioembolization workup: Comparison 141

of an early and late arterial phase protocol
Chapter 8. Use of C-arm cone beam CT during hepatic 157

radioembolization: Protocol optimization for
extrahepatic shunting and parenchymal enhancement
Part III: Novel treatment strategies
Chapter 9. Hepatic radioembolization as a true single-session 179

treatment
Chapter 10. Posttreatment PET-CT confirmed intrahepatic 185

radioembolization performed without coil embolization,
by using the anti-reflux surefire infusion system
Chapter 11. Innovation in catheter design for intra-arterial liver 199
cancer treatments results in favorable particle-fluid
dynamics
Chapter 12. Study protocol of the surefire infusion system versus 221
standard microcatheter use during holmium-166
radioembolization (SIM) trial – a within-patient RCT
Part IV: Evaluation of treatment toxicity and efficacy
Chapter 13. Clinical and laboratory toxicity after intra-arterial 239

radioembolization with 90Y microspheres for
unresectable liver metastases
Chapter 14. Radiation-induced cholecystitis after hepatic 261

radioembolization: Do we need to take precautionary
measures?
Chapter 15. Insights into the dose-response relationship of hepatic 277

radioembolization with resin yttrium-90 microspheres:
A prospective cohort study in patients with colorectal
cancer liver metastases
Chapter 16. Anatomical versus metabolic tumor response assessment 301

after radioembolization treatment
Chapter 17. Yttrium-90 radioembolization for colorectal cancer liver 321

metastases: A prospective cohort study on circulating
angiogenic factors and treatment response
Chapter 18. The effect of intra-arterial angiotensin II on the 343

hepatic tumor to non-tumor blood flow ratio for
radioembolization: A systematic review
Chapter 19. Summary and discussion 363
Chapter 20. Addendum

Dutch summary (Nederlandse samenvatting) 387
Review committee 407
List of publications 411
Biography 415
Acknowledgments (Dankwoord) 419

C hap ter
1
General introduction and outline
Chapter 1
General introduction
LIVER TUMORS
Liver tumors are a major cause of cancer-related morbidity and mortality. Prima-
ry liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic
cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide
in men, and sixth in women. In 2012, an estimated number of 782.500 new cases
and 745.500 deaths occurred. Interestingly, the incidence of primary liver cancer
is decreasing in some areas with historically high rates (China, Japan), presumably
due to a reduction in hepatitis B and C virus infections through improved hygiene
and sanitation. Yet, the incidence in the United States has tripled between 1975 –
2011, which may be explained by increased hepatitis C virus infections related to
intravenous drug abuse, as well as an increased prevalence of diabetes and obesity.
Other risk factors for primary liver cancer include alcoholic liver cirrhosis, con-
sumption of aflatoxin-contaminated food, and smoking.1
A great number of patients with primary tumors that originate outside the liver,
including colorectal cancer, neuroendocrine tumors, uveal melanoma and breast
cancer, will eventually develop liver metastases at advanced stages of their disease.
Patients with colorectal cancer are especially at high risk to develop liver metasta-
ses, due to the direct route between the bowel and the liver for hematological and
lymphatic spread of metastatic cells. Indeed, up to 20 % of patients with colorectal
cancer present with liver metastases at diagnosis, and a further one-third subse-
quently develops liver metastases in the course of their disease.2 Furthermore, up
to 90 % of all deaths in patients with metastatic colorectal cancer are caused by
tumor-related liver failure.3
Thus, it is no surprise that research focuses on improving the treatment of liv-
er tumors. Which treatment option is preferred largely depends on the disease
stage. In patients with localized and limited disease, surgery is the treatment of
first choice. Radiofrequency ablation is becoming accepted as a less invasive alter-
native for small liver tumors.4 Once the disease has become irresectable, systemic
therapy or transcatheter therapy is preferred, dependent on the tumor type. While
the development of new chemotherapeutic agents and monoclonal antibodies has
enabled successful treatment of colorectal liver metastases5, efficacy is limited in
other types of metastases6 and primary liver tumors7-8. Transcatheter therapies,
such as transarterial chemoembolization and intra-arterial radioembolization, are
relatively new treatment options.
During radioembolization, the hepatic arterial vasculature is catheterized and
radioactive microspheres are injected under image-guidance to irradiate liver tu-
mors from within. In the past decennium, radioembolization has evolved as a safe
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Chapter 1
and effective treatment option for unresectable chemorefractory liver metastases

and locally advanced primary liver tumors.9 Yet, there are still aspects that require
improvement before this treatment can live up to its true potential.
AIM OF THE RESEARCH

This dissertation is the result of radioembolization research performed at the De-
partment of Radiology and Nuclear Medicine of the University Medical Center
Utrecht between 2012 and 2015. The aim has been to optimize radioembolization
treatment for liver tumors, from patient workup to treatment evaluation. Since the
studies included in this dissertation were linked to clinical practice, it also reflects
the hands-on lessons that we have learned during these years, and it shows how ra-
dioembolization practice has evolved in our department. Of special interest is our
multidisciplinary approach to radioembolization, with intensive collaborations
between abdominal radiology, nuclear medicine and interventional radiology, as
well as the early adoption of innovative concepts in our center such as a one-day
treatment approach, a within-patient randomized controlled trial study design, a
novel anti-reflux catheter and holmium-166 (166Ho) microspheres.
OUTLINE OF THIS DISSERTATION

This dissertation is divided into four parts, each containing several different chap-
ters that discuss the different stages of radioembolization treatment.
Part I (Chapter 2) gives a comprehensive overview of hepatic radioembolization.
Part II describes anatomical considerations and imaging strategies that are im-
portant during the workup of radioembolization candidates. Existing anatomical
classifications of the hepatic arterial vasculature did not reflect all variants that are
important during radioembolization. Chapter 3 presents an extended classification
that was created based on the analysis of individual hepatic arterial configurations
and segmental vascularization patterns on CT and DSA in radioembolization can-
didates. In Chapter 4, the critical appraisal of our own aberrant hepatic artery de-
tection in clinical practice is discussed, and a practical approach is presented to
ensure correct identification of aberrant hepatic arteries during radioembolization
workup. Chapter 5 deals with the uncertainties that exist around the arterial vas-
cularization and targeting of the caudate lobe during radioembolization. Chapter
6, a comprehensive review about hepatic arterial anatomy, which also includes a
proposition for standardized terminology and a reporting system for anatomical
- 11 -
Chapter 1
variants. Part II is concluded with our work on tailoring existing imaging proto-
cols of pretreatment liver CT (Chapter 7) and C-arm cone beam CT (Chapter 8)
towards specific radioembolization purposes.
Part III describes different aspects of the treatment itself. Chapter 9 discusses the
feasibility of using a true single-session treatment approach, supported by data
showing that liver-to-lung shunting is negligible in patients with colorectal liver
metastases. The use of a novel anti-reflux catheter is the subject of Chapters 10 – 12.
In Chapter 10, it is demonstrated in a case series that routine coil embolization of
gastrointestinal side branches of the hepatic artery is not necessary when using the
anti-reflux catheter. Chapter 11 shows the results of an in vitro study investigating
the effects of using the anti-reflux catheter on particle-fluid dynamics. Given the
promising effects of the anti-reflux catheter, a prospective clinical trial has been
initiated in our center to evaluate whether the use of the anti-reflux catheter can
improve 166Ho-radioembolization, for which the motivation and study design are
described in Chapter 12.
Part IV is concerned with the evaluation of treatment toxicity and efficacy. Early
on, there was uncertainty about the normal range of laboratory abnormalities af-
ter radioembolization. In Chapter 13, a retrospective study is presented in which
laboratory and clinical toxicity were analyzed in patients with liver metastases
who underwent yttrium-90 (90Y) radioembolization treatment in our center. This
is followed by a combined case report and systematic review on the need to take
precautionary measures against radiation-induced cholecystitis in Chapter 14.
Chapters 15 – 17 address different research questions using data from the RADAR
trial; a prospective cohort study in which patients with colorectal liver metastases
underwent radioembolization treatment with 90Y microspheres. An investigation
of the complex dose-response relationship in radioembolization is described in
Chapter 15. In Chapter 16, two different methods for tumor response assessment
are compared: reduction in target lesion diameter on MRI and metabolic activity
on 18F-FDG-PET. Chapter 17 contains an analysis of the association between cir-
culating angiogenic factor level changes after therapy and tumor response. Chapter
18 provides a systematic review on the potential role of using the vasoconstrictor
angiotensin-II during radioembolization procedures to enhance tumor targeting.
Finally, this dissertation is summarized and discussed in Chapter 19.
- 12 -
Chapter 1
REFERENCES
1. Jemal A, Bray F, Center MM, et al. (2011) 5. Siriwardena AK, Mason JM, Mullamitha S,
Global cancer statistics. CA Cancer J Clin et al. (2014) Management of colorectal can-
61:69–90. cer presenting with synchronous liver me-
tastases. Nat Rev Clin Oncol 11:446–459.
2. Leporrier J, Maurel J, Chiche L, et al. (2006)
A population-based study of the incidence, 6. Spagnolo F, Caltabiano G, Queirolo P
management and prognosis of hepatic me- (2012) Uveal melanoma. Cancer Treat Rev
tastases from colorectal cancer. Br J Surg 38:549–553.
93:465–474.
7. El-Serag HB (2011) Hepatocellular carcino-
3. Nagorney DM, Gigot JF (1996) Primary ep- ma. N Engl J Med 365:1118–1127.
ithelial hepatic malignancies: Etiology, epi-
8. Maithel SK, Gamblin TC, Kamel I, et al.
demiology, and outcome after subtotal and
(2013) Multidisciplinary approaches to
total hepatic resection. Surg Oncol Clin N
intrahepatic cholangiocarcinoma. Cancer
Am 5:283–300.
119:3929–3942.
4. Kim G-A, Shim JH, Kim M-J, et al. (2016)
9. Braat AJAT, Smits MLJ, Braat MNGJA, et
Radiofrequency ablation as an alternative
al. (2015) 90Y hepatic radioembolization:
to hepatic resection for single small hepato-
An update on current practice and recent
cellular carcinomas. Br J Surg 103:126-135.
developments. J Nucl Med 56:1079–1087.
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PART I
OVERVIEW
C hap ter
PART I 2
Introduction to
hepatic radioembolization
A.F. van den Hoven

D.Y. Sze
M.G.E.H. Lam
Handbook of Radioembolization: Physics, Biology, Nuclear Medicine, and Imaging [accepted]

Introduction to hepatic radioembolization
Part I
Chapter 2
GENERAL INTRODUCTION
What is radioembolization?
Radioembolization is a therapy during which radioactive microspheres are admin-
istered through a microcatheter placed in the hepatic arterial vasculature in order
to irradiate liver tumors from within. This therapy is based on the principle that
liver tumors are almost exclusively vascularized by the hepatic artery, whereas the
healthy liver tissue receives the majority of its blood supply from the portal vein.
Therefore, microspheres will be carried preferentially towards the distal arterioles
in and around tumors following administration in the hepatic artery. Clusters of
microspheres are formed inside and in the periphery of tumors, where they emit
high-energy β-radiation to induce cell death, while relatively sparing the healthy
liver tissue.1 Radioembolization is a minimally invasive, image-guided, locoregion-
al alternative or adjunct to more conventional therapies such as surgery, systemic
chemotherapy and external beam radiation therapy for patients with liver-domi-
nant malignancies. The advantages of this treatment are the targeted delivery of a
very high radiation absorbed dose to tumors, with limited systemic side effects and
hepatotoxicity.2
The efficacy and safety of radioembolization have been proven in patients with
primary liver tumors such as hepatocellular carcinoma (HCC)3 and intrahepat-
ic cholangiocarcinoma (ICC)4, as well as in metastatic liver tumors from various
kinds of primary tumor types, with colorectal cancer (CRC)5, breast cancer (BrC),
neuroendocrine tumors (NET)6, and uveal melanoma7 being the most common.
Typically, radioembolization is performed as a stand-alone treatment in salvage
patients with liver-dominant disease, but several clinical trials are currently evalu-
ating its role in earlier lines of treatment and in combination with systemic therapy
or other locoregional treatments such as radiofrequency ablation.
‘Radioembolization’ is used as an umbrella term for the treatment of liver tumors
with varying disease extents ranging from a single focal subsegmental liver tu-
mor to extensive disseminated or infiltrative disease, which can be hypo- to hyper-
vascular in nature, situated in livers that are relatively healthy, cirrhotic, partially
resected, transplanted, or heavily pretreated with systemic or intra-arterial che-
motherapy. These situations pose different kind of challenges and require other
approaches with regard to safety precautions, treatment planning and dose calcu-
lation, microsphere type usage, and catheter positioning during administration.
Furthermore, treatment techniques and strategies are dependent on operator expe-
rience and preferences and may differ considerably between practices.
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Part I
Chapter 2
Research continues to provide new insights into how to optimize radioemboliza-
tion treatment, and new indications continue to arise. Among the latest introduc-
tions are radiation segmentectomy as a potentially curative technique to eradicate
focal solitary liver tumors8, downstaging of unresectable disease to enable poten-
tially curative surgical resection or transplantation9, and radiation lobectomy to
induce contralateral hypertrophy as an alternative to portal vein embolization in
surgical candidates10-11. Applying radioembolization principles to the treatment of
solid tumors in organs other than the liver has also been provisionally explored,
but falls outside the scope of this book.
A BRIEF HISTORY OF RADIOEMBOLIZATION

Several earlier studies and discoveries set the backdrop for the clinical develop-
ment of radioembolization as a technique to treat liver tumors. These investigations
showed that large quantities of glass microspheres could be safely administered
intra-arterially in animal experiments12, that radioactive gold covered charcoal
particles given intravenously or yttrium oxide particles administered via a pul-
monary artery catheter could be used to treat lung cancer patients successfully13,
and that liver tumors, even ones that reached the liver via the portal circulation,
were preferentially vascularized by the hepatic artery when they exceeded about
50 microns in diameter14. The first report on radioembolization was published
in 1960 by the American surgeon Edgar D. Grady and his colleagues, affiliated
with Piedmont Hospital and Georgia Institute of Technology in Atlanta, Georgia,
USA.15 Subsequent preclinical and clinical investigations by Kim et al., Calderola
et al., Blanchard et al., and Ariel followed shortly thereafter.16-19 However, technical
aspects such as the method to access the hepatic vasculature, the site of adminis-
tration, safety precautions, size and material of the particles, and the radioactive
isotope and the amount of activity to be infused still needed to be refined in the
years to follow.
Experiments with New Zealand rabbits demonstrated that injection of radioac-
tive microspheres via the hepatic artery established preferential tumor targeting,
whereas injection via the portal vein did not18, which echoed early clinical results
in humans22. However, it proved challenging to catheterize the hepatic artery in
both animals and humans. Access methods included antegrade catheterization of
the celiac artery via brachial artery access, retrograde catheterization through fem-
oral arteriotomy with the use of a balloon below the level of the celiac artery, and
catheterization of the hepatic artery by accessing the gastroepiploic artery during
laparotomy.
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Part I
Chapter 2
Through trial and error it was learned that additional safety precautions were re-
quired, since extrahepatic deposition of radioactive microspheres (in the gastro-
intestinal tract or lungs) as well as too much radiation exposure of the healthy
liver tissue could result in life-threatening complications.20 For this reason, routine
‘skeletonization’ (a surgical term used to describe isolation of the main vascular
trunk by ligating all side-branches) of the hepatic artery, as well as injection and
imaging of radiolabelled albumin particles before treatment to simulate the thera-
peutic microsphere distribution, were advocated and eventually became standard
of practice.21-22
Initially, glass microspheres of 50 – 100 micron diameter were used. Soon, howev-
er, it was recognized that smaller resin microspheres (15 – 30 micron) were easier
to keep in suspension and would still not pass through the capillaries. After several
years of experimentation with other isotopes such as phosphorus-32 (32P)17,23, yt-
trium-90 (90Y) established its dominance. Reported benefits of 90Y included a pure
high-energy yield of tumoricidal β-radiation (max energy of 2.28 MeV), a short
soft-tissue penetration (max 11 mm), and a 64-hour half-life, which limited poten-
tial safety hazards for persons in close proximity to a treated patient. Early reports
did, however, acknowledge the importance of imaging the posttreatment micro-
sphere distribution and the limited possibilities inherent to the use of 90Y.19,24 The
secondary bremsstrahlung γ-ray produced by β-activity could be detected with a
Geiger-Muller survey meter or a scintillation crystal probe. Ariel even added yt-
terbium-169 (169Yb; γ-ray 52-310 keV; T1/2 32 d.) to the microspheres as a radiation
source for imaging with a γ-camera.19
Determining the optimal treatment activity (pretreatment dosimetry) has been a
challenge from the start.20 It was already recognized that the intrahepatic micro-
sphere distribution is highly heterogeneous after treatment, but imaging methods
available at that time precluded the assessment of the tissue mass exposed to radia-
tion. Therefore, treatment activity could not be adapted to effective tumor absorbed
dose and safe healthy liver absorbed dose values. Instead, the required treatment
activity was calculated based on a target whole liver absorbed dose of 5000 rads (50
Gy), which had been demonstrated as a safe dose in animal experiments. Doses
were prescribed based on the formula that per gram of liver tissue, 1 millicurie (37
MBq) would be required to deliver an absorbed dose of 182 rads (1.82 Gy).22
The first efficacy reports were case series reporting posttreatment survival and the
clinical condition of patients with primary or metastatic liver cancer. These results
were generally promising, and some cases showed unprecedented disease control,
but these reports were written prior to the availability of computed tomography,
- 20 -
Part I
Chapter 2
magnetic resonance imaging, and quantitative ultrasonography. Patients with in-
operable disease had no good alternatives at that time, since the effectiveness of
systemic chemotherapy and external beam radiation therapy remained disappoint-
ing. In 1989, Gray et al. published the first prospective trial results on radioemboli-
zation demonstrating an objective treatment response, defined as a decline of CEA
levels after treatment in 9/10 treated patients with colorectal cancer liver metasta-
ses.25 In the next two decades, only a few prospective studies followed in patients
with primary liver cancer and colorectal liver metastases.26-28 Among these studies
was the first randomized controlled trial, which demonstrated that the addition
of radioembolization to regional hepatic arterial chemotherapy (floxuridine) in
salvage patients with colorectal cancer liver metastases resulted in significantly im-
proved tumor response.
Eventually, 90Y microspheres received CE mark in the European Union and FDA
approval in the United States for the treatment of HCC and metastatic colorectal
cancer, which in turn led to a broader availability of radioembolization to patients
and a renewed scientific interest.
The past two decades have been characterized by an enormous growth in the wide-
spread use of radioembolization to treat salvage patients, with either primary or
metastatic liver cancer. It is increasingly acknowledged that, as long as the liver
disease is the survival-limiting factor in the patients’ prognosis, radioemboliza-
tion treatment is expected to be beneficial in patients with all kinds of liver-domi-
nant tumor types. Patient selection, workup, treatment technique, and analyses of
treatment toxicity and response have all been vastly improved. Modern imaging
techniques including multidetector contrast-enhanced CT, MRI, and C-arm cone
beam CT now allow for a detailed assessment of tumor location, tumor character-
istics and individual hepatic arterial anatomy before treatment. This enables the
operator to set a feasible individualized treatment strategy with the aim to achieve
adequate tumor targeting, while minimizing the chance of treatment-related com-
plications. The advent of nuclear medicine imaging techniques such as SPECT/CT
and PET/CT, as well as the development of non-90Y microspheres such as holmi-
um-166 (166Ho) microspheres, has enabled imaging of the particle distribution and
quantification of radiation-absorbed doses. It is now possible to identify an unfa-
vorable particle distribution early on when the treatment plan can still be modi-
fied. Tumor response assessment is also becoming less observer-dependent with
all the possibilities that functional MRI and 18F-FDG-PET imaging have to offer.
The challenges for the near future will be to clarify which patients will benefit most
from radioembolization, to improve methods for treatment activity calculations,
- 21 -
Part I
Chapter 2
to maximize treatment efficacy, to reduce treatment-related toxicity, to standardize

treatment technique, to enhance our understanding of relevant particle-fluid dy-
namics, radiobiology and systemic treatment effects, to explore combination ther-
apies, and to strengthen scientific evidence by proving superiority over conven-
tional and emerging therapies in large-scale phase III randomized controlled trials.
INDICATIONS FOR RADIOEMBOLIZATION

At this moment, the indication for radioembolization as a stand-alone therapy for
patients with liver metastases is primarily based on unresectable, liver-dominant
metastases refractory to standard systemic therapy. The standard for systemic ther-
apy differs per primary tumor type and per geographical location, and may include
cytotoxic chemotherapeutic agents as well as targeted small molecules, monoclonal
antibodies, and immunomodulators. The prevailing principle is that no other ther-
apy should be available with more convincing scientific evidence of effectiveness.
Patients with contraindications to or unacceptable toxicity from systemic therapy
are also eligible. Since large randomized controlled studies are currently in process
investigating the role of radioembolization combined with systemic therapy in the
first and second line treatment of colorectal cancer liver metastases, radioembo-
lization may potentially be performed earlier in the treatment cycle in the future.
In patients with HCC, radioembolization is generally reserved for patients with in-
termediate and early advanced disease stages.1 These are patients with large multi-
nodular tumors (n > 3, ≥ 3 cm), with or without macrovascular invasion, sufficient
liver function (Child-Pugh A – B), and an acceptable clinical condition (WHO
performance status score 0 – 2), corresponding to Barcelona Clinic Liver Cancer
staging system stages B – C.29 Some patients may have already failed chemoembo-
lization and/or systemic treatment with sorafenib, but radioembolization is offered
as an alternative to chemoembolization in some practices, even for earlier stage
disease.
Treatment with radioembolization should be considered relatively aggressive, and
must be technically feasible and clinically tolerable. Additional important criteria
for patient selection are summarized in Table 1. It should be noted that indications
and contraindications are subject to change over time as clinical experience, both
positive and negative, accumulate over the years.
- 22 -
Table 1: Eligibility criteria and contraindications for radioembolization
Eligibility criteria Contraindications
Relative Absolute
Good clinical condition WHO/ECOG PS > 2*
Life-expectancy ≥ 3 months Life-expectancy < 3 months
Adequate vital functions Mild laboratory abnormalities Severe laboratory abnormalities indicating critical liver,
renal or bone-marrow failure
Adequate portal venous liver vascularization Portal vein thrombosis** Prior portal vein
embolization or main portal vein occlusion
Adequate functional hepatic reserve Cirrhotic liver (Child-Pugh Score > B7), Uncompensated liver failure
Total bilirubin > 2.0 mg/dL (= 34.2 μmol/L)
Liver tumor burden < 70 % Liver tumor burden ≥ 70 %
- 23 -
Undisturbed biliary system Biliary stent or prior sphincterotomy, Active cholangitis
choledochojejunostomy, or hepaticojejunostomy***
Adequate arterial access Celiac axis and superior mesenteric artery occluded Occluded intrahepatic arterial network
Successful preparatory angiographic procedure Uncorrectable gastrointestinal microsphere deposition;
expected lung dose > 30 Gy (or 50 Gy cumulative)
Interval since last dose of systemic therapy Interval since last dose of systemic therapy < 4 weeks Active use of antiangiogenic agents
≥ 4 weeks (bevacizumab, aflibercept)
The most important eligibility criteria and associated contraindications for radioembolization are presented in this table. A distinction between relative and absolute
contraindications is made. *Corresponds to Karnofsky score < 50. ** No contraindication in HCC. *** May require antibiotic prophylaxis to prevent liver abscesses.
Abbreviations: WHO/ECOG PS = world health organization / eastern cooperative oncology group performance score.
Chapter 2 Part I
Part I
Chapter 2
COMPARISON OF RADIOEMBOLIZATION AND EBRT PRINCIPLES

Radioembolization is also referred to as selective internal radiation therapy (SIRT),
indicating that it is a preferentially tumor targeted form of brachytherapy that dif-
fers considerably from external beam radiation therapy (EBRT). Both therapies
aim to achieve tumor cell death through radiation-induced apoptosis and prolifer-
ative capacity inhibition.30 However, differences in the technical methods to target
the tumor have an important impact on the radiation distribution, as well as the
dose-rate and the possibility to fractionate the treatment dose, which in turn deter-
mines inherent strengths and limitations of both treatment modalities.
Conventional whole liver EBRT is no longer considered a viable treatment op-
tion. The healthy liver tissue is very sensitive to radiation, and whole liver absorbed
doses exceeding 30 Gy are associated with an increased risk of potentially fatal
radiation-induced liver failure.31–33 This phenomenon is even more pronounced in
patients with cirrhotic liver disease, or a prior history of hepatotoxic systemic ther-
apy. However, the introduction of image-guided, conformal, intensity modulated,
stereotactic body radiation therapy (SBRT) has made it possible to achieve high-
ly preferential tumor targeting, thereby sparing much of the adjacent and remote
healthy liver tissue.32-33 A safety margin of up to 2 cm surrounding the tumor is re-
quired, which can result in some hepatotoxicity. Three-dimensional images of the
liver are acquired during a simulation procedure, allowing drafting of a detailed
therapy plan. Patients subsequently undergo multiple treatment sessions, during
which photon beams produced by a linear accelerator apply small fractions of the
total radiation dose. The greatest advantage of EBRT is that the radiation can be
actively targeted with precision, yielding a predictable dose and treatment-effect.
The most important disadvantages are that it is not feasible to treat patients with a
high tumor burden, and that the maximum radiation dose delivered is still limited
by potential hepatotoxicity.
Radioembolization, on the contrary, depends on a hemodynamic mechanism for
tumor targeting. The interplay between catheter positioning, particle-fluid dynam-
ics and tumor vascularization ultimately determines the dose delivered to tumors
and to normal liver. Pathological examination of explanted livers that were treated
with radioembolization showed that the posttreatment microsphere distribution
was highly heterogeneous. Furthermore, the microspheres tended to cluster pref-
erentially in the periphery of the tumors with a concentration up to 200 times
greater than in the tumor core or in healthy liver tissue.34-35 Therefore, the great-
est benefits of radioembolization are that very high tumor-absorbed doses can be
achieved, and that treatment feasibility is less dependent on tumor burden. How-
- 24 -
Part I
Chapter 2
ever, inherent disadvantages are that tumor targeting can turn out to be subopti-
mal in patients with relatively hypovascular tumors, yielding highly variable tumor
response rates and liver toxicity, and that the accurate prediction of the therapeutic
microsphere distribution is a great challenge.
TYPES OF MICROSPHERES AND RADIONUCLIDES USED

Different types of radioactive microspheres are commercially available. The type
of microspheres can be divided based on the embedded radioactive isotope (90Y
or 166Ho) or microsphere material (resin, glass or poly-L-lactic acid). These micro-
spheres all have different production processes, physical characteristics, and meth-
ods of use. The most important characteristics of the different microsphere types
are summarized in Table 2.
Table 2: Microsphere characteristics

Isotope Yttrium-90 (90Y) Holmium-166 (166Ho)
Half-life 64.1 hours 26.8 hours
Decay product Zirconium-90 (90Zn) Erbium-166 (166Er)
Radiation emission β (max 2.28 MeV) β (max 1.74 & 1.85 MeV),
γ (max 81 & 1.38 KeV)
Energy per activity 49.67 J/GBq 15.87 J/GBq
Tissue penetration 2.5 mm mean, 2.5 mm mean,
11 mm maximum 8.4 mm maximum
Imaging PET (internal pair production), SPECT (γ-imaging)
SPECT (bremsstrahlung) MRI (R2* mapping)
Material Glass (ceramic) Resin PLLA
Product name TheraSphere® SIR-Spheres® QuiremSpheres®
Size 20 – 30 μm 20 – 60 μm 20 – 50 μm
Density 3.3 g/cc 1.6 g/cc 1.4 g/cc
Spheres per vial 1.2 – 8 x 106 20 – 80 x 106 33 x 106
Specific activity per sphere 2500 Bq 40 – 70 Bq 450 Bq
Max activity per dose 20 GBq 3 GBq 15 GBq
Dosimetry method recommended MIRD-based BSA-method MIRD-based
by manufacturer
Embolic effect Low Moderate Moderate
The characteristics of the glass and resin yttrium-90 microspheres and holmium-166 microspheres
are summarized in this table. Abbreviations: BSA = body surface area; mCRC = metastatic colorectal
cancer; MIRD = medical internal radiation dose; PLLA = poly-L-lactic acid.
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Part I
Chapter 2
YTTRIUM-90 MICROSPHERES
90
Y is a nearly pure (99.99 %) β-emitter. It has a half-life of 64.1 hours, and decays to
stable zirconium-90 (90Zn). With maximum beta particle (β-) energy of 2.28 MeV
– resulting in an energy release of 49.67 J/GBq – and a range in water or soft-tissue
of 2.5 mm (mean) and 11 mm maximum, it is a suitable radionuclide to treat can-
cer with an appropriate safety profile. Radioactive 90Y can either be produced by
neutron irradiation of stable yttrium-89 (89Y) or by chemical separation from the
parent isotope strontium-90 (90Sr), a fission product of uranium.36 Imaging of the
radiation emission from 90Y is a challenge due to the absence of γ-radiation emis-
sion. SPECT images can only be acquired by the detection of bremsstrahlung, sec-
ondary γ-radiation produced by slowing of the beta particles in tissue (Figure 1A),
a modality with very limited spatial resolution. Actually, 90Y has a minor branch
to the first excited state of 90Zn at 1.76 MeV (0+-0+ transition). As a result, once in
every 32 million (31.86 x 106) decays, an electron-positron (β-/ β+) pair is created.
This process is called internal-pair production and enables positron-emission de-
tection with PET at high 90Y-activities (Figure 1A).37
Figure 1: Schematic illustration of the physical properties and decay of 90

Y (A) and 166Ho (B) in
the liver. The upper row displays examples of the microsphere biodistribution in the liver using 90Y
bremsstrahlung SPECT (A upper left), 90Y PET (A upper right) 166Ho-MRI (B upper left) and 166Ho-
SPECT (B upper right). With permission of Springer.69
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Part I
Chapter 2
Glass and resin 90Y microspheres currently have near worldwide commercial avail-
ability. In 2002, resin 90Y microspheres received FDA approval for the treatment
of metastatic colorectal cancer when given in conjunction with floxuridine, and
received CE mark for the treatment of inoperable liver tumors. Glass 90Y micro-
spheres received United States FDA approval under a humanitarian device exemp-
tion in 1999 for the treatment of patients with HCC, including those with branch
portal vein thrombosis, and received CE mark in 2005 for the treatment of hepatic
neoplasms.
GLASS MICROSPHERES
Glass 90Y microspheres (TheraSphere®, Nordion Inc. for BTG International, Otta-
wa, ON, Canada) are produced by incorporating 89Y oxide into the glass matrix of
the microspheres and subsequent activation by neutron bombardment in a nuclear
reactor facility.38 Compared to the other microsphere types, glass 90Y microspheres
have a relatively high density, and a high specific activity per sphere (2500 Bq/
sphere). Therefore, ten to twenty times less particles need to be injected than with
resin microspheres to administer the same treatment activity. As a consequence,
the embolic effect is much smaller during injection, so the entire treatment dose
can be injected at once with a lower risk of stasis and particle reflux.
RESIN MICROSPHERES
The production process of resin 90Y microspheres (SIR-Spheres®, Sirtex Medical
Limited, North Sydney, Australia) is different; in this type of microspheres, 90Y
cations in solution are chemically incorporated onto the bland microsphere sur-
face by binding to the carboxylic group of the acrylic polymer matrix.39-40 Resin
microspheres have a much lower density than glass microspheres, which could
potentially result in a more distal distribution in the tumor vasculature.41 Further-
more, the relatively low specific activity requires injection of a higher number of
microspheres, approximately 20-80 million since this involves a greater embolic
effect, stasis of blood flow may occur during administration. For this reason, resin
90
Y microspheres must be administered carefully by hand injection in smaller ali-
quots, with intervening angiography to reevaluate pace of flow and degree of stasis.
Glass and resin microspheres may be used in different or similar tumor types and
disease extents, but it remains controversial how the differences in distribution
patterns impact treatment efficacy.
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Part I
Chapter 2
HOLMIUM-166 MICROSPHERES
The isotope 166Ho emits both high-energy β-radiation and low-energy γ-radiation.
It has a shorter half-life than 90Y (26.8 hours), and decays with a relatively high
dose-rate to the stable element erbium-166 (166Er). 166Ho emits β-radiation at two
energy levels, maximum 1.74 MeV (48.7 %) and 1.85 MeV (50 %), with a maxi-
mum soft tissue range of 8.4 mm. The resulting energy release is much lower (15.87
J/GBq) than with 90Y; therefore a larger administered treatment activity is required
to achieve the same radiation absorbed dose in liver tissue.42 The biodistribution of
166
Ho microspheres can be visualized on SPECT (Figure 1B), using the low-energy
γ-radiation (81 KeV, 6.2 %; 1.38 KeV, 0.93 %), and with magnetic resonance imag-
ing, utilizing the paramagnetic properties of 166Ho (Figure 1B).43
165
Ho acetylacetonate poly (L-lactic acid) particles are manufactured through a sol-
vent evaporation process, and subsequently activated in a nuclear reactor facility to
create radioactive 166Ho acetylacetonate poly (L-lactic acid) microspheres.44-45 The
density, size, specific activity per sphere, number of injected 166Ho microspheres
and embolic effect are comparable to resin 90Y microspheres. 166Ho microspheres
received CE mark approval, but no FDA-approval yet. The transition towards com-
mercial availability in Europe is ongoing. The safety of 166Ho-radioembolization
has been demonstrated in a phase I dose escalation study in patients with unresect-
able chemorefractory liver metastases from various primary tumor types, and the
results of a phase II clinical trial that investigated treatment efficacy are expected
to be released soon.
PRETREATMENT WORKUP
A thorough pretreatment workup is essential to screen patients for treatment eli-
gibility, and to ensure that radioembolization treatment is performed as safely and
effectively as possible. A standard workup includes laboratory and clinical investi-
gations, pretreatment cross-sectional imaging, a preparatory angiographic proce-
dure, simulation scout dose imaging, and pretreatment activity calculation.
LABORATORY AND CLINICAL INVESTIGATIONS

Laboratory and clinical investigations are used to assess vital functions and general
clinical status, and to record baseline values as a reference for toxicity assessments.
The laboratory investigations should include parameters to assess hepatobiliary
function (albumin, total bilirubin, gamma-glutamyl transferase, alkaline phospha-
tase, alanine aminotransferase, aspartate aminotransferase), renal function (cre-
atinine, estimated glomerular filtration ratio), coagulation status (platelet count,
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Part I
Chapter 2
prothrombin time, activated partial thromboplastin time, thrombin time, inter-
nationalized normalized ratio), and hematological function (hemoglobin and he-
matocrit, white blood cell count). Additional parameters to consider are tumor
markers (carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), chromogr-
anin-A (CgA), etc., depending on the tumor type and biomarker secretion), and
indicators for an acute infection (c-reactive protein) or cell tissue damage (lactate
dehydrogenase).
Deviations from reference values are expected, considering the severity of disease
in most patients. However, severe deviations (Common Terminology Criteria for
Adverse Events [CTCAE] grade 3-4) should be considered indicators of organ dys-
function, which may render radioembolization treatment unsafe.
Previous treatments, chronic diseases, recent periods of acute illness, current med-
ication use and allergies (especially for contrast agents) should be recorded during
clinical investigation. The general clinical status can be summarized by perfor-
mance status (as defined by the World Health Organization/Eastern Cooperative
Oncology Group): 0 – asymptomatic, 1 – symptomatic but completely ambulatory,
2 – symptomatic < 50 % of time in bed, 3 – symptomatic > 50 % of time in bed but
not bedbound, 4 – bedbound, 5 – dead. A performance status > 2 is considered
an exclusion criterion for radioembolization. Occasionally, a poorer performance
status may reflect toxicity from other therapies that is expected to improve after
discontinuation of those therapies, a potential exception to the guidelines.
PRETREATMENT IMAGING: LIVER CT/MRI AND 18F-FDG-PET

Cross-sectional pretreatment imaging is used for the evaluation of the liver paren-
chyma, vasculature, and presence and extent of extrahepatic disease. Computed
tomography (CT), magnetic resonance imaging (MRI), and whole-body [18F-] flu-
orodeoxygluclose (18F-FDG-PET) all play an important role.
For the evaluation of the liver parenchyma – characterization and localization of
liver tumors and their relation with surrounding vessels and biliary ducts – MRI
is superior to CT in terms of soft tissue contrast. Dynamic contrast-enhanced
sequences can be used to assess tumor hypervascularity and washout in a larg-
er number of phases, while diffusion weighted and T2-weighted imaging provide
options for high sensitivity tumor detection. Imaging with CT is faster, cheaper,
higher spatial resolution, and less susceptible to motion artifacts, but this comes
at the cost of ionizing radiation and iodinated contrast agent burden. When us-
ing CT, multiphasic images (arterial, portal venous, equilibrium phase) should be
acquired, and adequate timing of these phases is especially important to depict
- 29 -
Part I
Chapter 2
tumor types with different degrees of arterial vascularization. A late arterial phase
and an equilibrium phase are recommended for the imaging of hypervascular tu-
mors, while relatively hypovascular tumors are often best visualized on a portal
venous phase.46
An arterial phase and a portal venous phase are required for vascular assess-
ment. The arterial phase can be used to evaluate accessibility of the hepatic artery
(through the celiac axis and superior mesenteric artery), to reveal the individual
hepatic arterial anatomy including variants and parasitized arteries, and to identify
tumor-feeding branches. The portal venous phase allows for evaluation of the por-
tal and hepatic veins for patency and tumor invasion, and it confirms segmentation
of the liver.
The importance of oncological 18F-FDG-PET imaging is increasingly acknowl-
edged. 18F-FDG-PET has a high sensitivity for the detection of liver metastases,
especially in patients with tumor types that are expected to be PET-avid (chol-
angiocarcinoma, liver metastases from colorectal cancer, breast cancer and uveal
melanoma).47 Furthermore, 18F-FDG-PET shows more extrahepatic lesions than
CT during radioembolization workup in patients with mCRC, which can lead
to considerable changes in management.48 In patients with HCC and NET liver
metastases, the role of 18F-FDG-PET remains secondary, due to a less reliable tu-
mor-avidity on 18F-FDG-PET. Other tracers such as gallium-68 DOTATATE are
currently in development to improve the sensitivity of PET or scintigraphy in these
tumor types.
The liver tumor burden can be determined on all three imaging modalities, and
programs are being developed to segment the liver automatically based on thresh-
olds for contrast enhancement or metabolic activity. Some tumors replace liver pa-
renchyma, and some add to the total liver volume. Guidelines warn against treating
patients with liver tumor burden >70 % to ensure enough healthy liver tissue re-
serve to tolerate radioembolization; a measurement of volume and function of liver
tissue would be more valid, but is not currently standard.
ASSESSING THE INDIVIDUAL HEPATIC ARTERIAL ANATOMY

The functional anatomy of the liver is based on the branching pattern of the portal
vein, which usually parallels the hepatic artery and biliary ducts. According to the
Couinaud model of segmental anatomy, eight (or nine in the Couinaud-Bismuth
model) liver segments can be distinguished with a distinct vascularization and bili-
ary drainage. An avascular plane, called the portal scissura, separates the function-
al left and right liver. Cantlie’s line – an imaginary line drawn anteriorly from the
- 30 -
Part I
Chapter 2
middle of the gallbladder fossa to the inferior vena cava posteriorly – or the course
of the middle hepatic vein can be used to indicate this division on cross-sectional
imaging. The right hemi-liver is divided into an anterior and posterior sector by
the right portal scissura, as indicated by the course of the right hepatic vein. The
level of the portal bifurcation marks the distinction of superior and inferior seg-
ments in these sectors (segments 5/8 anterior, and segments 6/7 posterior). The
left hemi-liver is similarly divided into an anterior and posterior sector by the left
portal scissura, as indicated by the course of the left hepatic vein. The fissure for
the falciform ligament divides segment 3 and 4 in the left anterior sector, whereas
segment 2 forms the only segment of the left posterior sector. Segment 4 can also
be divided into cranial and caudal subsegments 4a and 4b. Segment 1 is situated
between the portal bifurcation and the inferior vena cava. This independent seg-
ment receives small branches from the left and right portal vein.49-50
Deep within the liver, hepatic arterial branches, portal venous branches and biliary
ducts run alongside one another, enclosed in the Glissonian sheath. The hepatic
arterial anatomy is nevertheless more complex and variable than the portal venous
anatomy. The reason for this is that anatomical variants of the hepatic artery can
occur on three different levels: the origin of hepatic arterial branches, the branch-
ing pattern of the hepatic arterial tree, and the segmental territory vascularized by
the individual hepatic arterial branches.51 Anatomical variants of the portal vein,
on the contrary, are mainly limited to variants in branching order.52
The standard arterial anatomy of the adult liver is described as a common hepatic
artery (CHA) originating from a celiac trifurcation that gives off the gastroduode-
nal artery branch (GDA) and then continues as the proper hepatic artery (PHA), to
divide into the left (LHA) and right (RHA) hepatic artery, vascularizing segments
2 – 4 and 5 – 8 respectively. However, approximately half of radioembolization
candidates have a variant to this configuration.51
An explanation of why variants of the hepatic arterial anatomy are so common
lies in the embryological development. During early development, three main ar-
teries exist: an embryological LHA (eLHA) originating from the left gastric artery
(LGA), an embryological middle hepatic artery (eMHA) from the celiac axis, and
an embryological right hepatic artery (eRHA) from the superior mesenteric artery
(SMA). The eLHA and eRHA should eventually regress, so that the eMHA forms
a separate LHA and RHA that take over the vascularization of the entire liver.53
However, one (or both) of the embryological arteries often persists, resulting in the
presence of a hepatic artery with an aberrant origin, a so-called aberrant hepatic
artery. Logically, most aberrant hepatic arteries originate from the LGA or SMA.
Aberrant hepatic arteries can be divided into replaced hepatic arteries that are the
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Part I
Chapter 2
main supply to the right or left hepatic lobe (or both in the case of a replaced
CHA), and accessory hepatic arteries that only supply a part of the lobe. In the lat-
ter case, the remaining part of the liver lobe is vascularized by a normally derived
counterpart of the aberrant LHA/RHA.
A variant in the order of arterial branching is present in up to 20 % of patients. In
these patients, an early branching LHA/RHA may be present as (part of) the LHA
or RHA that originates proximal to the GDA. Another variant is a trifurcation (or
quadrifurcation) of the CHA. This means that the PHA is absent, so that the CHA
branches into a GDA, LHA, RHA (and MHA).
Variants in the segmental vascularization pattern include variants in the origin
of the arteries vascularizing segments 1 and 4, as well as unexpected vascular ter-
ritories of aberrant hepatic arteries. The arterial feeding branch(es) to segment 4
may originate from the LHA, RHA, both, or from a separate origin of the CHA/
PHA. Segment 1 may in addition be vascularized by a branch originating from the
segment 4 artery.
All of the above outlined anatomical variants can coincide, leading to complex and
unexpected individual hepatic arterial configurations and segmental vasculariza-
tion patterns. Failing to identify aberrant hepatic arteries may result in incomplete
treatment, whereas incorrect judgment of the segmental vascularization pattern
may result in under- or overdosing of the treatment activity.54 Thus, it is essential
to assess the individual hepatic arterial anatomy in each patient.
Assessment on pretreatment arterial-enhanced CT or MRI enables identification
and characterization of anatomical variants, while providing guidance for subse-
quent catheterization during the preparatory angiography. Reading the pretreat-
ment CT or MRI should be done systematically, scanning all potential sources for
hepatic arterial branches, and following them up to their segmental territory of
vascularization, with attention for the order of branching. The fissure for the liga-
mentum venosum and the portocaval space should be screened with special atten-
tion, since these are the locations were the majority of aberrant LHAs and aberrant
or early branching RHAs respectively course before entering the liver.51,54
PREPARATORY ANGIOGRAPHY AND INTRAPROCEDURAL IMAGING

Preparatory angiography is performed before treatment to map the arterial anat-
omy, to allow prophylactic or redistributive coil embolization of arterial branches
if necessary, to determine optimal catheter positioning, and to administer a sim-
ulation scout tracer. Intra-arterial access is gained through transcutaneous punc-
ture, using the Seldinger technique, either through a transfemoral or transradial
approach. After securing the access site, a pre-shaped catheter is used to enter the
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Part I
Chapter 2
source of the hepatic arterial vasculature (usually the celiac axis). A standard end-
hole microcatheter is advanced over an atraumatic microguidewire for further se-
lectively catheterization.
Intra-procedural imaging with digital subtraction angiography (DSA) and C-arm
cone beam CT (CBCT) plays a pivotal role during the preparatory angiography.
DSA provides two-dimensional images of the vasculature at a high spatial reso-
lution, providing a high-resolution projectional map to guide the catheterization.
Furthermore, cinematic DSA images can be acquired during high rate contrast
administration with a power injector, thereby depicting arterial flow rates, tumor
blushes, and altered dynamics.
CBCT is a relatively new imaging modality that enables the acquisition of three-di-
mensional CT-like images, depicting contrast-enhanced vessels in relation to their
surrounding soft-tissue structures, by rotation of the C-arm mounted flat-panel
detector around the patient. The timing between contrast-injection and start of
the scan can be adjusted to influence whether the images mainly depict contrast
enhancement of the arterial tree (early arterial phase), the liver and tumor paren-
chyma (late arterial phase, Figures 2A-B), or both.55 The hepatic arterial anatomy
is mapped by a combination of DSA and CBCT. ‘Complete’ hepatic arteriography
should be performed to depict comprehensively all arteries supplying any portion
of the liver.54,56-58
A B
Figure 2: C-arm CT images demonstrating the arterial perfusion territory of the right (A) and left (B)
hepatic artery. These late arterial phase images were separately acquired, with contrast injection by a
microcatheter placed in the right and left hepatic artery respectively. Both the healthy liver parenchyma
and the tumor in the posterior part of the right liver lobe show contrast enhancement. Note how the
vascular territories of both arteries complement each other.
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Part I
Chapter 2
‘Complete’ hepatic angiography requires identification of parasitized extrahepatic

arteries (Figure 3). These are tumor-feeding branches that have been recruited from
arteries outside the hepatic vasculature (including prominent phrenic, intercostal,
omental, internal mammary, adrenal, renal capsular, gastric and pancreaticodu-
odenal arteries) by stimulation of neovascularization, and are found in 17 % of
radioembolization patients. These branches can often be embolized, causing intra-
hepatic arteries to take over the entire blood supply to the tumor, in order to ensure
complete tumor coverage during treatment.59 Failure to recognize these arteries
results in incomplete treatment.
Figure 3: Parasitized left inferior phrenic artery. A) The arterial phase of the pretreatment CT shows
a prominent left inferior phrenic artery coursing adjacent to the upper part of a large hypervascular
tumor mass (arrow). The suspected presence of a parasitized extrahepatic artery was confirmed during
angiography. B) Digital subtraction angiography acquired after selective catheterization of the left
inferior phrenic artery demonstrates intrahepatic tumor blush (arrow).
Since extrahepatic deposition of radioactive microspheres may cause serious com-

plications, it should be assessed whether side branches of the hepatic arterial vas-
culature pose a risk. The gastroduodenal artery (GDA), right gastric artery (RGA),
and supraduodenal arteries (SDA) deserve special attention. Non-target deposi-
tion into the cystic artery and the falciform artery are less likely to be life threat-
ening. The catheter can often be positioned distal to these side branches without
sacrificing tumor coverage, but this may require splitting of doses. If that is not
possible, prophylactic embolization with coils or vascular plugs may be performed.
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Part I
Chapter 2
Routine embolization of the GDA was previously a standard of care but has be-
come controversial, since this may actually induce the hypertrophy of new, very
small hepatofugal vessels during the interval between the preparatory angiography
and treatment.60-62 Alternatively, administration of yttrium microspheres using an
anti-reflux catheter or occlusion balloon catheter may provide a solution.63-64
Choosing the optimal catheter position(s) requires attention for the risk of extra-
hepatic shunting by evaluating the distance between catheter tip and patent gas-
trointestinal side branches, by evaluating tumor coverage by making sure that the
catheter is placed proximal to all tumor-feeding branches, and by evaluating flow
dynamics by recognizing preferential flow directions. In general, it is considered
impractical to use more than 2 – 3 injection positions. Coil embolization of in-
trahepatic arterial branches (for example the S4A, or an accessory LHA) may be
used as a means to reduce the number of required injection positions, since this
will induce redistribution of blood flow through intrahepatic collateral vessels.65-66
At the end of the preparatory angiography, it is advisable to do a test-injection
with contrast agent from the intended treatment positions. A gentle hand-injection
simulating the administration injection may reveal problematic flow dynamics
resulting in a disproportional microsphere distribution over tumor-bearing liver
segments, while a late arterial phase CBCT may show unintentional gastrointesti-
nal shunting or lack of target segment perfusion.55
After confirming adequacy of the catheter position(s), a simulation tracer test dose
of scout particles are injected. Circa 30 – 150 MBq technetium-99m (99mTc)-MAA
is used as a surrogate for 90Y microspheres, while a scout dose (250 MBq) of iden-
tical 166Ho microspheres is available for 166Ho microspheres treatment. DSA images
of the exact catheter position during injection should be stored.
The access site is closed by manual compression until hemostasis, or by using a
closure device.
IMAGING OF THE SCOUT DOSE DISTRIBUTION

Currently, imaging of the scout dose distribution is mainly performed for safety
reasons; to quantitate hepatopulmonary shunting and to rule out unintentional ex-
trahepatic deposition. Planar scintigraphy can be used to calculate the lung shunt
fraction after administration of 99mTc-MAA. For resin microspheres the manufac-
turer recommends to lower the treatment activity in patients with a lung shunt
fraction of 10 – 20 %, and to refrain from treatment in patients with a lung shunt
fraction of > 20 %. This is a convenient and simple recommendation, based on
whole liver treatment of average sized persons, but with some critical flaws. For
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Part I
Chapter 2
one, lung shunt fraction is less important than the estimated lung absorbed dose.
The latter should be kept below 30 Gy (or 50 Gy cumulatively in patients who un-
dergo sequential treatments). Second, planar scintigraphy based assessment gives
a less accurate estimation of the lung absorbed dose than SPECT/CT, often times
averaging hepatic dome activity into right lung base activity.67 Third, it has been
demonstrated that the use of 99mTc-MAA itself leads to an overestimation of the
true liver-to lung shunting, probably due to differences in particle characteristics,
the broad range of 99mTc-MAA particle size, and circulating free pertechnetate. 68-69
SPECT/CT is considered the gold standard for detection of unintentional extrahe-
patic activity in Europe. However, its relatively low spatial resolution and potential
occurrence of misregistration between the SPECT dataset and the low-dose CT
dataset can make the distinction between intra- and extrahepatic activity accu-
mulation challenging. For this reason, many centers now base their assessment of
extrahepatic perfusion primarily on CBCT.
The intrahepatic scout dose distribution should ideally be a good predictor for
the treatment distribution, since determining the particle distribution in tumorous
and non-tumorous tissue (T/N ratio) would enable a patient-tailored treatment
strategy. However, it has been demonstrated that the intrahepatic distribution of
99m
Tc-MAA is not a reliable predictor for the 90Y microsphere distribution, espe-
cially not in patients with relatively hypovascular liver tumors.70 This may be ex-
plained by the fact that the difference in particle characteristics, including different
particle size, density, shape and number, strongly impact the particle distribution.71
In patients with markedly hypervascular HCCs, preferential tumoral blood flow is
so strong that these differences in particle characteristics have less influence, mak-
ing the 99mTc-MAA distribution a more reliable predictor.72-73
Using a scout dose of particles identical to the treatment microspheres, such as
with 166Ho microspheres, may provide a more accurate prediction of the intrahe-
patic therapeutic microsphere distribution. Further investigation is required to
confirm this hypothesis, because differences in catheter positioning between the
scout procedure and the therapy procedure may also play an important role, the
embolic effect of a scout dose could theoretically change flow patterns, and even
the beginning and end of a partially embolic therapeutic administration could
have different dynamics.74-75
PRETREATMENT ACTIVITY CALCULATIONS

Different methods for pretreatment activity calculations (pretreatment dosimetry)
have been proposed. The empirical method is the simplest method. According to
this method, a fixed treatment activity of 90Y between 2 – 3 GBq (depending on the
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Part I
Chapter 2
tumor burden) is prescribed. This method is no longer advocated, because it has
been associated with unacceptable clinical toxicity.69
The Body Surface Area (BSA) method adjusts the prescribed activity for the pa-
tient’s BSA and the fractional tumor burden. It assumes a correlation between BSA
and liver weight, but this is not necessarily true for patients with liver cancer. As a
consequence, small patients with a relatively large liver will be undertreated, po-
tentially resulting in progressive disease, while tall patients with a small cirrhotic
liver will receive too much activity, which may result in hepatotoxicity.76 In the
vast majority of cases, however, it is a safe method to use, but it may be overly con-
servative for tumor-enlarged livers. The manufacturer of resin 90Y microspheres
recommends the use of this method.
The method based on Medical Internal Radiation Dose (MIRD) is recommended
by the manufacturer of glass 90Y microspheres. With this method, the prescribed
activity is determined by calculating the activity required to achieve a desired ab-
sorbed dose (usually between 80 – 120 Gy), assuming a homogeneous intrahepatic
microsphere distribution throughout the treated portion of the liver, and a known
yield of 50 Gy per GBq 90Y per kilogram of liver tissue. Although this method
accounts for liver mass, it neglects the inter- and intra-patient variability of in-
trahepatic microsphere distribution between tumorous and non-tumorous tissue
(T/N ratio). Nor does it account for fractional or total tumor burden. The activity
calculation method for 166Ho microspheres is also a MIRD method, with a fixed
target whole liver absorbed dose of 60 Gy (maximum tolerable dose derived from a
phase I trial), and the 166Ho specific energy yield of 15.87 Gy per GBq per kilogram.
An anatomic partition model could be the most scientifically sound method for
pretreatment activity calculations. This method extends the MIRD calculation by
incorporating the T/N microsphere uptake ratio, the weight of the healthy liver
tissue, and the maximum tolerable healthy liver absorbed dose. Partition models
are currently applicable for patients with few and well defined tumors where a T/N
ratio can be estimated. However, partitioning the liver into only 2 discreet volumes
is at best inaccurate and in many cases impossible when disease is diffuse, infiltra-
tive, and/or hypovascular. Physiologic and functional imaging methods are being
developed to address this patient population.
TREATMENT
Most centers perform the preparatory angiography and treatment sessions as out-
patient procedures, but some patients may require admission to the hospital before
and/or after undergoing treatment, since clinical observation and drug therapy
may be required. The treatment procedure is typically scheduled circa 1 – 2 weeks
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Part I
Chapter 2
after a successful preparatory angiography, but in some circumstances, can even be

performed on the same day as the preparatory angiography.
MEDICATION AND PERI-PROCEDURAL CARE

Monitoring of vital signs, with a heart rate monitor, ECG registration, pulse oxym-
etry, and periodic blood pressure measurements is considered standard. The use
of proton pump inhibitors or H2-receptor antagonists during the first week before
treatment and a month after treatment is recommended as prophylaxis for gastro-
intestinal ulcer formation. Furthermore, corticosteroids given for a few days or
weeks may help to mitigate the expected symptoms of postembolization syndrome.
Intravenous analgesia and sedation should also be considered during the proce-
dure to control pain and anxiety.77 Heparin (up to 50 IU/kg) may be administered
intra-arterially or intravenously at the beginning of the procedure, for thrombosis
prophylaxis. Intra-arterial administration of a vasodilator (nitroglycerine or a cal-
cium antagonist) is indicated if vasospasm occurs at any time during the procedure.
Patients treated for NET may require aggressive somatostatin analog prophylaxis
against carcinoid crisis from sudden hormonal release. Patients with entero-biliary
reflux from prior surgery, ERCP, sphincterotomy, biliary drainage, or biliary stent
are at high risk for abscess formation, and should be administered a long course of
prophylactic antibiotics before and after the procedure.
TREATMENT TECHNIQUE
During treatment, radioactive microspheres should be administered at the same
catheter position as during the preparatory angiography unless contraindications
were discovered from the scout dose simulation. In patients with bilobar disease,
treatment of both lobes can either be performed at once or in two staged treatment
sessions. The latter may be advisable in patients with a high tumor-burden, to allow
a more careful approach with regard to toxicity.
It is advisable to perform a last check with DSA and/or CBCT before the adminis-
tration, to make sure that no new hepatico-enteric collaterals have been recruited
in the interval between the preparatory angiography and treatment, and that the
catheter is indeed placed in the same position.
Although the administration systems of the different microspheres slightly differ
from each other, they all have: a vial that contains the radioactive microspheres in
an acrylic container, an afferent line that allows the operator to inject solution into
the vial, and an efferent line that connects the vial with the microcatheter. After
setting up the administration system, ensuring that no air is present in any of the
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Part I
Chapter 2
lines, administration of the microspheres can be started.
A 5 % glucose solution has replaced the formerly recommended sterile water for in-
jection of resin microspheres. Sterile water presumably leads to temporary changes
in blood osmolality, causing hemolysis, vascular endothelial damage, vasospasm,
and premature stasis of blood flow during injection. Recently, it has been demon-
strated that using isotonic 5 % glucose water instead reduces the occurrence of sta-
sis, reduces periprocedural pain, and improves the percentage delivered activity.78
Saline and iodinated contrast should not be used, to avoid the risk of displacement
of the yttrium-90 from resin microspheres via an ion exchange mechanism.
The injection technique differs significantly between glass 90Y microspheres and
resin 90Y microspheres or 166Ho microspheres, due to the significantly lower num-
ber of injected microspheres. Glass microspheres can be injected in a single bolus,
without angiographic monitoring, since stasis of blood flow or reflux is not ex-
pected. A typical injection with glass microspheres may be completed in less than
5 minutes. When using resin 90Y microspheres or 166Ho microspheres, however,
injection should be performed carefully, using short pulsatile pressure strokes on
the syringe (ideally a small syringe of 3 – 5 cc). The blood flow velocity should be
regularly checked, since the administration should be paused in slow flow condi-
tions, and stopped entirely when stasis occurs to prevent particle reflux. A change
in preferential blood flow direction can sometimes be observed during the admin-
istration, which may be explained by stasis in some branches and subsequent redis-
tribution of blood flow towards other branches. The treatment is completed if the
entire activity is administered, or when the administration is stopped prematurely
for stasis, which can take up to 30 minutes in total.
In order to determine the net administered activity, the vial, administration lines
and catheter may be checked for remnant activity with a dose-calibrator.
CATHETER TYPES AND PARTICLE-FLUID DYNAMICS

Two types of administration catheters are commercially available for radioembo-
lization procedures. The standard end-hole microcatheter remains the standard
default catheter for all embolotherapies in interventional radiology. This may be
explained by the low cost, simplicity of use, atraumatic character, and wide range
of available sizes and flexibility that allow for catheterization of small, tortuous
vessels. However, a disadvantage is that the catheter has no fixed support in the
vessel lumen. Therefore the microcatheter may deviate towards a vessel wall during
injection of microspheres, which can lead to streaming and preferential deposition
in daughter branches on the side of deviation.
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Part I
Chapter 2
A microcatheter specifically designed for embolotherapy, the Surefire Infusion Sys-

tem (Surefire Medical Inc., Westminster, CO, USA), has been developed to prevent
reflux during radioembolization. The tip of this anti-reflux catheter (ARC) dynam-
ically expands radially to make contact with the vessel wall during administrations
to prevent particle reflux without blocking antegrade blood flow. Using this ARC
makes embolization of side-branches proximal to the administration site unneces-
sary.79-81 Earlier studies also used occlusion balloons for administration, with similar
objectives.
It is the complex interplay between patient hemodynamics, vessel geometry, tumor
vascularization, microsphere characteristics, and catheter design/positioning and in-
jection technique that determines particle-fluid dynamics during the microsphere
injection. It is presumed that these factors have an important impact on the final
microsphere distribution, but unfortunately particle-fluid dynamics are still poorly
understood.
Under normal conditions, the flow pattern of blood in the hepatic arteries is laminar.
This means that blood flows in laminar columns, parallel layers of fluid that do not
cross laterally. If a microcatheter tip position is offset in the cross-sectional vessel
plane, aiming towards one of the vessel walls proximal to a bifurcation, and micro-
spheres are released into these blood flow layers at the same speed as the blood flow
velocities, down-stream branch targeting will be skewed towards the side of catheter
tip deviation.75 From clinical experience it is known that the slightest changes in cath-
eter position can have an impact on flow dynamics, as can be seen with DSA.64 Lab
experiments and computer simulations using computational fluid dynamics model-
ing demonstrated that downstream branches can actually be purposefully targeted
(in a controlled experimental setting) if the catheter position in the cross-sectional
vessel plane can be manipulated.82-86
When using an ARC, hemodynamics and particle outflow dynamics are affected.
One effect is that deployment of the ARC causes a blood pressure drop in the vas-
cular compartment distal to the tip.87 It is theorized that this may increase tumor
penetration by lowering the high interstitial pressure in tumors with hyperpermeable
tumor vasculature.87-88 Another distinct feature of the ARC tip is that deployment
of the tip converts the ordered laminar flow pattern into a chaotic turbulent flow
pattern. This may lead to a more homogeneous particle distribution over first-order
target branches than with a SMC, and may thereby prevent unintentional lack of tu-
mor coverage.75 Although a clinical study comparing tumor targeting with a standard
microcatheter and the ARC during radioembolization showed promising results89,
it remains unclear how the centro-luminal catheter position, down-stream pressure
gradient, turbulent particle-outflow pattern, and tumor vascularization would co-act
to improve selective targeting of tumorous tissue.
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Part I
Chapter 2
IMAGING OF THE THERAPEUTIC MICROSPHERE DISTRIBUTION
Imaging of the therapeutic microsphere distribution is increasingly performed.
Bremsstrahlung SPECT/CT was formerly the only technique available to depict
the 90Y distribution after treatment, and was limited by poor spatial resolution.
More recently, internal-pair production based PET/CT has largely replaced brems-
strahlung SPECT/CT due to its superior spatial resolution and lower scatter.90-91
The biodistribution of 166Ho microspheres can also be imaged by SPECT, using the
primary γ-radiation emission, as well as by MRI, by measuring the R2* dephasing
effects induced by the paramagnetic microspheres.43,92-93
Confirming an adequate intrahepatic treatment distribution as well as lack of ex-
trahepatic activity distribution seems a logical part of treating patients with ra-
dioembolization. However, this has not yet become standard of care. One of the
reasons is lack of financial reimbursement. Furthermore, low signal-to-noise ratio
on these images may limit the accuracy of both visual and quantitative assessments
of the 90Y-activity on PET/CT.94 Also, the clinical consequences of finding an unfa-
vorable microsphere distribution on posttreatment imaging remain uncertain and
irreversible. Nevertheless, 90Y-PET/CT and 166Ho-SPECT/CT should be incorpo-
rated into study protocols of future clinical trials on radioembolization, to gather
data about dosimetry and treatment outcomes.
DOSE-RESPONSE RELATIONSHIP
Several studies have shown an association between tumor absorbed dose and tu-
mor response and overall survival after radioembolization. Therefore, the goal is to
strive for a high tumor absorbed dose (Figure 4). However, a clear threshold or goal
for effective tumor absorbed dose has not been found.
Most dose-response investigations have been performed in patients with HCC
treated with glass 90Y microspheres.8,72,95-100 These dose-response relationships may
not apply to other cell types and microsphere types.101-104 The difference in tumor
biology between different tumor types may require a different amount of radiation
to induce tumor cell death, similar to findings in external beam radiation thera-
py.105 Furthermore, due to activity and distribution differences between resin and
glass 90Y microspheres, generally higher tumor absorbed doses are reported for
glass microspheres, without a significantly different biological effect.106
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Chapter 2 Part I
- 42 -
Figure 4: Clinical examples of colorectal carcinoma liver metastasis patients with adequate and inadequate tumor targeting. The upper row (A-E) shows a patient with
a large tumor mass on pretreatment T2W MRI (A) and 18F-FDG-PET (B) that extends from the central liver to the left liver lobe, which did not show a sufficient
tumor absorbed dose on 90Y-PET/CT (C). At 1 month posttreatment, progressive disease was noted on the MRI (D) and 18F-FDG-PET (E). The patient in the lower
row (F-J), on the contrary, had a metastasis in the posterior sector of the right liver lobe (F-G) that did have a sufficient tumor absorbed dose on 90Y-PET/CT (C). The
posttreatment MRI (I) at 1-month follow-up showed reduction in size, and 18F-FDG-PET demonstrated a complete metabolic response.
Part I
Chapter 2
Some authors report that an absorbed dose of 120 Gy is commonly considered
tumoricidal for HCC8, whereas colorectal cancer liver metastases may require at
least 70 Gy98. Yet, a recent literature review showed that the range of reported ef-
fective tumor absorbed dose values is extremely wide, with 66 – 495 Gy for resin
microspheres and 163 – 1214 Gy for glass microspheres. The differences in study
population and methods for quantifying tumor dose and response in these stud-
ies certainly contributes to this uncertainty. Even within an individual liver, two
studies independently demonstrated that there is high intra-individual dose-distri-
bution heterogeneity, and that inadequate treatment of at least one tumor is fairly
common in patients with colorectal cancer liver metastases.43,101
If effective tumor absorbed dose thresholds can be established for the different
types of microspheres and tumors, and imaging can monitor actual distribution
of therapeutic dose, an iterative administration technique should be feasible. Ad-
ditional treatment could be given to tumors that appear to have received inade-
quate initial treatment. If feasible, such a strategy should translate into improved
outcomes.
TREATMENT-RELATED LABORATORY AND CLINICAL TOXICITY

Complaints during treatment
Microsphere administration may sometimes induce complaints such as abdominal
discomfort, pain, nausea and vomiting. This can be accompanied by a vasovagal
reaction. The exact cause of these symptoms remains unclear, but clinical observa-
tion suggest that complaints often occur simultaneously with stasis of blood flow,
indicating that the embolic effect of therapy is causing symptoms. The symptoms
are self-limited and can last for days, but usually resolve on the day of treatment
with supportive medical therapy.
Laboratory toxicity
Abnormal laboratory values (liver function tests, complete blood count) should
be expected for several weeks after treatment. Mild to severe (CTCAE grade 3 –
4) laboratory toxicity may even occur in one-third of patients without signs of
associated clinical toxicity.107 Therefore, laboratory investigations are not suited to
discriminate between patients with and without a normal reaction to treatment.
Abnormal liver function tests (especially bilirubin level) in combination with asci-
tes, however, is an alarming finding that may indicate radioembolization-induced
liver disease (REILD).
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Part I
Chapter 2
Postembolization syndrome
The most common symptoms after radioembolization are fatigue, abdominal pain,
nausea, vomiting, low-grade fever and anorexia/cachexia. These symptoms con-
stitute the so-called post-radioembolization syndrome, which is related to com-
plaints after other embolo-therapies.108 These symptoms are considered an expect-
ed reaction to radioembolization treatment, and they are usually self-limited and
manageable with standard supportive medical treatment. Failure to recognize this
may unfortunately result in unnecessary extension of patient hospitalization.
Treatment complications
Treatment complications are uncommon, but can occur by accumulation of radio-
active microspheres outside the liver, or overexposure of the healthy liver tissue to
radiation.
Extrahepatic activity in the gallbladder wall, pancreas and gastrointestinal tract
may respectively result in radiation-induced cholecystitis, pancreatitis or gastric/
duodenal ulceration. Radiation-induced cholecystitis and pancreatitis are often
subclinical in presentation, but may in some cases cause severe morbidity. Radia-
tion-induced ulcers are particularly cumbersome because they originate from the
serosal surface instead of the mucosal surfaces as in normal peptic ulcers, impair-
ing the healing process and complicating surgical intervention. Detecting and cor-
recting extrahepatic shunting before treatment can prevent these complications.108
Accumulation of too much radioactive microspheres in the lung causes tissue
damage due to the combined effects of ischemia and radiation. Cases of radiation
pneumonitis have been described in the literature, many of them fatal, often asso-
ciated with hepatic venous and/or portal venous tumor invasion. To prevent this,
estimated lung absorbed doses should be kept < 30 Gy (or 50 Gy cumulatively).109
Additional exposure to pulmonary toxins such as chemotherapy may also com-
pound the risk.
Exposing the healthy liver tissue to high radiation absorbed doses during radio-
embolization may lead to the development of REILD within the first two months
after treatment. Clinically, it is characterized by jaundice, weight gain, ascites, and
a distinct rise in bilirubin, while transaminases and alkaline phosphatase are only
mildly increased. Pathologically, REILD is characterized by sinusoidal congestion,
venule occlusion by sloughed necrotic endothelium, and eventually fibrosis of the
liver. If severe, REILD can be fatal in the acute phase, but some patients with mild-
er REILD may develop chronic hepatic insufficiency and complications of portal
hypertension. The radiation tolerance of the liver tissue depends on the involved
volume, previous exposure to hepatotoxins including many common systemic
chemotherapeutics, and underlying cirrhosis.110
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Part I
Chapter 2
TUMOR RESPONSE ASSESSMENT
A variety of methods can be used to assess tumor response after radioembolization
treatment. These methods can be divided into morphologic and physiologic tumor
response assessment methods. Morphologic or anatomical assessment methods
only evaluate the treatment effect on tumor size/volume as visualized on cross-sec-
tional imaging. Physiologic or functional assessment methods assess the treatment
effect on tumor biology, including arterial vascularization, water diffusivity, and
glucose uptake (Figure 5). All of these methods strive to provide valuable prog-
nostic information using a reproducible method. In general, morphologic tumor
assessment is simple, standardized, relatively subjective, variably reproducible, and
time-consuming. Physiologic tumor assessments, on the other hand, are complex,
objective, and partly automated, but reproducibility is heavily dependent on the
technique for image acquisition, reconstruction and analysis. Unfortunately, only
few comparative studies have been performed to assess which methods work best
in radioembolization patients.
Figure 5: Early detection of tumor recurrence on functional imaging. This patient with colorectal cancer
liver metastasis had a good response after initial treatment with radioembolization, but developed
tumor recurrence in segment 4, 9 months after treatment. The metastasis is hardly visible on a standard
(T2W) MRI sequence (A), but was detected on DW-MRI (B) and on 18F-FDG-PET. The patient received
additional treatment of segment 4, based on this finding, and responded well to treatment again.
ANATOMICAL TUMOR RESPONSE ASSESSMENT

The ‘World Health Organization’ (WHO) published the first response criteria in 1981.
These criteria use the sum of the product (SPD) of tumor diameters (longest diam-
eter in the axial imaging plane and the one perpendicular to it) to evaluate whether
therapy led to significant tumor shrinkage. Response was classified into complete re-
sponse (CR, -100 %), partial response (PR, -50 – 99 %), stable disease (SD, -49 – +25
%) and progressive disease (PD, > +25 %), based on the percentage of change in SPD.
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Part I
Chapter 2
The Response Evaluation Criteria In Solid Tumors (RECIST) system was intro-
duced to simplify the evaluation, was found to correlate highly with the WHO
system, and version 1.1 is now the most widely used response classification system
in solid tumors. It uses the sum of the longest one-dimensional tumor diameters
in two target lesions on cross-sectional imaging to classify response into the same
categories as the WHO criteria (CR -100 %, PR -30 – 99 %, SD -30 – +20 %, PD
> +20 %). Target lesion response can also be extended to liver response and over-
all (whole-body) response, by incorporating information about the size change in
non-target lesions, and the appearance of new lesions in or outside the liver.111
Studies generally report either the best response during follow-up, or the objective
response rate (CR + PR) or disease control rate (CR+PR+SD) at a specific time of
follow-up.
There are no guidelines on the required time-intervals for follow-up imaging, but
most oncology studies adapt follow-up to chemotherapy treatment cycles (for ex-
ample in intervals of 3 weeks) and interventional radiology treatments often use
1, 2, and/or 3 months posttreatment. If scans are performed with short intervals
(i.e., < 6 weeks), parameters such as time to progression (TTP) or progression free
survival (PFS) may be used.112
RECIST has been adopted as the standard for response assessment by both re-
search institutions and regulatory authorities. It functions as a surrogate endpoint
for overall survival, provides important prognostic information (especially in ther-
apies where tumor shrinkage is expected such as cytotoxic chemotherapy), is rela-
tively simple and reproducible, and does not require state-of-the-art imaging facil-
ities. However, its validity is questioned for therapies where response to therapy is
not always associated with lesion shrinkage, such as radioembolization, ablation,
and some systemic treatments such as immunotherapy.
FUNCTIONAL TUMOR RESPONSE ASSESSMENT

Modern imaging technology has enabled a more physiological approach to tumor
response assessment. Modified RECIST (mRECIST) has been developed to ad-
dress the issue that a change in arterial tumor vascularization might be more rep-
resentative than a change in entire tumor size in patients with HCC treated with
locoregional therapy. Similar to RECIST, longest diameter is measured but only of
the viable (arterially enhanced) portion of the tumor. Lack of arterial tumor en-
hancement on follow-up imaging, even if the total lesion size is unchanged or even
increased, is considered a complete response (CR).113 The other response catego-
ries are defined similarly as with RECIST, based on the enhanced tumor diameter
measurement.
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Part I
Chapter 2
More quantitative approaches are offered by dynamic contrast-enhanced magnetic
resonance imaging (DCE-MRI). With DCE-MRI, serial images are acquired be-
fore, during and after contrast agent administration, allowing for contrast kinet-
ic modeling with time–signal intensity curves.114 MRI can also be used to assess
functional tumor response by diffusion-weighted imaging (DWI). The principle
behind this imaging technique is that the water diffusivity is restricted in tumors,
as opposed to healthy liver tissue. Diffusivity can be quantified by calculating ap-
parent diffusion coefficients (ADC). An increase of ADC after treatment indicates
treatment response.115
18
F-FDG-PET is also increasingly used to assess treatment response. Standardized
uptake values (SUV) can be used to quantify the selective uptake of the 18F-isotope
labeled glucose analogue in malignant tissues.116 A combination of SUV and met-
abolic tumor volume – called tumor lesion glycolysis or metabolic product – may
be especially interesting, since this reflects the total glucose turnover in a tumor.
Many options are available when acquiring, reconstructing and analyzing PET
data, yet none of these methods has proven to be clearly superior to the others, and
they may lead to different results.117 An attempt to standardize response analysis,
‘PET Response Criteria In Solid Tumors’ (PERCIST) has not resulted in the same
widespread adaptation as with the RECIST criteria.
CONCLUSION
In the past decades, radioembolization has evolved into a safe and effective liver
cancer therapy. Despite major advances brought by modern imaging technology
and clinical experience, improvement of patient workup, treatment technique, tox-
icity and response assessment is an ongoing process. In the following chapters,
these subjects will be discussed in further detail.
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Part I
Chapter 2
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PART II
TREATMENT
PLANNING
C hap ter
PART II 3
Hepatic arterial configuration
in relation to the segmental
anatomy of the liver;
observations on MDCT
and DSA relevant to
radioembolization treatment
A.F. van den Hoven

M.S. van Leeuwen
M.G.E.H. Lam
M.A.A.J. van den Bosch
CardioVascular and Interventional Radiology 2015

Hepatic arterial configuration in relation to the segmental anatomy of the liver
Chapter 3 Part II
ABSTRACT
Purpose
Current anatomical classifications do not include all variants relevant for radioem-
bolization (RE). The purpose of this study was to assess the individual hepatic ar-
terial configuration and segmental vascularization pattern and develop an individ-
ualized radioembolization treatment strategy based on an extended classification.
Materials and Methods
The hepatic vascular anatomy was assessed on MDCT and DSA in patients who
received a workup for radioembolization between February 2009 and November
2012. Reconstructed MDCT studies were assessed to determine the hepatic arterial
configuration (origin of every hepatic arterial branch, branching pattern and ana-
tomical course) and the hepatic segmental vascularization territory of all branches.
Aberrant hepatic arteries were defined as hepatic arterial branches that did not
originate from the celiac axis/CHA/PHA. Early branching patterns were defined as
hepatic arterial branches originating from the celiac axis/CHA.
Results
The hepatic arterial configuration and segmental vascularization pattern could be
assessed in 110 of 133 patients. In 59 patients (54 %) no aberrant hepatic arteries
or early branching was observed. Fourteen patients without aberrant hepatic arter-
ies (13 %) had an early branching pattern. In the 37 patients (34 %) with aberrant
hepatic arteries, 5 also had an early branching pattern. Sixteen different hepatic
arterial segmental vascularization patterns were identified and described, differing
by the presence of aberrant hepatic arteries, their respective vascular territory and
origin of the artery vascularizing segment 4.
Conclusion
The hepatic arterial configuration and segmental vascularization pattern show
marked individual variability beyond well-known classifications of anatomical
variants. We developed an individualized radioembolization treatment strategy
based on an extended anatomical classification.
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Part II Chapter 3
INTRODUCTION
The extensive research of the past has provided insight in the large individual vari-
ability in the origin of the hepatic arteries.1-6 However, current classifications of
variant hepatic arterial anatomy do not include all variants relevant for hepatic
radioembolization, such as early branching patterns, a variable origin of the ar-
tery vascularizing segment 4 (S4), and the vascular territory of aberrant hepatic
arteries. Correct identification of these variants may have a significant impact on
treatment strategy, including coil embolization of aberrant arteries, planning the
number of injection positions, and pretreatment activity calculation.
Both the origin and the vascular territory of the hepatic arteries differ notably in
the embryological from the adult liver. In the early stages of hepatic formation,
an embryological left hepatic artery (eLHA) originates from the left gastric artery
(LGA) and supplies S2, whilst an eRHA originates from the superior mesenteric
artery (SMA) and vascularizes segments 6-7. The eMHA originates from the celiac
axis and vascularizes the remaining S3,4,5,8 of the liver.7-8 Eventually, the eLHA
and eRHA regress and the eMHA persists, resulting in a normal hepatic arterial
configuration of the adult liver, in which the celiac axis gives rise to a left (LHA)
and right hepatic artery (RHA). When the eLHA or eRHA fails to regress, one or
more aberrant hepatic arteries persists.
Aberrant hepatic arteries, defined as hepatic arterial branches that do not originate
from the celiac axis, common (CHA) or proper hepatic artery (PHA), are common
(reported prevalence, 21 – 45 %).1-5 Frequently encountered variants are aberrant
LHAs originating from the LGA and aberrant RHAs originating from the SMA.
According to the early work of Michels, aberrant hepatic arteries can be further
divided into accessory and replaced hepatic arteries, both with a unique territory
of blood supply within the liver.1 A replaced hepatic artery is a full substitute for
the LHA or RHA originating from the celiac axis. An accessory hepatic artery, on
the other hand, complements its normally derived counterpart, and only supplies
a part of the right or left hemi-liver.1,9
To the best of our knowledge, the relation between the individual arterial branches
and their corresponding arterial segmental territories has not been described for
patients with aberrant hepatic arteries. Therefore, the vascular territory of accesso-
ry hepatic arteries remains unknown. The combination of aberrant hepatic arteries
and a variable origin of the artery vascularizing S4 can result in highly variable
individual patterns of segmental hepatic arterial vascularization that may require
different treatment strategies.10-11 Technological advances enable an accurate pre-
treatment assesment of the hepatic arterial anatomy on multidectecor computed
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Chapter 3 Part II
tomography (MDCT). Consequently, a treatment strategy, tailored to the patient’s

individual anatomy, can be determined before the pretreatment angiography.
The aim of this study was to assess the individual hepatic arterial configuration
(presence of aberrant hepatic arteries and order of arterial branching) and the arte-
rial segmental vascularization pattern on triphasic MDCT and digital subtraction
angiography (DSA) in patients receiving a workup for radioembolization. Further-
more, we aimed to develop an individualized radioembolization treatment strategy
based on an extended classification of variant hepatic arterial anatomy.
PATIENTS AND METHODS

Patients
All patients who were evaluated for radioembolization between February 2009 and
November 2012 in our institute were included in this study. These patients were
all diagnosed with primary or metastatic liver cancer and received a triphasic liver
MDCT and standard pretreatment angiography specifically to assess the eligibility
for radioembolization. During the angiography, DSA of the hepatic arteries was
obtained (Allura Xper FD 20, Philips Medical Systems, Best, The Netherlands) and
technetium-99m-labelled macro-albumin aggregates (99mTc-MAA, TechneScan
LyoMaa, Mallinckrodt Medical, Petten, The Netherlands) were administered to
assess the eligibility for radioembolization. Exclusion criteria for this study were:
prior extensive liver surgery, non-assessable anatomy of the hepatic vasculature
due to severe cirrhotic liver disease or massive tumor involvement. These data were
also used in another study.12 Our institutional ethics committee waived the need
for informed consent for this retrospective study.
Imaging Protocol
A 16-, 64-, or 256-detector row CT scanner (MX 8000; Brilliance 64; Brilliance
iCT; Philips Medical Systems, Eindhoven, The Netherlands) was used to obtain
triphasic MDCT images. Alternatively, in some patients the triphasic liver CT scan
was acquired on an integrated positron emission tomography – computed tomog-
raphy (PET-CT) system (BiographTM mCT, Siemens Healthcare, Erlangen, Germa-
ny). After injection of intravenous contrast, hepatic arterial, venous and equilibri-
um phase images were obtained with a postthreshold (aorta, > 100 HU) delay of
20, 55 and 300 s respectively. All patients received 1 L of oral diluted water-soluble
contrast agent (Telebrix Gastro, 300 mgl/ml). Depending on body weight, 150 or
200 ml contrast (Iopromide 300 mgl/ml; Ultravist, Bayern Schering Pharma AG,
Berlin, Germany) was injected in an anticubital vein, at a rate of 5 ml/s.
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Part II Chapter 3
Image interpretation
CT images were analyzed on a workstation (Intellispace Portal; Philips Medical
Systems). First, the portal phase was reviewed to determine the schematic liver
segmentation, based on Couinaud’s classification of segmental liver anatomy. To
this purpose, the left, middle, and right hepatic veins were used to indicate the ver-
tical scissurae, and a horizontal plane through the right portal trunk was assumed
to indicate the transverse scissura.
Subsequently, axial and coronal maximum intensity projections (MIP) of the ar-
terial phase were reviewed to determine the origin of all hepatic arterial branches
and follow their course up to their segmental territory of the liver. We named this
the hepatic arterial segmental vascularization pattern (Table 1).
Table 1: Terminology
Term Definition
Standard hepatic arterial configuration No early branching pattern and no aberrant hepatic
arteries.
Variant hepatic arterial configuration Early branching pattern of the hepatic arteries and/or
aberrant hepatic arteries.
Trifurcation of the CHA (i.e. absence of the PHA), early
branching LHA and/or RHA from the CHA (proximal to
Early branching pattern
the origin of the GDA) or LHA and/or RHA originating
directly from the celiac axis.
Aberrantly derived hepatic artery, not originating from the
Aberrant hepatic artery celiac axis, CHA or PHA. Aberrant hepatic arteries can be
divided into accessory and replaced hepatic arteries.
Aberrant hepatic artery that vascularizes the left (S2)
Accessory hepatic artery or right hemi-liver partially (any segments), existing in
addition to a normally derived LHA and RHA.
Aberrant hepatic artery that vascularizes the left (S2-3 or
S2-4) or right hemi-liver (S5-8). A rCHA exists when the
Replaced hepatic artery
entire hepatic trunk is replaced to another source than the
celiac axis.
Arterial segmental Hepatic segmental estuaries of the individual hepatic
vascularization pattern arteries.
Segment 4 artery (A4) Hepatic arterial branch vascularizing S4, and originating
from the LHA and/or RHA.
Middle hepatic artery (MHA) Hepatic arterial branch vascularizing S4, and originating
directly from the CHA or PHA.
The definitions for the anatomical terminology used in this manuscript are summarized in this table.
The definitions for aberrant hepatic arteries, replaced and accessory hepatic arteries are in accordance
with the work by Michels.1 The distinction between A4 and MHA is based on the definition used
by Wang et al..13 The definitions for hepatic arterial configuration, arterial segmental vascularization
pattern, early branching pattern, and specification of segments that can be vascularized by replaced
and accessory left hepatic arteries, were created as part of the extended anatomical classification of
variant hepatic arterial anatomy described in this manuscript.
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Chapter 3 Part II
The artery vascularizing S4 was named a middle hepatic artery (MHA) when orig-
inating from the CHA/PHA as a hilar artery, and a S4 artery (A4) when originating
as an intrahepatic branch from the LHA and/or RHA.13 Aberrant hepatic arteries
were defined as hepatic arterial branches that did not originate from the celiac
axis directly, or indirectly through the common (CHA) or proper hepatic artery
(PHA).1 Aberrant hepatic arteries were further classified into accessory and re-
placed hepatic arteries. We also assessed the branching pattern of the CHA. The
CHA was defined as the hepatic arterial branch between the celiac axis and the gas-
troduodenal artery (GDA). Early branching patterns were defined as a trifurcation
of the CHA (i.e., absence of PHA), early branching of the LHA and/or RHA from
the CHA (proximal to the origin of the GDA), or LHA and/or RHA originating di-
rectly from the celiac axis. The combination of the origin of the hepatic arteries and
the branching pattern of the CHA was termed the hepatic arterial configuration. In
the absence of aberrant hepatic arteries and early branching patterns, patients were
classified as having a standard hepatic arterial configuration.
After review of the MDCT images, DSA images of the hepatic arterial vasculature
in the frontal plane were reviewed to confirm the order of arterial branching. All
imaging was assessed by two readers (AvdH and MSvL) in consensus.
Statistics
Descriptive statistics were performed with the use of SPSS software version 20 for
windows (IBM SPSS Statistics, Chicago, IL). Percentages were rounded to the near-
est whole number.
RESULTS
Patients
Of 133 patients who received a workup for radioembolization with MDCT and
DSA, 19 (14 %) were excluded for the following reasons: previous extensive liver
surgery (n = 12), severe liver cirrhosis distorting the liver anatomy (n = 4), or large
tumor mass distorting the liver anatomy (n = 3). The hepatic arterial configura-
tion and arterial segmental vascularization of the remaining patients were assessed
(Figure 1). However, in four patients (4 %), the arterial segmental vascularization
could not be assessed reliably on MDCT, due to the very small caliber of the arteri-
al branches. Consequently, we present the results of the hepatic arterial configura-
tion and arterial segmental vascularization of the remaining 110 patients.
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Part II Chapter 3
Workup for
radioembolization with
MDCT + DSA
n = 133
Exclusion (n = 19):
• Liver surgery (n = 12)
• Severe liver cirrhosis (n= 4)
• Tumor mass distorting anatomy (n = 3)
Assesment of the
hepatic arterial anatomy
n = 114
Segmental arterial
vascularization non-assessable
on MDCT
n=4
Arterial configuration
and segmental vascularization
pattern assessed
n = 110
Figure 1: Patient inclusion
Hepatic arterial configuration and segmental vascularization pattern

Fifty-nine (54 %) patients had a standard hepatic arterial configuration, without
aberrant arteries and/or early branching, i.e. standard hepatic arterial anatomy.
Fourteen patients (13 %) had normally derived hepatic arteries, but one or more
arteries with an early branching pattern (Table 2).
In 37 patients (34 %) a variant origin of at least one hepatic artery was present
(Table 3). All aberrant LHAs originating from the LGA coursed upward in the cra-
nial part of the lesser omentum and entered the hilar plate through the fissure for
the ligamentum venosum, before continuing their course alongside the left portal
trunk within the umbilical fissure, to reach their respective segmental territory of
liver parenchyma. All aberrant RHAs originating from the SMA displayed a retro-
portal course within the hepatoduodenal ligament, traversing between the main
portal vein and inferior vena cava, before entering the hilar plate. Four out of five
(80 %) early branching RHAs (including one RHA originating directly from the
celiac axis) displayed a similar retroportal course.
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Chapter 3 Part II
Table 2: Observed early branching patterns

Early branching pattern Prevalence (%)
Early branching patterns in patients without aberrant hepatic arteries 14 (13 %)
Trifurcation CHA in GDA, LHA and RHA 9 (8 %)
Early branching LHA from CHA 2 (2 %)
Early branching RHA from CHA 1 (1 %)
Early branching LHA and RHA from CHA 1 (1 %)
RHA originating directly from CA 1 (1 %)
Early branching patterns in patients with aberrant hepatic arteries 5 (5 %)
rRHA (SMA) and trifurcation CHA in GDA, LHA and MHA 2 (2 %)
rRHA (SMA) and early branching LHA from CHA 1 (1 %)
rLHA (LGA) and RHA originating directly from CA 1 (1 %)
rCHA (SMA) and early branching RHA from CHA 1 (1 %)
In this table, early branching patterns (in patients without and with aberrant hepatic arteries) are
displayed. Abbreviations: CHA = common hepatic artery, GDA = gastroduodenal artery, LHA = left
hepatic artery, RHA = right hepatic artery, MHA = middle hepatic artery, rRHA = replaced right
hepatic artery, rLHA = replaced left hepatic artery, rCHA = replaced common hepatic artery, SMA =
superior mesenteric artery, LGA = left gastic artery, CA = celiac axis.
Table 3: Observed aberrant hepatic arteries

Variant configuration Origin Prevalence Michels / Hiatt classification
No aberrant hepatic arteries - 73 (66 %) Type I / I
rLHA LGA 9 (8 %) Type II / II
rRHA SMA / Aorta 16 (15 %) / 1 (1 %) Type III / III
rLHA + rRHA LGA / SMA 3 (3 %) Type IV / IV
aLHA LGA 1 (1 %) Type V / II
aRHA SMA / GDA 0 (0 %) / 1 (1 %) Type VI / III
aLHA + aRHA LGA / SMA 1 (1 %) Type VII / IV
aLHA + rRHA LGA / SMA 1 (1 %) Type VIII / IV
rLHA + aRHA LGA / SMA 1 (1 %) Type VIII / IV
rCHA SMA 3 (1 %) Type IX / V
In this table, observed configurations of aberrantly derived hepatic arteries are displayed with the
origin of the accessory or replaced hepatic artery, and observed prevalence denoted in number of
patients (percentage of total). The Michels and Hiatt classification types are displayed to allow for
comparison. Abbreviations: rLHA = replaced left hepatic artery, aLHA = accessory left hepatic artery,
rRHA = replaced right hepatic artery, aRHA = accessory right hepatic artery, rCHA = replaced
common hepatic artery, LGA = left gastric artery, SMA = superior mesenteric artery, GDA =
gastroduodenal artery.
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Part II Chapter 3
The hepatic arterial segmental vascularization patterns are summarized in Table 4
and schematically illustrated in Figures 2, 3, 4, 5 and 6. An example of DSA and mul-
tiplanar MDCT images of the hepatic arterial segmental vascularization pattern is
shown in Figure 7 for a patient with a rRHA originating from the SMA.
Table 4: Segmental hepatic arterial vascularization patterns
Type Originating from the Celiac Axis Originating Originating Prevalence Figure
from the SMA from the LGA
1) No aberrant hepatic arteries 73 (66 %) 2
1a LHA [2-4] & RHA [5-8] - - 51 (46 %) 2A
1b LHA [2-3] & RHA [4-8] - - 21 (19 %) 2B
1c LHA [2-3], MHA [4] & RHA [5-8] - - 1 (1 %) 2C
2) Aberrant left hepatic arteries 10 (9 %) 3
2a RHA [4-8] - rLHA [2-3] 7 (6 %) 3A
2b RHA [5-8] - rLHA [2-4] 2 (2 %) 3B
2c LHA [3-4] & RHA [5-8] - aLHA [2] 1 (1 %) 3C
3) Aberrant right hepatic arteries 18 (17 %) 4
3a LHA [2-4] rRHA [5-8]* - 15 (14 %) 4A
3b LHA [2-3] rRHA [4-8] - 1 (1 %) 4B
3c LHA [2-4] rRHA [4-8] - 1 (1 %) 4C
3d LHA [2-3], RHA [4,6-8] & aRHA [5]** - 1 (1 %) 4D
4) Aberrant right and left hepatic arteries 6 (6 %) 5
4a MHA [4] rRHA [5-8] rLHA [2-3] 2 (2 %) 5A
4b - rRHA [5-8] rLHA [2-4] 1 (1 %) 5B
4c LHA [3-4] & RHA [7-8] aRHA [5-6] aLHA [2] 1 (1 %) 5C
4d LHA [3-4] rRHA [5-8] aLHA [2] 1 (1 %) 5D
4e RHA [7] aRHA [5,6,8] rLHA [2-4] 1 (1 %) 5E
5) Replaced common hepatic artery 3 (3 %) 6
LHA [2-4] &
5 - - 3 (3 %) 6
RHA [5-8]
The segmental arterial vascularization patterns are summarized in this table. The main arterial branches
are followed by their segmental territory of vascularization between brackets. *In one patient the rRHA
originated from the aorta instead of the SMA. **aRHA originating from the GDA. Abbreviations:
LHA = left hepatic artery; RHA = right hepatic artery; MHA = middle hepatic artery; aRHA/aLHA =
accessory RHA/LHA; rRHA/LHA = replaced RHA/LHA.
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Chapter 3 Part II
No aberrant hepatic arteries
A n = 51 (46%) B n = 21 (19%) C n = 1 (1%)

Figure 2: Schematic representation of the hepatic arterial vascularization pattern in patients without aberrant hepatic arteries. (The illustrative concept of Figures 2-6
is redrawn from ‘Jin et al., Anatomical variations of the origin of the segment 4 hepatic artery and their clinical implications, Liver transplantation 2008;14:1180-1184.’)
Aberrant left hepatic arteries
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A n = 7 (6%) B n = 2 (2%) C n = 1 (1%)

Figure 3: Schematic representation of the hepatic arterial vascularization pattern in patients with aberrant left hepatic arteries.
Aberrant right hepatic arteries
A n = 15 (14%) B n = 1 (1%) C n = 1 (1%)
Aberrant left and right hepatic arteries
A n = 15 (14%) B n = 1 (1%) C n = 1 (1%) D n = 1 (1%)

Figure 4: Schematic representation of the hepatic arterial vascularization pattern in patients with aberrant right hepatic arteries.
- 69 -
A n = 2 (2%) B n = 1 (1%) C n = 1 (1%)
D n = 1 (1%)
A n = 2 (2%) B n = 1 (1%) C n = 1 (1%) D n = 1 (1%) E n = 1 (1%)

Figure 5: Schematic representation of the hepatic arterial vascularization pattern in patients with a combination of aberrant right and left hepatic arteries.
Part II Chapter 3
Replaced CHA
Chapter 3 Part II
Replaced CHA
Figure 6: Schematic representation of the hepatic arterial

vascularization pattern in patients with a replaced common
n = 3 (3%) hepatic artery.
DISCUSSION
In this study, we assessed the origin, branching pattern, course and segmental vas-
cularization pattern of the hepatic arteries on triphasic liver MDCT and DSA in
110 patients receiving a workup for radioembolization. The prevalence and config-
urations of aberrant hepatic arteries (Table 3) and early branching patterns (Table 2)
were comparable to those previously published.1-6 Sixteen different hepatic arterial
segmental vascularization patterns were identified, differing by the presence of ac-
cessory or replaced hepatic arteries, their respective vascular territory, and the or-
igin of artery vascularizing S4. This marked variability reflects the complex nature
of the arterial liver vascularization, justifying a detailed pre-procedural assessment
of the individual hepatic arterial configuration and segmental vascularization pat-
tern prior to radioembolization.
The extensive research conducted in the past five decades has greatly enhanced our
knowledge of variant hepatic arterial anatomy.1-6,14 In 1966, Michels introduced
an internationally recognized classification of hepatic arterial variations, in which
he described ten types of arterial configuration, based on his observations in 200
autopsy dissections.1 Later, Hiatt et al. introduced a reduced classification with six
types, based on a review of operative reports in 1,000 patients who underwent liver
harvesting for orthotopic transplantation. In this adaptation, the distinction be-
tween replaced and accessory hepatic arteries was abandoned.2 Subsequent stud-
ies on this subject described the prevalence of aberrant hepatic arteries in a large
number of patients, based on surgical dissection5, angiography3-4,6 and later also
CT angiography (CTA)15-18, and extended Michels’ and Hiatt’s classifcations with
early branching patterns and rare variants. However, none of these studies includ-
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Part II Chapter 3
Figure 7: DSA (A-B) and multiplanar MDCT (C-F) images of the hepatic arterial segmental
vascularization pattern in a patient with a rRHA originating from the SMA. A) Superior mesenteric
arteriogram shows a replaced right hepatic artery (white arrowhead) originating from the SMA. B) DSA
obtained from the CHA. The CHA divides into GDA and LHA (black asterisk). The LHA first gives of
a branch to S2 (black arrowhead), and bifurcates more distally into a branch to S3 (white arrow) and S4
(black arrow). C-D) Corresponding arterial phase coronal MIP images. E-F) Corresponding arterial
phase axial MIP images. Note the retroportal course of the rRHA (white arrowhead), and the perfect
intrahepatic coordination between distal portal and arterial branches.
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Chapter 3 Part II
ed the origin of the artery vascularizing S4 and the vascular territory of aberrant
hepatic arteries in their overview of variant hepatic arterial anatomy. This may be
attributable to the fact that only CT imaging can provide a complete overview on
the origin, branching pattern and segmental vascularization of the hepatic arterial
branches. Our study, therefore, is the first to provide a comprehensive overview of
the hepatic arterial segmental vascularization patterns in patients with and without
aberrant hepatic arteries.
In the 73 patients without aberrant hepatic arteries, we identified three vascular-
ization patterns, differing by the origin of the artery vascularizing S4 (Figure 2).
Studies that previously investigated the origin of this arterial branch, often used
different definitions, and terms, such as S4 artery (A4) and middle hepatic artery
(MHA) were interchangeably used.8,13,19 From an anatomical point of view, the
term MHA refers to a hilar artery that originates from the CHA or PHA, between
the origins of the LHA and RHA, whereas A4 can also refer to a small intra-hepatic
branch that originates from the distal LHA or RHA.13 Previous studies showed
contradictory results, which may be attributable to these differences in definition.
Two recent studies indicated that the artery vascularizing S4 predominantly origi-
nated from the RHA and less frequently from the LHA, from both hepatic arteries
or directly from the PHA in a trifurcation.8,13 Our results are more in agreement
with earlier studies1,9,19, suggesting that the artery vascularizing S4 predominantly
originates from the LHA and less frequently from the RHA, both hepatic arteries
or the PHA.
We identified various arterial segmental vascularization patterns in patients with
aberrant hepatic arteries. Major differences were observed in the origin of the ar-
tery vascularizing S4 and the liver territory vascularized by the aberrant hepatic
arteries. Wang et al. suggested that in patients with a rLHA or rRHA, a MHA con-
sistently arises from the CHA.13 Although this was true for the majority of patients
with a rLHA or rRHA in our study, we also found A4s originating from replaced
hepatic arteries. One patient even had a double vascularization of S4, with one A4
originating from the rRHA and the other A4 originating from the LHA (Figure 4C).
Moreover, in patients with a combination of a rLHA and rRHA, S4 was vascular-
ized by a MHA originating from the CHA in two patients (Figure 5A) and by an A4
originating from the rLHA in one patient (Figure 5B). Three hitherto unreported
arterial vascularization patterns were identified in patients with aRHAs (Figures
4D, 5C and 5E). This emphasizes the importance of characterizing an aberrant he-
patic artery as being accessory or replaced, defined by the extent of its territory of
blood supply and coexistence of a normally derived LHA and RHA.1 Due to the
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Part II Chapter 3
variable vascularization of S4, we believe that the distinction between an accessory
and replaced LHA should not depend on the origin of the artery vascularizing S4.
Hence, an aLHA vascularizes S2 only, and an rLHA may vascularize S2-3 or S2-4.
Early anatomical studies that investigated the spatial relation between the portal
venous and hepatic venous vasculature in corrosion casts of the liver have founded
the concept of functional liver anatomy.9,20-24 These studies revealed that the liver
consists of a functional independent left and right hemi-liver, divided by the main
portal scissura. Later, Couinaud’s concept of eight haemodynamically distinct liver
segments, each with their own arterial and portal blood supply and biliary drain-
age, was adopted.7,25 Since the general acceptance of Couinaud’s segmental anato-
my model, the arterial segmental vascularization pattern has not received much
scientific attention. This might be attributable to the recognition that the hepatic
arterial branches are intimately related to the corresponding portal venous and
biliary duct branches within the liver tissue and, therefore, display a similar course.
However, this does not signify that the segmental vascularization pattern of the
main hepatic arterial branches is equal to that of the major portal trunks that irri-
gate the, portal-venous defined, left and right hemi-liver.
The treatment principle of intra-arterial radioembolization is based on selective
targeting of tumor invested liver tissue.26 In current clinical practice, the calculated
treatment activity of resin yttrium-90 microspheres (SIR-spheres®, SIRTeX, Lane
Cove, Australia) is based on the assumption that the LHA and RHA vascularize
the entire left and right hemi-liver respectively. Our findings suggest that this as-
sumption is often not in agreement with anatomic reality, and that, in the presence
of aberrant hepatic arteries, this method may lead to erroneous results. Therefore,
we advocate the utilization of personalized dosimetry for radioembolization, based
on the individual hepatic arterial vascularization pattern.27
Following limitations of this study should be discussed. First, it was not our pur-
pose to evaluate seperately the diagnostic accuracy of MDCT and DSA in de-
tecting aberrant hepatic arteries and early branching patterns. Instead, we used
a combined approach of MDCT and DSA. DSA proved to be especially useful to
determine the order of hepatic arterial branching in the area of the GDA, and to
rule out the presence of a PHA when a trifurcation of the CHA was suspected on
MDCT. Second, we could not assess the segmental arterial vascularization pattern
in 4 of 114 patients (4 %), due to the small size of the hepatic arterial branches.
Third, we deemed it unreliable to assess the origin of the arteries vascularizing S1.
In the absence of tumor-induced hypertrophy, the small caliber of multiple feed-
ers to S1 are beyond the resolution of current MDCT scanners. Fourth, we used
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Chapter 3 Part II
Couinaud’s model of segmental liver anatomy to describe the segmental arterial

vascularization pattern. This model is a comprehensive topographical concept of
functional liver anatomy that is easily interpretable and can be applied in most
patients. However, there is an increasing body of evidence suggesting that this con-
cept may be an oversimplification.28-32 Anatomical and radiological investigations
have confirmed that the segmental boundaries, as indicated by the hepatic veins
and the level of the right portal trunk, do not consistently coincide with the exact
location of the true portal scissurae in individual patients.29-30,32 As a consequence,
the true target volume of arterial branches can slightly differ from Couinaud’s liver
segments, which may have important implications for pretreatment dosimetry and
the idenfication of tumor-feeding arteries. During the pretreatment angiography,
C-arm cone beam computed tomography, a relatively new imaging modality inte-
grated in modern angio-suites, may be used to delineate the exact territory of arte-
rial perfusion through contrast enhancement of the perfused liver parenchyma.33
RECOMMENDATIONS FOR AN INDIVIDUALIZED RADIOEMBOLIZATION

TREATMENT STRATEGY
There is no consensus about how to deal with early branching patterns and aber-
rant hepatic arteries during radioembolization. The ideal treatment strategy en-
compasses a safe, simple, and complete administration, with a low risk of non-tar-
get embolization, few sites of selective administration, and adequate coverage of
the target volume.
We developed an extended classification of variant hepatic arterial anatomy that
can be used to characterize clinically relevant anatomical variants on MDCT before
the pretreatment angiography and guide treatment planning. This MDCT-based
assessment may reduce the procedural time, contrast, and radiation burden of the
pretreatment angiography by superseding extensive mapping of the hepatic arteri-
al anatomy with DSA. Futhermore, it may help to standardize treatment strategies
in patients with complex anatomy and facilitate interdisciplinary communication
with other physicians. We propose an individualized radioembolization treatment
strategy, based on patients’ type of variant anatomy (Table 5).
Various treatment strategies are feasible with regard to aberrant arteries. One strat-
egy is to use aberrant hepatic arteries as a target vessel for selective administration
with a standard end-hole microcatheter. For the administration in branches at high
risk for non-target embolization, such as aberrant hepatic arteries originating from
the LGA, an anti-reflux catheter such as the Surefire Infusion System® (Surefire
Medical Inc., Westminster, CO) may be used.34 Another strategy is to coil embolize
- 74 -
Table 5: Recommendations for radioembolization treatment strategies in patients with variant hepatic arterial anatomy
Type of anatomical variant Number of High risk for Coil Special indication Number of Recommendation
major arterial non-target embolization for anti-reflux injection
branches embolization? favorable? catheter? positions
LHA [S2-4] + RHA [S5-8] 2 No No No 2 Administration in LHA & RHA
LHA [S2-3] + RHA [S4-8] 2 No No No 2 Administration in LHA & RHA
LHA [S2-3] + MHA + RHA [S5-8] 3 No No No 3 Administration in LHA, MHA &
RHA
rLHA [LGA, S2-3] 2 Yes Yes No 1 Coil embolize rLHA, administration
in RHA
rLHA [LGA, S2-4] 2 Yes No Yes 2 Administration in rLHA and RHA
aLHA [LGA, S2] 3 Yes Yes No 2 Coil embolize aLHA, administration
in LHA & RHA
aLHA [GDA] 3 Yes Yes No 2 Coil embolize aLHA, administration
in LHA & RHA
rRHA [SMA, S5-8] 2 No No No 2 Administration in rRHA & LHA
rRHA [SMA, S4-8] 2 No No No 2 Administration in rRHA & LHA
rRHA [SMA, S4-8] + LHA [S2-4] 2 No No No 2 Administration in rRHA & LHA
- 75 -
aRHA [GDA] 3 Yes Yes Yes 2 Coil embolize aRHA, administration
in LHA & RHA
Aberrant right and left hepatic arteries
rLHA [LGA, S2-3] + rRHA [SMA, S5-8] 3 Yes Yes No 2 Coil embolize rLHA, administration
+ MHA in rRHA and MHA
rLHA [LGA, S2-4] + rRHA [SMA, S5-8] 2 Yes No Yes 2 Administration in rLHA and rRHA
aLHA [LGA, S2] + aRHA [SMA, Sx] 4 Yes Yes No 2 Coil embolize aLHA + aRHA,
administration in LHA & RHA
aLHA [LGA, S2] + rRHA [SMA, S5-8] 3 Yes Yes No 2 Coil embolize aLHA, administration
in rRHA & LHA
rLHA [LGA, S2-4] + aRHA [SMA, Sx] 3 Yes Yes Yes 2 Coil embolize aRHA, administration
in rLHA and RHA
Replaced common hepatic artery
rCHA [SMA] 2 No No No 2 Selective administration
Early branching LHA and/or RHA Variable No No No Variable Selective administration

[CHA]
Trifurcation or Quadrifurcation of CHA 2-3 Yes No Yes 2-3 Administration in LHA, (MHA) and
RHA
Part II Chapter 3
Chapter 3 Part II
aberrant hepatic arteries to induce a redistribution of blood flow through small

intrahepatic collateral pathways and administer microspheres in the hepatic artery
that took over the coiled artery's vascular territory, resulting in a simplified and
safe administration.35-36
In the absence of a direct comparison with regard to safety and treatment efficacy,
neither of the strategies can be regarded as superior. After carefully weighing the
risks and benefits for the different treatment strategies, we recommend coil em-
bolization for aberrant hepatic arteries at increased risk for non-target emboliza-
tion that do not supply an entire hemi-liver such as an aLHA (vascularizing S2) or
rLHA (vascularizing S2-3) originating from the LGA, and an accessory hepatic ar-
tery originating from the GDA (rare). Coil embolization also may be favorable for
an aRHA originating from the SMA in patients who in addition have an aberrant
left hepatic artery originating from the LGA. This can reduce significantly the com-
plexity of the administration by limiting the number of selective administration
sites. Other variants, such as rRHAs originating from the SMA, do not increase the
risk for non-target embolization, and supply a large territory of the liver that may
not be sufficiently vascularized by small intrahepatic collaterals to allow for com-
plete passage of all infused resin microspheres.35 They therefore are recommended
to be used as target vessel. Replaced left hepatic arteries vascularizing S2-4 increase
the risk for non-target embolization but do supply a rather large part of the liver.
An anti-reflux catheter may be used for selective administration in these variants.
The latter strategy also can be applied in patients with a trifurcation or quadrifur-
cation of the CHA, because it has been demonstrated that this is a risk factor for
the development of gastric ulceration due to non-target embolization during radi-
oembolization.37 It is important to note that the recommended treatment strategies
reflect our opinion, outlining the need for individualized radioembolization strat-
egies, and may need further tailoring towards the individual patient’s case when
used in clinical practice, to adjust for variants that could not be included in the
extended anatomical classification, such as variants in the origin of extrahepatic
branches or the presence of parasitized extrahepatic arteries.
CONCLUSION
The hepatic arterial configuration and segmental vascularization pattern show
marked individual variability beyond well-known classifications of anatomical
variants, relevant to radioembolization. Therefore, it is recommended to assess the
individual hepatic arterial configuration and segmental vascularization on MDCT,
before the pretreatment angiography. We developed an individualized radioembo-
lization treatment strategy based on an extended classification of variant hepatic
arterial anatomy.
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Part II Chapter 3
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C hap ter
PART II 4
Identifying aberrant
hepatic arteries prior
to intra-arterial radioembolization
A.F. van den Hoven

M.L.J. Smits
B. de Keizer
M.S. van Leeuwen
M.G.E.H. Lam

Identifying aberrant hepatic arteries prior to intra-arterial radioembolization
ABSTRACT
Purpose
Chapter 4 Part II
Failing to identify aberrant hepatic arteries before radioembolization may com-

promise its treatment efficacy, due to inadequate biodistribution of radioactive mi-
crospheres. The purpose of this study was to evaluate how often aberrant hepatic
arteries were correctly identified in clinical practice, with computed tomography
(CT), and during angiography in patients with liver tumors who received a workup
for radioembolization.
Methods
The presence and vascularization pattern of aberrant (i.e., accessory and replaced)
hepatic arteries was assessed on triphasic liver CT in 110 patients. Subsequently,
radiological reports on CT and angiographic procedures were reviewed to deter-
mine whether aberrant hepatic arteries were identified correctly in clinical prac-
tice. The intrahepatic biodistribution of 99mTc-MAA and radioactive microspheres
was assessed on SPECT/CT and PET/CT in all patients with unidentified aberrant
hepatic arteries.
Results
Thirty-seven of 110 patients (34 %) had aberrant hepatic arteries. In 18 of 37 (49 %)
patients, the aberrant hepatic arteries were correctly identified on CT, and in 32 of
37 (86 %) during angiography. Aberrant right hepatic arteries were identified more
frequently than aberrant left hepatic arteries on CT (54 vs. 44 %) and during angi-
ography (100 vs. 69 %, p = 0.007). In five patients (14 %), an aberrant left hepatic
artery remained unidentified, resulting in a lack of 99mTc-MAA and 90Y activity in
the segmental territory of the unidentified aberrant hepatic arteries.
Conclusion
Aberrant left hepatic arteries were the most common unidentified aberrant hepat-
ic arteries, resulting in incomplete radiation coverage. We formulated a practical
approach to identify aberrant hepatic arteries correctly before radioembolization.
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INTRODUCTION
With the increasing application of interventional liver directed therapies, such as
Part II Chapter 4
intra-arterial radioembolization for primary and metastatic liver cancer, it becomes
apparent that a thorough understanding of hepatic arterial anatomy and the ability
to recognize anatomical variants is indispensable to the interventional radiologist.
In a standard hepatic arterial configuration, the celiac axis trifurcates into the left
gastric artery (LGA), splenic artery, and common hepatic artery (CHA). Distal to
the origin of the gastroduodenal artery (GDA), the CHA continues as the proper
hepatic artery (PHA) and bifurcates, in the region of the hilar plate, into a right
hepatic artery (RHA) and left hepatic artery (LHA).1 Anatomical variants of the
arterial liver vasculature are very common. Frequently encountered variants in-
clude hepatic arteries that are derived from sources other than the celiac axis, oc-
curring in approximately 21 – 45 % of patients.2-6 These aberrant hepatic arteries
are historically classified as accessory or replaced, in accordance with the early
work of Michels.6 When the RHA or LHA does not arise from the celiac axis, it is
considered “replaced”, and when the RHA or LHA exists in addition to normally
derived right and left hepatic arteries originating from the celiac axis, it is consid-
ered “accessory”.
In clinical practice, certain configurations of aberrant hepatic arteries may be
missed when radiologists do not use a systematic approach to identify these an-
atomical variants. This may compromise the treatment efficacy of radioemboli-
zation, due to inadequate biodistribution of radioactive microspheres. In 2007,
Lewandowski et al. published a landmark paper on radioembolization practice,
providing in-depth recommendations for the technical aspects of this treatment.7
According to this recommended technique, a superior mesenteric, celiac, and gas-
troduodenal arteriogram should be obtained by digital subtraction angiography
(DSA) to identify aberrant hepatic arteries originating from the SMA, LGA, and
GDA respectively. There is, however, no clear guidance on how to use other imag-
ing modalities, such as multiphase liver computed tomography (CT), C-arm cone
beam CT (C-arm CT) or catheter-directed computed tomographic angiography
(CTA), and nuclear scintigraphy, to ensure correct identification and character-
ization of aberrant hepatic arteries. Implementation of a multimodality strategy,
in which the aforementioned pre, per and postprocedural imaging modalities are
systematically evaluated will likely result in an improved understanding of the in-
dividual patient’s anatomy and allows for preprocedural treatment planning, which
may ultimately translate in reduced procedural time and complexity.
In this study, we assessed how often aberrant hepatic arteries were correctly iden-
- 83 -
tified in clinical practice and evaluated the intrahepatic biodistribution of micro-

spheres in patients with unidentified aberrant hepatic arteries. In addition, we
Chapter 4 Part II
aimed to formulate a practical approach to ensure correct identification of aberrant

hepatic arteries in future practice.
METHODS
Patients
Our institutional review board approved this study, and waived the need for in-
formed consent for patients who were not participating in one of the prospective
trials on radioembolization at our center (RADAR trial, HEPAR trial). All patients
who were participating in one of these prospective trials had already provided in-
formed consent. We assessed the presence and segmental vascularization pattern
of aberrant hepatic arteries in patients with primary or metastatic liver cancer who
received a workup angiography for radioembolization with yttrium-90 (90Y) or
holmium-166 (166Ho) microspheres, during a 4-year period (2009–2012). The pa-
tients who received the 166Ho microspheres were part of a phase I clinical dose-es-
calation study.8 Patients with a history of prior extensive liver surgery, cirrhotic liv-
er disease, and tumor involvement distorting the anatomy were excluded. Baseline
and treatment characteristics were extracted from the patient’s records.
Imaging and angiographic procedures
All patients had received a triphasic liver CT (MX8000; Brilliance 64; Brilliance
iCT; Philips Medical Systems, Eindhoven, The Netherlands) before radioembo-
lization. The presence and segmental vascularization pattern of aberrant hepatic
arteries was retrospectively assessed on sectional and reconstructed images of tri-
phasic liver CT. This served as reference standard for the evaluation of the iden-
tification of aberrant hepatic arteries in clinical practice. Reconstructions of CT
images, including maximum intensity projections of the arterial phase in axial
and coronal orientation, were analyzed on an interactive workstation (Intellispace
Portal; Philips Medical Systems, Eindhoven, The Netherlands). Aberrant hepatic
arteries were defined as hepatic arterial branches that did not originate from the
celiac axis directly, from the CHA or PHA. They were further classified as acces-
sory or replaced, depending on their segmental territory of vascularization. Liver
segmentation was performed according to the Bismuth adaptation of Couinaud’s
model of segmental liver anatomy.9 To this purpose, the hepatic veins and right
portal trunk on the portal phase of the triphasic liver CT were used to delineate
the intersegmental boundaries, respectively indicating the portal scissurae and
transverse scissura. Subsequently, all hepatic arterial branches were followed up to
- 84 -
their segmental territory of the liver. In this paper, the term middle hepatic artery
(MHA) refers to a hepatic arterial branch vascularizing segment 4 that originates
Part II Chapter 4
from the CHA/PHA, while the term segment 4 artery (A4) is used for branches
originating from the LHA or RHA. The presence of parasitized extrahepatic arter-
ies, i.e., tumor-feeding arteries recruited from extrahepatic sources during tumor
growth, was not evaluated in this study.
Digital subtraction angiography (DSA) was acquired during a standard pretreat-
ment angiography.7 During this angiography, through a femoral artery approach,
selective catheterization of the SMA, celiac axis and the main hepatic arterial
branches was performed to map the hepatic arterial anatomy. In addition to a su-
perior mesenteric arteriogram, an indirect portogram was performed to evaluate
patency of the portal vein. All extrahepatic branches originating from the hepatic
artery or one of its branches were coil embolized to “skeletonize” the hepatic arte-
rial vasculature and to prevent non-target embolization. Next, 150 MBq of techne-
tium-99m-labelled macro-albumin aggregates (99mTc-MAA; TechneScan LyoMaa,
Mallinckrodt Medical, Petten, The Netherlands) were administered in the target
vessel(s) to simulate the distribution of the radioactive microspheres on planar
nuclear imaging and single-photon emission computed tomography (SPECT) or
(fused) SPECT/CT images. Based on planar images, a lung-shunt fraction was
calculated. When SPECT imaging revealed extrahepatic activity of 99mTc-MAA, a
repeat pretreatment angiography was performed to identify and coil embolize the
patent branch(es), causing the extrahepatic shunting.
After a successful pretreatment angiography, either 90Y (SIR-Spheres®; SIRTeX
Medical Ltd., Lane Cove, Australia) or 166Ho microspheres (in house preparation)
were administered in the same injection position as during the pretreatment an-
giography. Subsequently, the postprocedural distribution of 90Y microspheres was
assessed on either bremsstrahlung SPECT/CT or positron emission tomography
(PET/CT), and the distribution of the therapy dose of 166Ho microspheres was as-
sessed on fused SPECT/CT imaging. Acquisition protocols used for 90Y-brems-
strahlung SPECT, 90Y-PET, and 166Ho-SPECT have been described elsewhere in
detail.10-11
Identification of aberrant hepatic arteries
Radiological reports on CT and pretreatment angiographies were reviewed to eval-
uate how often aberrant hepatic arteries were correctly identified in clinical prac-
tice. All CTs were obtained as routine part of the treatment workup, with the spe-
cific request to evaluate whether the patient was suitable for radioembolization. An
unambiguous notification of the presence of an aberrant left and/or right hepatic
- 85 -
artery in the radiological report of the CT was considered “identification on CT”.

“Identification during pretreatment angiographies” was determined by an unam-
Chapter 4 Part II
biguous notification of the presence of aberrant hepatic arteries in the radiological

report of the angiographic procedure or an attempt to catheterize these arteries
selectively. All cases in which aberrant hepatic arteries were detected during a re-
peat pretreatment angiography (after a lack of 99mTc-MAA activity in one or more
liver segments had been noted on SPECT/CT) also were classified as “identifica-
tion during pretreatment angiographies”. First, the number of identified individu-
al configurations of aberrant hepatic arteries, including combinations of aberrant
right and left hepatic arteries in one patient, was determined. Next, all aberrant left
and right hepatic arteries were grouped separately to assess whether one of the two
types was identified more frequently on CT and/or during angiography.
All aberrant vessels that remained unidentified after the pretreatment angiogra-
phies were further analyzed. In these cases, the segmental distribution of 99mTc-
MAA on SPECT/CT and radioactive microspheres on either SPECT/CT or PET/
CT was independently reviewed by two observers (AvdH, BdK) to assess whether
the expected lack of activity in the segmental liver territory of the unidentified
aberrant hepatic artery could be confirmed. Disagreements were resolved by con-
sensus. The segmental distribution of 99mTc-MAA and 90Y or 166Ho microspheres
was analyzed on a PACS workstation (IDS7, Sectra, Linköping, Sweden), by re-
viewing which hepatic segments contained activity on fused SPECT/CT or PET/
CT images. Cases for which fused SPECT and PET images were not available were
excluded from this analysis. In addition, the presence of tumors at baseline in the
untreated liver segments was evaluated on the portal venous and arterial phase of
a pretreatment triphasic liver CT. A schematic outline of the study design is dis-
played in Figure 1.
Finally, after having reviewed all possible causes of the failure to identify aberrant
hepatic arteries on CT and during pretreatment angiographies, we formulated a
practical approach that may be used to ensure a correct identification of aberrant
hepatic arteries before radioembolization.
Statistical analysis
The proportions of correctly identified aberrant left and right hepatic arteries were
compared by means of a two-tailed Fisher’s exact test. A p value of < 0.05 was con-
sidered statistically significant. All percentages were rounded to the nearest whole
number. SPSS version 20.0 for windows (IBM SPSS, Chicago, IL, USA) was used
to perform statistics.
- 86 -
Figure 1: In this flowchart, the study results are depicted. Part II Chapter 4
RESULTS
The flowchart in Figure 1 summarizes the results of this study.
Patients
In total, 133 patients who received a CT and angiography during workup for ra-
dioembolization were considered for inclusion. Nineteen patients were excluded
based on a history of prior extensive liver surgery (n = 12), cirrhotic liver dis-
ease (n = 4), and tumor involvement distorting the arterial liver anatomy (n = 3).
- 87 -
The presence and segmental vascularization pattern of aberrant hepatic arteries was
assessed in the remaining 114 patients. However, four patients were non-assessable
Chapter 4 Part II
due to very small caliber arterial branches that could not be assessed reliably on CT.
Thirty-seven of 110 patients (34 %) had aberrant hepatic arteries (Figure 1). The con-
figurations of these aberrant hepatic arteries are displayed in Table 1. The baseline
and treatment characteristics of these patients are presented in Table 2. The major-
ity of the patients had liver metastases from colorectal cancer (n = 18, 49 %). Mean
age was 60 years (standard deviation 12 years), and male gender was predominant
(n = 23, 62 %). Nine patients (24 %) did not receive treatment due to the following
contraindications: persistent extrahepatic 99mTc-MAA deposition (n = 5), extensive
arterial portal shunting (n = 1), lung-shunt fraction of 39 % (n = 1), tumor-feeding
hepatic artery inaccessible for catheterization (n = 1) and unsuitable anatomy of
the hepatic vasculature (n = 1, Figure 2). A total of 28 patients with aberrant hepatic
arteries were treated with either 90Y microspheres (n = 26, 70 %) or 166Ho micro-
spheres (n = 2, 6 %).
Table 1: Configuration of aberrant hepatic arteries in 37 patients receiving a workup for RE

Aberrant hepatic arteries Origin Number of patients (%)
rRHA SMA / Aorta 16 (43.2 %) / 1 (2.7 %)
rLHA LGA 9 (24.3 %)
aRHA GDA 1 (2.7 %)
aLHA LGA 1 (2.7 %)
rRHA & rLHA SMA & LGA 3 (8.1 %)
aRHA & aLHA SMA & LGA 1 (2.7 %)
rRHA & aLHA SMA & LGA 1 (2.7 %)
aRHA & rLHA SMA & LGA 1 (2.7 %)
rCHA SMA 3 (8.1 %)
Configurations of aberrant hepatic arteries are displayed with the origin of the accessory or replaced
hepatic artery. Abbreviations: rLHA = replaced left hepatic artery, aLHA = accessory left hepatic
artery, rRHA = replaced right hepatic artery, aRHA = accessory right hepatic artery, rCHA = re-
placed common hepatic artery, LGA = left gastric artery, SMA = superior mesenteric artery, GDA =
gastroduodenal artery.
- 88 -
Part II Chapter 4
Figure 2: Unsuitable anatomy of the hepatic vasculature.
A) DSA image with the catheter positioned in the origin of the celiac axis. This patient had an rLHA
from the LGA, an RHA originating directly from the celiac axis and a CHA bifurcating into a MHA
and GDA. The MHA had numerous small extrahepatic branches (white arrow), inaccessible for cath-
eterization and therefore did not allow for a safe administration of radioactive microspheres and no
99m
Tc-MAA was administered either. B) DSA image with the catheter positioned at the branching point
of the MHA. The multiple small extrahepatic branches originating from the MHA are clearly visible in
this image (white arrows). Abbreviations: rLHA = replaced left hepatic artery; CA = celiac axis; GDA =
gastroduodenal artery; RHA = right hepatic artery; MHA = middle hepatic artery.
Table 2: Baseline and treatment characteristics of 37 patients with aberrant hepatic arteries
Baseline/Treatment characteristics Value

Male gender 23 (62 %)
Mean age in years 60 ± 12
Primary tumor type
Colorectal cancer 18 (49 %)
Cholangiocarcinoma 5 (13 %)
Uvea melanoma 4 (11 %)
Neuroendocrine tumor 4 (11 %)
Other liver metastases 4 (11 %)
Primary liver cancer 2 (5 %)
Administration of 99m
Tc-MAA 36 (97 %)
Radioembolization treatment 28 (76 %)
90
Y microspheres 26 (70 %)
166
Ho microspheres 2 (6 %)
Baseline and treatment characteristics of patients with aberrant hepatic arteries are presented. Values
are displayed as number of patients (percentage of total) or mean ± standard deviation. Abbreviations:
99m
Tc-MAA = Technetium-99m-labelled Macro-Albumin Aggregates; 90Y = yttrium-90; 166Ho = hol-
mium-166.
- 89 -
Identification of aberrant hepatic arteries in clinical practice

In 18 of 37 (49 %) patients, all aberrant hepatic arteries were correctly identified on
Chapter 4 Part II
CT and in 32 of 37 (86 %) during the pretreatment angiographies. Some patients

had a combination of aberrant left and right hepatic arteries, resulting in a total of
24 aberrant RHAs (21 rRHA and 3 aRHA) and 16 aberrant LHAs (13 rLHA and 3
aLHA). Aberrant right hepatic arteries were identified more frequently than aber-
rant left hepatic arteries on CT (54 vs. 44 %) and during angiography (100 vs. 69
%), the difference in identification of right- (24/24, 100 %) and left-sided (11/16,
69 %) aberrant hepatic arteries was statistically significant (Fisher’s exact test, p =
0.007; Figure 1).
In two patients, the aberrant hepatic arteries (rRHA from the SMA and rLHA
from the LGA) were only identified during a repeat angiographic procedure, after
SPECT/CT had revealed a lack of 99mTc-MAA activity in the segmental liver terri-
tory of these arteries (segments 5-8 and 2-3 respectively). In one of these patients,
the rRHA was overlooked during the initial angiography, because the catheter was
positioned too distal in the SMA, thereby missing the rRHA originating from the
proximal part of the SMA (Figure 3). The rRHA was used as a selective injection
position in addition to the LHA originating from the celiac axis in a repeat angiog-
raphy, and a whole liver treatment was completed, confirmed by the distribution
of 166Ho microspheres on fused SPECT/CT images. In the other patient, the rLHA
was identified during a repeat pretreatment angiography after the SPECT/CT had
Figure 3: rRHA from the SMA initially overlooked during catheterization.

Selective arteriograms of the SMA. A) During the first pretreatment angiography the rRHA, originating
from the origo of the SMA, was not recognized due to the distal catheter position in the SMA. B) After
SPECT/CT had revealed lack of activity in the entire right hemi-liver, selective arteriogram obtained
from the origo of the SMA during a repeat angiography revealed an rRHA originating from the origo
of the SMA.
- 90 -
revealed a lack of activity in segments 2-3 and was found to be inaccessible for
selective catheterization. In the absence of tumors in the left hemi-liver, it was de-
Part II Chapter 4
cided to treat the right hemi-liver only.
In five patients (14 %), aberrant left hepatic arteries (2 rLHA, 3 aLHA) remained
unidentified. All of these patients were treated with 90Y-radioembolization. Two
independent observers reviewed the distribution of 99mTc-MAA on SPECT/CT and
90
Y microspheres on PET/CT (Table 3). One patient with an unidentified aLHA
vascularizing segment 2 (Table 3, case 1) was excluded from this analysis, because
fused SPECT and PET images were not available in this patient. The interobserv-
er reliability in the remaining four patients was 100 %. In two patients with an
unidentified rLHA vascularizing segments 2-3 both SPECT/CT and PET/CT re-
vealed a distinct lack of activity in these segments, despite the intent to target the
whole liver (Table 3, cases 2 and 3). In the other two patients with an unidentified
aLHA vascularizing segment 2, SPECT/CT and PET/CT revealed a lack of activity
in segment 2 (Figure 4), also despite the intent to target the whole liver (Figure 1;
Table 3, cases 4 and 5). Four out of five patients (80 %) with unidentified aberrant
hepatic arteries had tumor involvement of the entire liver, including the untreated
segments.
Management of aberrant hepatic arteries
Seven patients (19 %) would have received different treatment, if all aberrant he-
patic arteries had been identified during the first pretreatment angiography. Iden-
tification of the aberrant hepatic arteries would have enabled whole liver treatment
in five of these patients and an unnecessary repeat angiography could have been
prevented in two patients.
The aberrant hepatic arteries were successfully used as a target vessel in 21 of 23 pa-
tients (91 %) with identified aberrant hepatic arteries who received treatment. This
was confirmed by activity in the segmental territory of the aberrant hepatic arteries
on posttreatment scintigraphy. In one of the remaining patients, the rLHA from
the LGA was inaccessible for catheterization. In the other patient, with an aRHA
originating from the GDA vascularizing segment 5, it was decided to coil embolize
the aberrant hepatic artery, because it was deemed unsafe to use it as a target vessel.
- 91 -
Chapter 4 Part II
Table 3: Patients with aberrant hepatic arteries, unidentified during angiography

Case Primary tumor Aberrant hepatic arteries Intrahepatic Injection Segmental Injection position Segmental Tumor
[segmental territory] distribution of position MAA lack of MAA treatment lack of 90Y involvement
MAA/90Y assessable? in untreated
segments?
1 Breast cancer aLHA [2] No* LHA & RHA - LHA & RHA - Yes
2 Pancreatic cancer rRHA + rLHA [2-3] Yes MHA + rRHA S2-3 MHA + rRHA S2-3 Yes
3 Colorectal cancer rLHA [2-3] Yes A4 + RHA S2-3 A4 + RHA S2-3 Yes
- 92 -
4 Colorectal cancer aRHA + aLHA [2] Yes aRHA + RHA + LHA S2 aRHA + RHA + LHA S2 No
5 Colorectal cancer rRHA + aLHA [2] Yes LHA + rRHA S2 LHA + rRHA S2 Yes
Cases of unidentified aberrant hepatic arteries. The unidentified component of the variant configuration is depicted in bold, with its segmental vascularization terri-
tory between brackets. Abbreviations: MAA = Technetium-99m-labelled Macro-Albumin Aggregates; 90Y = yttrium-90; aLHA = accessory left hepatic artery, rLHA
= replaced left hepatic artery, aRHA = accessory right hepatic artery, rRHA = replaced right hepatic artery, MHA = middle hepatic artery, A4 = segment 4 artery,
S2-3 = segment 2 and 3. *The intrahepatic distribution 99mTc-MAA and 90Y microspheres was not assessable in case 1, because fused SPECT and PET-images were
not available.
Part II Chapter 4
* *
* *
Figure 4: Triphasic liver CT, SPECT/CT and 90Y PET/CT in a patient with an unidentified aLHA.
A) Triphasic liver CT axial MIP of the arterial phase. The aLHA (white arrow) from the LGA enters the
liver in the fissure for the ligamentum venosum and courses alongside the portal branch (black arrow)
to supply segment 2. B) Coronal MIP of the arterial phase. The aLHA (black arrow) originates from the
LGA (white arrow). C) Axial 99mTc-MAA SPECT/CT. D) Coronal 99mTc-MAA SPECT/CT. E) Axial 90Y
PET/CT. F) Coronal 90Y PET/CT. The SPECT/CT and PET/CT images (C-F) reveal a lack of activity in
segment 2 (white asterisk).
- 93 -
DISCUSSION
In this study, we evaluated how often aberrant hepatic arteries were identified in
Chapter 4 Part II
clinical practice during a workup for radioembolization. The observed identifica-

tion rate of 49 % on CT and 86 % during angiography is clearly insufficient. Re-
markably, a significant difference in the identification of right-sided and left-sided
aberrant hepatic arteries was demonstrated (100 vs. 69 %, p = 0.007). Aberrant left
hepatic arteries remained unidentified in five patients, resulting in the absence of
activity in the tumor involved segmental territory of the aberrant left hepatic ar-
teries on postprocedural SPECT and PET imaging, despite the intent to target the
whole liver. The treatment efficacy of radioembolization is based on local tumor
control. Therefore, progression of disease can be expected when a tumor bearing
part of the liver is left untreated. In up to 19 % of the patients with aberrant hepatic
arteries, improvement in tumor targeting or prevention of redundant angiograph-
ic procedures could have been achieved when all aberrant hepatic arteries would
have been identified before radioembolization. This emphasizes the need for rec-
ommendations on how to use multimodality imaging to warrant the identification
and correct characterization of aberrant hepatic arteries in clinical practice. We
propose a practical approach at the end of the discussion, complementing previ-
ously described recommendations for the technical aspects of radioembolization.7
The preprocedural multiphase liver CT may be the modality that will allow for the
greatest improvement in clinical practice, because it is readily available in almost
all centers and enables a detailed assessment of the hepatic arterial anatomy before
the angiography. When systematically assessed, the preprocedural CT can function
as a guide for the pretreatment angiography, enabling treatment planning before
the angiography. Consequently, perprocedural imaging modalities, such as DSA,
C-arm CT or CTA, can be used during the angiography to confirm the observa-
tions already made on the preprocedural CT. This will undoubtedly enhance the
interventional radiologist’s understanding of the individual patient’s anatomy and
may even result in increased procedural time efficiency. In clinical practice, only
half of the aberrant configurations were correctly identified on CT. In our retro-
spective assessment, we were able to identify aberrant hepatic arteries that were
not recognized in clinical practice by reviewing the hepatic arterial configuration
and vascularization pattern in a systematic way on sectional and reconstructed
thin slice CT images, aided by additional reconstructions, such as maximum in-
tensity projections in axial and coronal orientations. This may raise the question
about who should be responsible for the assessment of the pretreatment CT in
clinical practice. The workup for radioembolization is a multidisciplinary process
- 94 -
that typically involves diagnostic radiologists, interventional radiologists, nuclear
Part II Chapter 4
medicine physicians, and radiation oncologists. In our opinion, this means that the
responsibility to assess the anatomy of the hepatic arterial vasculature is shared by
these professionals and therefore should be coordinated accordingly.
The pretreatment angiography should, for most part, be performed according to
standard technique.7 However, when the portal venous and arterial phase of the
pretreatment CT demonstrate a patent portal vein and no aberrant hepatic arteries
originating from the SMA, selective catheterization of the SMA becomes superflu-
ous. A standard celiac arteriogram and gastroduodenal arteriogram, obtained by
power injection angiography, should further help to ensure the identification of
(small) aberrant hepatic arteries originating from the LGA or GDA. Although not
indispensable, a routine use of C-arm CT or CTA is recommended, because it can
be used to identify aberrant hepatic arteries and simultaneously determine their
vascular territory. Finally, the intrahepatic distribution of 99mTc-MAA on SPECT/
CT and 90Y microspheres on PET/CT should be thoroughly assessed to exclude an
absolute lack of activity in one or more liver segments and to confirm an adequate
targeting of the liver tumors.
The correct terminology should be used to characterize aberrant hepatic arteries.
Aberrant hepatic arteries are historically classified as accessory or replaced, de-
pending on the extent of the liver territory vascularized by the aberrant hepatic
artery.6 We believe that the vascularization of segment 4 cannot be used to distin-
guish between accessory and replaced left hepatic arteries, due to the highly vari-
able origin of the hepatic arterial branch vascularizing segment 4, and therefore
should only depend on the vascularization of segment 2 (aLHA) or segments 2-3
(rLHA).6,12 In our study, all aLHAs vascularized segment 2 only, and the majority
of rLHAs did not vascularize segment 4, but vascularized segments 2-3 only. Re-
markably, we also observed rRHAs vascularizing segment 4 in addition to the right
hemi-liver. This stresses the importance of clearly describing the segmental terri-
tory of vascular supply, based on cross-sectional imaging assessment, in patients
with aberrant hepatic arteries. Accordingly, the term gastrohepatic trunk should be
avoided, because it does not contain functional information.
Once aberrant hepatic arteries are identified, two different treatment strategies can
be applied. Aberrant hepatic arteries may be used as a target vessel, when adminis-
tering microspheres selectively in the aberrant hepatic arteries or they may be coil
embolized to induce a redistribution of blood flow through intrahepatic collateral
pathways. In the latter strategy, activity is administered in the hepatic artery that
- 95 -
took over the coiled artery’s vascular territory, resulting in a simplified and safe
administration. Recently, Abdelmaksoud et al. reviewed the technical and clinical
Chapter 4 Part II
success of coil embolizing aberrant hepatic arteries before radioembolization in 43

patients, to induce a redistribution of blood flow and create simpler and safer injec-
tion positions. The redistribution of blood flow was assessed on DSA, C-arm CT,
and by the distribution of 99mTc-MAA on SPECT. The clinical success was assessed
by comparing the treatment response of tumors in territories that were previously
supplied with those not supplied by the coil embolized aberrant hepatic arteries.
While this strategy was considered to be technically successful in all patients on
immediate DSA and C-arm CT, SPECT revealed a lack of 99mTc-MAA activity in
the embolized territory in 7 % of the patients, and clinical success could not be
proven in up to 33 % of the patients.13 In our study, we were able to successfully
use the aberrant hepatic artery as a target vessel without compromising safety in
92 % of the treated patients with identified aberrant hepatic arteries, including six
patients with aberrant left hepatic arteries originating from the LGA.
The retrospective character of our study has evident limitations. We focused on
aberrant hepatic arteries only, because these are most important for radioembo-
lization treatment planning. However, tumors also may derive their blood from
parasitized extrahepatic arteries. Aberrant hepatic arteries result from a variant
embryological development and have their distinct segmental territory of blood
supply, whereas parasitized extrahepatic arteries are recruited from various extra-
hepatic origins (e.g., phrenic, intercostal, adrenal or renal arteries) to form an ad-
ditional source of blood supply to liver tumors. We did not evaluate the presence
of parasitized extrahepatic arteries in our cohort, because these branches often are
too small to allow for a reliable investigation on CT.14 Another limitation of this
study is the lack of blinding for the presence of the aberrant hepatic artery during
the intrahepatic biodistribution assessment in patients with unidentified aberrant
hepatic arteries. This was impossible, because the course of the aberrant hepatic
artery was visible on the SPECT/CT and PET/CT images. To limit the influence of
potential observer bias, two observers independently reviewed the distribution of
99m
Tc-MAA on SPECT/CT and 90Y microspheres on PET/CT.
PRACTICAL APPROACH
Based on the findings of this study, we postulate a practical approach that may help
to ensure a correct identification of aberrant hepatic arteries. The key points of this
- 96 -
Table 4: Key points of the practical approach, complementary to standard technique
A multiphase liver CT should be performed and reviewed systematically prior to the pretreatment
Part II Chapter 4
angiography to identify aberrant hepatic arteries and function as a guide for the interventional ra-
diologist
Replaced or accessory right hepatic arteries originating from the superior mesenteric artery (SMA)
display a retroportal course within the hepatoduodenal ligament, before entering the liver.
Replaced or accessory left hepatic arteries originating from the left gastric artery (LGA) enter the
liver in the fissure for the ligamentum venosum.
A selective arteriogram of the SMA is not necessary when patency of the portal vein and absence of
aberrant hepatic arteries originating from the SMA is demonstrated on the pretreatment CT.
A selective arteriogram of the celiac axis and gastroduodenal artery should be obtained to warrant
the identification of small aberrant hepatic arteries originating from the LGA or GDA.
When an aberrant hepatic artery is identified, it should be classified as accessory or replaced depend-
ing on its segmental liver territory.
The vascularization of segment 4 should not be used to distinguish between an aLHA and rLHA. An
aLHA vascularizes segment 2 only, whereas an rLHA vascularizes segments 2-3 or 2-4. An aRHA only
vascularizes a part of the right hemi-liver, whereas an rRHA vascularizes the entire right hemi-liver.
The use of C-arm CT or CTA is recommended to assess the hepatic arterial configuration and seg-
mental vascularization pattern during the pretreatment angiography.
Pretreatment SPECT/CT and posttreatment PET/CT-images should be evaluated on activity in all

targeted liver segments.
approach are summarized in Table 4.

Multiphase contrast enhanced helical CT of the liver
Multiphase liver computed tomography (CT), at least consisting of an arterial and
portal venous phase, should be performed in all patients. The use of thin slices, en-
abling a maximum intensity projection (MIP) of the early arterial phase, is strongly
recommended. When reviewing the CT, the radiologist should review the arterial
configuration systematically, starting at the aorta, followed by the celiac axis with
all its branches (including the GDA), continuing to the LGA, and ultimately the
SMA, carefully following all hepatic branches up to the liver parenchyma.
Replaced or accessory right hepatic arteries originating from the SMA display a
characteristic retroportal course. In this study, all replaced and accessory right he-
patic arteries from the SMA displayed a retroportal course before entering the area
- 97 -
A B
Chapter 4 Part II
B
Figure 5: Characteristic course of aberrant right and left hepatic arteries.
Triphasic liver CT images with an axial MIP of the arterial phase. A) rRHA from the SMA displaying
a characteristic retroportal course (black arrow) before entering the liver. B) rLHA from the LGA en-
tering the liver at the fissure for the ligamentum venosum (black arrow) before joining the umbilical
portion of the left portal vein.
of the hilar plate (Figure 5A). However, right hepatic arteries branching early from
the common hepatic artery proximal to the GDA can have an identical retroportal
course and should therefore be distinguished from aberrant right hepatic arteries.
Once an aberrant right hepatic artery has been identified, it should be determined
whether it is an accessory or replaced right hepatic artery. Replaced right hepatic
arteries vascularize the entire right hemi-liver (and in some patients also segment
4), whereas accessory right hepatic arteries vascularize only a part of the right
hemi-liver and exist in addition to a normally derived RHA originating from the
celiac axis that vascularizes the complementary part of the right hemi-liver.
Replaced or accessory left hepatic arteries predominantly originate from the LGA.
Therefore, the LGA should be checked routinely for contributory branches to the
liver parenchyma. A replaced or accessory left hepatic artery originating from the
LGA enters the liver at the fissure for the ligamentum venosum (Figure 5B). A help-
ful tool for recognizing replaced or accessory left hepatic arteries is to review the
MIP of the arterial phase in coronal orientation. Once the aberrant left hepatic ar-
tery has been identified, it should be classified as accessory or replaced. Particularly
accessory LHAs can be very small in caliber. An aLHA vascularizes segment 2 only,
and an rLHA vascularizes segments 2-3 or segments 2-4.
- 98 -
Angiographic procedure
The pretreatment CT should function as a guide for the angiographic procedure.
Part II Chapter 4
For the pretreatment angiography, it was routine practice to selectively catheterize
the SMA and perform an indirect portogram, with the purpose to evaluate the
patency of the portal vein and detect aberrant hepatic arteries originating from the
SMA.7 However, relevant portal vein abnormalities should be detected already on
the pretreatment CT during eligibility assessment. Furthermore, as demonstrated
in this study, aberrant hepatic arteries originating from the proximal part of the
SMA can still be missed during angiography when the catheter is positioned too
distal in the SMA (Figure 3). Therefore, we recommend evaluating the patency of
the portal vein and existence of aberrant hepatic arteries on the pretreatment CT.
When the portal vein is patent and no aberrant hepatic arteries originate from the
SMA, selective catheterization of the SMA is not necessary.
A routine celiac arteriogram by power injection arteriography is already mentioned
in the recommendations for the pretreatment angiography.7 The importance of this
acquisition is emphasized by our findings, with 31 % of the aberrant left hepatic ar-
teries not being identified before treatment. In retrospect, we noted that the rLHAs
were visible on selective arteriograms of the celiac axis as ill-defined branches orig-
inating from the LGA, coursing back toward the liver (Figure 6). When confronted
with this image, it should raise the suspicion of an aberrant left hepatic artery, and
a left gastric arteriogram should be obtained. When a replaced or accessory left
hepatic artery exists, the CHA will give rise to more than one hepatic branch. This
configuration can imitate a normal configuration with a complete RHA and LHA,
whereas in fact the “LHA” is an arterial branch that vascularizes segment 4 only, or
an incomplete LHA. Performing a thorough assessment of the hepatic arterial con-
figuration and the segmental vascularization pattern of the main arterial branches
on CT before the angiographic procedure can prevent this confusion.
Furthermore, it is recommended to check for aberrant hepatic arterial branches
originating from the GDA, before coil embolizing this vessel.7 If safety aspects ne-
cessitate coil embolization of aberrant hepatic arteries from this origin, redistribu-
tion of blood flow through intra-arterial collateral pathways should be evaluated
with angiography, C-arm CT, and postprocedural scintigraphic imaging.13
- 99 -
LHA
RHA LGA
GDA
PHA
A B
Chapter 4 Part II
LHA
LGA
LGA rLHA
RHA
GDA
PHA
B 6: Celiac axis arteriogram reveals rLHA from LGA.

Figure
A) rLHA from the LGA can be visualized on a celiac axis arteriogram as a branch originating from the
LGA and coursing back toward the liver parenchyma (white arrow). B) Selective arteriogram of the
LGA. The rLHA is clearly visible. Abbreviations: CA = celiac axis; LGA = left gastric artery; CHA =
LGA
rLHA artery; GDA = gastroduodenal artery; PHA = proper hepatic artery; LHA = left he-
common hepatic
patic artery (originating from the celiac axis); RHA = right hepatic artery. rLHA = replaced left hepatic
artery.
C-arm CT and CTA

C-arm cone beam computed tomography (C-arm CT) is an advanced imaging mo-
dality that uses rotational C-arm flat panel fluoroscopy systems, integrated in an
angiographic suite, to acquire and display three-dimensional images of digitally
subtracted contrast enhanced vessels and surrounding soft tissue.15 C-arm CT has
been shown to provide additional anatomic information, beyond DSA, during he-
patic arterial interventions, and therefore can aid the identification of aberrant he-
patic arteries during the angiographic procedures.16 It has been demonstrated that
the use of C-arm CT improves the visibility of extrahepatic arterial branches16-17
and tumor-feeding arteries18-20, compared to using only DSA, and can affect the
treatment planning of radioembolization in up to one-third of the patients16,17,21,22,
while resulting in negligible increases in patient radiation exposure.23 Moreover,
delayed imaging acquisition enables the visualization of parenchymal contrast en-
hancement and can therefore be used to delineate the territory of liver perfusion
of aberrant hepatic arteries, and consequently distinguish accessory from replaced
hepatic arteries.21 In addition, with the use of C-arm CT it is possible to detect
parasitized extrahepatic arteries, tumor-feeding arterial branches developed from
an extrahepatic source (e.g., inferior phrenic arteries), that may be too small to be
visible on multidetector CT.14
Perprocedural CTA is an alternative to C-arm CT, in which a conventional MDCT
scanner is used to acquire contrast enhanced CT-images, either by transferring the
- 100 -
patient from the angio-suite to the CT scanner with the catheter in situ, or by using
a hybrid CT/angiography system built-in within the angiography suite.24-25 The first
Part II Chapter 4
form is time consuming and may place a high burden on logistics and procedure
time but comes at no additional costs. The second form is not available in all cen-
ters and may be quite expensive.
Both C-arm CT and CTA can be used to visualize hepatic arterial branches and
contrast enhanced perfusion territory of target vessels. C-arm CT may be less cum-
bersome in its use, but CTA has a larger field of view and provides cross-sectional
images with higher resolution and less artifacts.25 Although not indispensable, we
recommend the use of C-arm CT or CTA during the pretreatment angiography,
whenever available.
Scintigraphy
Fused SPECT/CT images, instead of SPECT or planar imaging only, are superi-
or to assess the anatomical localization of 99mTc-MAA activity, after the pretreat-
ment angiography.26 On non-fused SPECT and planar imaging, it is impossible to
delineate the intersegmental boundaries and, therefore, lack of activity in one of
the liver segments may be missed. However, when SPECT is fused with a readily
available CT, it should be verified that an adequate co-registration of both imag-
ing modalities is achieved. A lack of activity in one or more liver segments can
be caused by various factors. First, it should be checked whether the catheter was
unintentionally positioned distal to an important side-branch. If not the case, the
presence of an unidentified aberrant hepatic artery should be considered. Another
possible explanation may be the influence of preferential flow towards other liver
segments.26 Preferential flow usually does not cause an absolute lack of activity
and often occurs when the catheter is positioned in close proximity to a bifurca-
tion. Finally, posttreatment SPECT/CT or PET/CT should demonstrate activity of
90
Y microspheres in all targeted liver segments. The intrahepatic biodistribution of
90
Y microspheres may be different to that of 99mTc-MAA, due to intrinsic different
characteristics of these particles.27
CONCLUSION
Aberrant left hepatic arteries were the most common unidentified aberrant hepat-
ic arteries, resulting in incomplete radiation coverage. We formulated a practical
approach to identify aberrant hepatic arteries correctly before radioembolization.
- 101 -
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patic distribution of the hepatic artery in al. (2013) Quantitative comparison of PET
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2. Abdullah SS, Mabrut JY, Garbit V, et al.
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(2006) Anatomical variations of the hepatic
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MAAJ, et al. (2013) In vivo dosimetry based
3. Gruttadauria S, Foglieni CS, Doria C, et al.
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cies. J Nucl Med 54:2093–2100.
701 cases. Clin Transplant 15:359–363.
12. Wang S, He X, Li Z, et al. (2010) Charac-
terization of the middle hepatic artery and
Surgical anatomy of the hepatic arteries in
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5. Koops A, Wojciechowski B, Broering DC, 741.
13. Abdelmaksoud MHK, Louie JD, Kothary
N, et al. (2011) Consolidation of hepatic ar-
terial inflow by embolization of variant he-
Radiol Anat 26:239–244.
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14. Kim HC, Chung JW, An S, et al. (2009) Left
7. Lewandowski RJ, Sato KT, Atassi B, et al. inferior phrenic artery feeding hepatocel-
(2007) Radioembolization with 90Y micro- lular carcinoma: Angiographic anatomy
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15. Orth RC, Wallace MJ, Kuo MD (2008)
8. Smits MLJ, Nijsen JFW, van den Bosch C-arm cone-beam CT: General principles
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16. Wallace MJ, Murthy R, Kamat PP, et al.
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17. Heusner TA, Hamami ME, Ertle J, et al. 23. Kothary N, Abdelmaksoud MHK, Tognoli-
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(2010) Angiography-based C-arm CT for ni A, et al. (2011) Imaging guidance with
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and digital subtraction angiography. AJR The effect of catheter-directed CT angiog-
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20. Miyayama S, Yamashiro M, Hashimoto 99m
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al. (2013) 99mTc-macroaggregated albumin
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C hap ter
PART II 5
The caudate lobe –
the blind spot in radioembolization or
an overlooked opportunity?
M.N.G.J.A. Braat
A.F. van den Hoven
P.J. van Doormaal
R.C.G. Bruijnen
M.G.E.H. Lam
CardioVascular and Interventional Radiology [accepted]

The caudate lobe – the blind spot in radioembolization or an overlooked opportunity?
ABSTRACT
Purpose
The caudate lobe (CL) is impartial to the functional left and right hemi-liver and
has outspoken interindividual differences in arterial vascularization. Unfortunate-
ly, this complexity is not specifically taken into account during radioembolization
Chapter 5 Part II
treatment, potentially resulting in under- or overtreatment of the CL. The objective

of this study was to evaluate the CL coverage in radioembolization and determine
the detection rate of the CL arteries on CT angiography during workup.
Methods
In all consecutive patients who underwent radioembolization treatment be-
tween May 2012 – January 2015 99mTc-MAA SPECT/CT and posttreatment scans
(90Y-bremsstrahlung SPECT/CT, 90Y-PET/CT, or 166Ho-SPECT/CT) were reviewed
for activity in the CL. Pretreatment CT angiographies were reviewed for the visi-
bility of the CL arteries.
Results
Eighty-two patients were treated. In 32 of 82 (39 %) the CL was involved. In 6 of 32
(19 %) patients no activity was seen on the posttreatment scan in the CL, whereas
the CL was treated in 40 of 50 (80 %) patients without CL tumor involvement.
99m
Tc-MAA SPECT/CT and final posttreatment scans were discordant in 16 of 78
(21 %). 99mTc-MAA SPECT/CT had a positive and negative predictive value of 94
% and 46 % respectively for activity detection in the CL after radioembolization.
In untreated CLs significant hypertrophy was observed with a median volume in-
crease of 33 % (p = 0.02). CL arteries were seldom visible on the pretreatment CT;
the identification rate was 12 – 17 %.
Conclusion
Currently in radioembolization treatments, targeting or sparing of the CL is highly
erratic and independent of tumor involvement. Intentional treatment or bypassing
of the CL seems worthwhile to either improve tumor coverage or enhance func-
tional liver remnant.
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INTRODUCTION
The caudate lobe (segment 1 and 9 according to Couinaud’s classification) is not
regarded as a distinct part of the functional left or right hemi-liver, due to its high-
ly variable vascular anatomy. Cadaveric dissection and radiologic studies have
found a range of 1 – 5 arterial branches supplying the caudate lobe (CL), with 2 – 3
Part II Chapter 5
branches being the most common.1,2 These branches can originate from the right
hepatic artery (RHA), left hepatic artery (LHA), middle hepatic artery (MHA)/
segment 4 artery (S4A) and/or the right posterior hepatic artery (RPHA). At dis-
section Lee et al. identified a CL branch originating from the RHA or RPHA in 38
of 45 livers (84 %) and a branch originating from the LHA in 20 of 45 livers (44 %).1
Hence, dual supply of the CL is a common normal variant.
The CL is usually not targeted separately during radioembolization treatments,
nor is its volume and vascularization considered during prescribed activity cal-
culations. The latter is of lesser importance during whole liver treatments with the
catheter positioned in the common (CHA) or proper hepatic artery (PHA). How-
ever, in most treatments the RHA and LHA are separately injected, which necessi-
tates a division of the planned target volume.
The aim of this study was to evaluate the effect of radioembolization treatment
on the CL and its relation to CL tumor involvement. Secondly, we determined the
visibility of CL arteries on CT angiography and the associated interobserver repro-
ducibility.
METHODS
Study population and design
Sixty-eight consecutive radioembolization candidates with both primary and sec-
ondary liver tumors underwent radioembolization treatment between May 2012
and January 2015. All patients had unresectable tumors and were refractory to
standard treatment. We retrospectively reviewed the imaging data related to the
radioembolization treatment. The medical ethics committee of our institution has
waived the need for informed consent for the review of imaging data from radio-
embolization patients.
Treatment
All patients underwent screening with 18F-FDG-PET and multiphase liver CT. All
CT scans were acquired on an integrated PET/CT scanner (Biograph mCT, Sie-
mens Healthcare, Erlangen, Germany) with 40 detector rows, using a matrix size
of 512 x 512, rotation time of 0.4 – 0.5 s, pitch of 0.9 – 1.2, and fixed 120 kV tube
potential.
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For the CT 150 – 185 ml (depending on body weight) Iopromide 300 mg/ml (Ul-
travist, Bayern Schering Pharma AG, Berlin Germany) was injected at a rate of 5
ml/s followed by a 50 ml saline chaser. Two CT protocols were applied in this pop-
ulation, differing only in arterial phase (early or late arterial phase). The arterial
phase was either obtained with a postthreshold delay (abdominal aorta enhance-
Chapter 5 Part II
ment > 100 HU) of 20 s at a tube current of 150 mAs, or with a postthreshold delay
of 10 s at a tube current of 150 mAs or 200 mAs (200 mAs in patients > 85 kg). The
portal venous phase was obtained with equal parameters.
A pretreatment angiography (DSA) was subsequently performed. Approximately
150 MBq technetium-99m-macroaggregated albumin (99mTc-MAA) (TechneScan
LyoMaa, Mallinckrodt Medical, Petten, The Netherlands) was injected intra-arte-
rially, followed by a 99mTc-MAA planar scintigraphy and single-photon emission
computed tomography (SPECT)/CT (Symbia 16T, Siemens Healthcare, Erlangen,
Germany).
Radioembolization was performed using yttrium-90 (90Y)-labeled resin micro-
spheres (SIR-Spheres, SIRTeX, Lane Cove, Australia) according to international
guidelines, or holmium-166 poly(L-lactic acid) microspheres (166Ho) as previously
described.3 The position of the catheter tip was similar during radioembolization
treatment and the 99mTc-MAA injection position(s). Depending on the micro-
spheres used, a 90Y-bremsstrahlung SPECT/CT, 90Y-positron emission tomography
(PET)/CT, or 166Ho-SPECT/CT was performed to assess the activity distribution.
Our acquisition protocols were published earlier.3-4 Only patients who underwent
posttreatment imaging were included.
Image analyses
All images were stored in a picture archiving and communication system. For anal-
ysis of the arterial supply and CL volume the images were exported, anonymized,
and loaded into OsiriX (version 5.8, 32-bit, MacOS X).
Two radiologists (MB and PJvD) scored the presence, number and origin of the
CL arteries on CT angiography. They were blinded for all patient data, including
angiographies and posttreatment scans. If present, the origin was marked by each
of the observers. To assess the volumetric changes of the CL, one observer (MB)
manually segmented the CL on the pretreatment liver CT and on the last available
abdominal CT. CL tumor(s) were excluded from the volume. In case of repeated
radioembolization treatment, the last CT before the second treatment was used.
Only first treatments were analyzed.
The deposition of activity in the CL was assessed after treatment on 90Y brems-
strahlung SPECT/CT, 90Y-PET/CT, or 166Ho-SPECT/CT. CL deposition was con-
- 108 -
sidered present if the majority (> 2/3) of the CL showed activity. The 99mTc-MAA
SPECT/CT was assessed in a similar fashion. The presence of CL tumor(s), activity
on the posttreatment scan and 99mTc-MAA-SPECT/CT, as well as the CL volumes
were scored by one observer (MB), at different time points. In case of doubt, a sec-
ond reader (ML) was consulted and a consensus was reached.
Part II Chapter 5
Statistics
Descriptive statistics and independent-samples T-tests were used to explore
baseline characteristics and CL artery origin locations. Data with a normal and
non-normal distribution are presented as mean ± standard deviation and median
(range) respectively.
A Wilcoxon rank sum test was used to test for differences in CL volume between
patients. A Wilcoxon signed rank test was used to assess intra-individual chang-
es in the CL volume. Chi-square tests and Fisher’s exact tests were used to com-
pare the visibility of CL arteries and the 99mTc-MAA SPECT/CT and posttreatment
scans in relation to the presence of tumor.
All analyses were performed with IBM SPSS Statistics version 22. A p value < 0.05
was considered statistically significant.
RESULTS
A total of 86 patients underwent radioembolization treatment and posttreatment
imaging. Four patients were excluded because of prior CL resection. The baseline
characteristics of the remaining 82 patients are presented in Table 1.
In 32 patients (39 %), a tumor was located in the CL. Patients with CL tumor in-
volvement had a higher liver tumor burden than those without CL tumor involve-
ment, with a median of 19 % and 7.5 % respectively (p = 0.015). All patients with a
tumor burden > 50 % (n = 4) had CL tumor involvement.
CL activity (Table 2)
In 6 of 32 (19 %) patients with CL tumor involvement, no activity was seen on
the posttreatment scan in the CL (Figure 1). Conversely, 40 of 50 (80 %) patients
without CL tumor did show activity in the CL. There was no association between
posttreatment CL activity and CL tumor involvement or microsphere type.
CL volumetric measurements were possible in 57 of 82 (70 %) patients. The me-
dian interval between measurements was 153 days (21 – 827 days). After radio-
embolization, the median CL volume increased from 36 ml to 48 ml in patients
with an untreated CL (median volume increase 33 %; range -1 – 243 %; p = 0.02).
In patients with a treated CL, a non-significant decrease from 38 ml to 32 ml was
observed.
- 109 -
Table 1: Baseline characteristics
Characteristic All patients CL tumor No CL tumor P value*

(n=82) (n=32) (n=50)
Age (years) 64 ± 11 64 ± 10 64 ± 11 NS
Gender
Chapter 5 Part II
Male 47 (57 %) 19 (59 %) 28 (56 %) NS

Female 35 (43 %) 13 (41 %) 22 (44 %)
BMI 27 ± 4 27 ± 5 27 ± 4 NS
Primary tumor
CRC 57 (70 %) 22 (69 %) 35 (70 %) NS
Cholangiocarcinoma 8 (10 %) 5 (16 %) 3 (6 %)
Uveal melanoma 6 (7 %) 1 (3 %) 5 (10 %)
Breast carcinoma 4 (5 %) 3 (9 %) 1 (2 %)
Othersa 7 (9 %) 1 6
Liver tumor burden
< 25 % 73 (89 %) 25 (78 %) 48 (96 %) 0.02
25-50 % 5 (6 %) 3 (9 %) 2 (4 %)
> 50 % 4 (5 %) 4 (13 %) 0
Previous liver treatment

Right hemihepatectomyb 5 (6 %) 3 (9 %) 2 (4 %) NS
Segmentectomy/metastasec- 7 (9 %) 3 (9 %) 4 (8 %)
tomy 1 (1 %) 1 (3 %) 0
RFA
Treatment
Whole liver in one session 71 (90 %) 27 (84 %) 47 (94 %) NS
Sequential lobar 5 (6 %) 3 (9 %) 2 (4 %)
Lobar (right-sided) 3 (4 %) 2 (6 %) 1 (2 %)
Microsphere
90
Y 52 (63 %) 18 (56 %) 34 (68 %) NS
166
Ho 30 (37 %) 14 (44 %) 16(32 %)
Posttreatment scan
90
Y-SPECT 2 (2 %) 0 2 (4 %) NS
90
Y-PET 50 (61 %) 18 (56 %) 32 (64 %)
166
Ho-SPECT 27 (27 %) 13 (41 %) 14 (44 %)
166
Ho-PET 2 (2 %) 1 (3 %) 1 (2 %)
MRIc 1 (1 %) 0 1 (2 %)
a
Pancreatic carcinoma (n = 2), Gastric carcinoma (n = 1), Thymoma (n = 1), oesophageal carcinoma
(n = 1), NET (n = 1), RCC (n = 1). b Right hemi-hepatectomy (n = 1), extended right hemi-
hepatectomy (n = 4). c No 166Ho-SPECT imaging was performed in one case, though deposition of
166
Ho microspheres in the CL was clearly seen on follow up MRI. * p < 0,05 is considered significant.
NS = not significant.
- 110 -
Table 2: Comparison of treatments with and without CL activity

Activity in CL No activity in CL P value*
CL tumor
Yes 26 (81 %) 6 (19 %) 0.889
No 40 (80 %) 10 (20 %)
Part II Chapter 5
Microsphere
90
Y 43 (83 %) 9 (17 %) 0.569
166
Ho 23 (77 %) 7 (23 %)
CL volume pretreatment (in ml)a 38 (2 – 154) 36 (19 – 80)
CL volume posttreatment (in ml)a 32 (0 – 115) 48 (9 – 244)
Activity in CL on MAA scanb
Yes 51 (80 %) 3 (21 %) < 0.001†
No 13 (20 %) 11 (79 %)
a
In 24 of 79 cases follow up did not include a portal venous CT scan for volume measurements.
Caudate lobe tumor(s) were subtracted from the volume of the caudate lobe; the volume of 0 ml cor-
responds to a caudate lobe that is completely engulfed by tumor. Values expressed in median (range).
b
In 4 cases no 99mTc-MAA SPECT/CT was performed; only a 166Ho-scout SPECT/CT. * Fisher’s exact
test. † p < 0.05 is considered significant. Significant differences are marked.
Additionally, 99mTc-MAA SPECT/CTs and posttreatment scans were compared.

In 13 of 24 (54 %) cases with a negative 99mTc-MAA SPECT/CT, the posttreatment
scan did show activity in the CL. Conversely, in 3 of 14 negative posttreatment
scans, the 99mTc-MAA SPECT/CT did show activity in the CL. These results corre-
spond to a positive predictive value of 94 %, negative predictive value of 46 %, false
negative rate of 54 % and false positive rate of 6 %.
Reviewing the DSA images in the patients with negative posttreatment scans re-
vealed that in all cases the LHA, RHA (and sometimes MHA) were separately in-
jected. Reviewing the DSA images in patients with discrepant 99mTc-MAA SPECT/
CT and posttreatment scans revealed no consistent explanation (Supplement 1)
(Figure 2, Figure 3).
CL arteries
Forty-four patients were scanned in the early arterial phase and 38 patients in the
late arterial phase. In 10 of 82 (12 %) patients, both observers identified 1 CL ar-
tery, whereas in 4 cases only one rater identified a CL artery. In 68 of 82 (83 %)
both observers could not identify a CL artery. The specific proportion of agreement
including the exact origin of a CL artery was 95 % (78/82). A CL artery originated
from the LHA (n = 4), RHA (n = 3), CHA (n = 2) and PHA (n = 1). In 11 of 32 (34
%) cases with CL tumor involvement a CL artery was identified, compared to 3 of
- 111 -
A B
Chapter 5 Part II
C D
Figure 1: Failure to treat a CL metastasis in a patient bilobar metastases of an uveal melanoma. A)

On the coronal maximum intensity projection (MIP) image of the early arterial phase (postthreshold
delay of 10 s) 2 CL arteries can be identified. One branch arising from the RHA and one arising from
the LHA; only the branch arising from the LHA was identified by both raters. B) A large metastasis is
present in the CL, mainly occupying the Spigelian lobe. The patient was treated with 90Y, using sequential
deliveries; the left lobe was treated 6 weeks after the right lobe had been treated. C) The 90Y-PET/CT
acquired after treatment of the left side shows no activity in the CL, similar to the treatment of the right
lobe (not shown). D) The contrast enhanced CT obtained 6 months after left-sided radioembolization
treatment shows progression of the lesion in the CL, whereas the lesions in the right lobe are still smaller
then on the baseline scan (compare to image B).
Figure 2: Unintentional CL targeting during 99mTc-MAA

administration in a patient with bilobar colorectal liver
metastases, but no CL metastasis. DSA of the end-hole
catheter position during 99mTc-MAA injection. A large
caliber CL artery (arrow) was mistakenly interpreted as
the artery of segment 4, resulting in massive accumulation
of 99mTc-MAA in the CL on SPECT/CT (Figure 3A).
- 112 -
Part II Chapter 5
Figure 3: Unintentional CL targeting (clinical example of Figure 2 continued). A) 99m
Tc-MAA
SPECT/CT: massive accumulation of 99mTc-MAA in the CL. At radioembolization treatment, this
easily identifiable artery was intentionally bypassed. B) 166Ho-SPECT/CT after radioembolization
treatment: no activity in the CL. Contrast enhanced CT pretreatment (C) and follow-up 6 months
after radioembolization (D) at the level of a portal branch arising from the left portal vein (arrow)
demonstrate hypertrophy of the CL by 279 % (24 ml to 67 ml).
50 (6 %) cases without CL tumor involvement (p = 0.002). Visibility of the CL ar-

teries was not related to the presence of activity in the CL after radioembolization
or to the pretreatment CL volume.
Nearly all visible CL arteries (12/14, 85 %) were detected on the early arterial phase.
DISCUSSION
Our results show that the CL was often treated, regardless of CL tumor involve-
ment or identification of the CL arteries. Identification its arteries on CT was sub-
optimal, but when visible there was often CL tumor involvement.
In this context, it is important to address the highly variable and complicated anat-
omy of the CL. The CL is subdivided into 3 parts: the paracaval portion, Spigelian
- 113 -
lobe and caudate process.1 Vascular supply of these parts varies considerably with 1
– 6 portal branches and 1 – 5 arterial branches. The paracaval portion and caudate
process are nearly always supplied by the RHA, whereas the Spigelian lobe can be
supplied by the LHA, RHA or MHA/S4A or a combination.1,2
Separate assessment of the parenchymal territories of the CL arteries mandates a
Chapter 5 Part II
high spatial resolution; i.e., higher than most acquired posttreatment scans. There-
fore the CL was considered adequately treated if more than two thirds showed ac-
tivity. Hence, in some cases not all CL arteries will have been injected with particles
(Figure 4). Currently only one report on the presence of activity in the CL has been
published. Gates et al. found 99mTc-MAA activity in the CL in 19 of 51 (37 %) pa-
tients after proximal RHA injection.5 In comparison, 79 % of our patients showed
CL activity, pleading for a substantial contribution of the LHA or more proximal
branches.
A B
Figure 4: Unnecessary partial treatment of the CL in a patient with bilobar liver metastases of a
neuroendocrine tumor without CL tumor involvement. The patient was treated in a single whole liver
treatment session. 90Y-PET/CT after radioembolization treatment: two levels are shown (A-B). Due to
intrahepatic shunting (not shown) the left liver lobe received a larger part of the dose. A) In the cranial
part of the Spigelian lobe accumulation of 90Y is clearly seen. B) The caudal part of the Spigelian lobe
and caudate process show no activity (even less than the right lobe).
Another important consideration is treatment planning. In our practice, the CL is

incorporated in the right hemi-liver volume (presumed RHA territory) for activity
calculations. Considering the variable interindividual arterial anatomy and CL vol-
ume, this might lead to errors in planned target volume, and under or overdosage
of the CL or the adjacent arterial territory.
Also, the potential contribution of parasitized extrahepatic arteries has to be con-
sidered, especially in hepatocellular carcinoma (HCC). Several small studies have
been published on intra-arterial treatments of CL HCC.2,6-7 All report multiple cas-
- 114 -
es with 2 – 4 CL arteries and at least one case with a feeding artery arising from the
right inferior phrenic artery. This does not only necessitate a proximal injection
during angiography or C-arm CT to evaluate all CL arteries, but also a search for
possible extrahepatic sources.
A large number of our patients (39 %) had CL tumor involvement. This is consid-
Part II Chapter 5
erably higher than in previously published hepatectomy and TACE series with an
incidence of 4.5 – 7.5 %.2,6,8 Consistent with our findings, these studies observed
a higher liver tumor burden in patients with CL involvement. This difference in
incidence is probably attributable to the higher tumor burden in patients referred
for radioembolization and the increased prevalence of metastases.
We observed a surprising disconcordance between the deposition of the 99mTc-
MAA and 90Y or 166Ho in the CL. 99mTc-MAA particles vary substantially from 90Y
and 166Ho particles. The larger size, specific gravity, injected particle load, inject-
ed volume and embolic potential of the latter two are known to cause stasis and
potential retrograde reflux.9 Reflux or redistribution into the proximal branching
CL arteries is most likely the cause of this disconcordance, especially since direct
comparison of the injection positions revealed no consistent differences.
Hypertrophy of untreated lobes is a known by-effect of radioembolization treat-
ment. Some advocate replacing portal vein embolization with radiation lobectomy
to induce hypertrophy whilst treating the underlying liver tumors.10 In these cases
sparing of a tumor-free CL could be beneficial, either as bridge to surgery or as im-
portant functional liver remnant in case of repeated radioembolization treatments
(Figure 5).
Caudate lobe resections have high complication rates and mortality rates, together
with smaller tumor-free margins, more positive resection margins and higher re-
currence rates.8 Ibrahim et al. report on radioembolization treatment in 8 patients
with CL HCCs, resulting in downstaging in 4 patients and subsequent liver trans-
plantation in 3 patients.7 Thus, radioembolization might be an attractive option for
downstaging and diminishing positive resection margins in CL resections.
This study is most importantly limited by its retrospective design. Identification
of CL arteries is notoriously difficult on two-dimensional projections due to their
unknown origin and number, small caliber and overlap with other hepatic arter-
ies.2,6 During the pretreatment angiography the CL arteries were not selectively
examined and the DSA images available for review were not acquired in a stan-
dardized fashion and only at one projection angle, prohibiting reliable review of
the CL artery origins. C-arm CT could benefit their detection6, yet was not consis-
tently acquired.
- 115 -
A B
Chapter 5 Part II
C D
Figure 5: Compensatory hypertrophy after intentional sparing of the CL in a patient with colorectal
liver metastases, not involving the CL. A) Pretreatment T2-weighted image of the liver with multiple
bilobar metastases. The CL has a volume of 68 ml. B) 90Y-PET/CT after the first radioembolization
treatment, showing no accumulation of 90Y in the CL (non-intentional). C) T2-weighted image
obtained 9 months after radioembolization treatment. The CL has hypertrophied to a volume of 308
ml. A persisting metastasis is seen in liver segment 6 (arrow). Because of the good initial response
to radioembolization treatment and absent extrahepatic disease, this patient has now undergone 2
retreatments. As the CL continued to be free of metastases it was bypassed. D) C-arm CT obtained
during the first retreatment. The catheter is positioned relatively distal in the left hepatic artery; no
parenchymal enhancement of the hypertrophied CL is seen.
In conclusion, though the CL is often neglected during radioembolization plan-

ning or treatment, its consideration seems worthwhile. If CL tumor involvement
is present, identification of its feeding arteries is necessary to obtain a compre-
hensive treatment result. Moreover, intentional sparing of a tumor-free CL should
be endeavored to enhance the future functional liver remnant for additional liver
directed therapies.
- 116 -
REFERENCES
1. Lee UY, Murakami G, Han SH (2004) Arteri- 6. Choi WS, Kim H-C, Hur S, et al. (2014) Role of
al supply and biliary drainage of the dorsal C-Arm CT in identifying caudate arteries
liver: A dissection study using controlled supplying hepatocellular carcinoma. J Vasc
specimens. Anat Sci Int 79:158–166. Interv Radiol 25:1380-1388.
Part II Chapter 5
2. Yoon CJ, Chung JW, Cho BH, et al. (2008) 7. Ibrahim SM, Kulik L, Baker T, et al. (2012)
Hepatocellular carcinoma in the caudate Treating and downstaging hepatocellular
lobe of the liver: Angiographic analysis of carcinoma in the caudate lobe with yttri-
tumor-feeding arteries according to sub- um-90 radioembolization. Cardiovasc In-
segmental location. J Vasc Interv Radiol terv Radiol 35:1094–1101.
19:1543–1550
8. Thomas RL, Lordan JT, Devalia K, et al. (2011)
3. Elschot M, Vermolen BJ, Lam MGEH, et al. Liver resection for colorectal cancer metas-
(2013) Quantitative comparison of PET tases involving the caudate lobe. Br J Surg
and Bremsstrahlung SPECT for imaging 98:1476–1482.
the in vivo yttrium-90 microsphere distri-
9. Bult W, Vente MAD, Zonnenberg BA, et al.
bution after liver radioembolization. PLoS
(2009) Microsphere radioembolization of
One 8:e55742.
liver malignancies: Current developments.
4. Elschot M, Nijsen JFW, Lam MGEH, et al. Q J Nucl Med Mol Imaging 53:325–335.
(2014) (99m)Tc-MAA overestimates the
10. Garlipp B, de Baere T, Damm R, et al. (2014)
absorbed dose to the lungs in radioemboli-
Left-liver hypertrophy after therapeutic
zation: A quantitative evaluation in patients
right-liver radioembolization is substantial
treated with 166Ho-microspheres. Eur J Nucl
but less than after portal vein embolization.
Hepatology 59:1864–1873.
5. Gates VL, Singh N, Lewandowski RJ, et al.
(2015) Intraarterial hepatic SPECT/CT im-
aging using 99mTc-macroaggregated albu-
min in preparation for radioembolization.
J Nucl Med 56:1157–1162.
- 117 -
SUPPLEMENT 1
DSA review in cases with negative and discordant 99mTc-MAA SPECT/CT and
posttreatment scans
Review of the DSAs in the patients with negative posttreatment scans revealed
that in all of these cases the LHA, RHA (and sometimes the MHA) were separately
Chapter 5 Part II
injected. Secondly, the angiographies of the discrepant 99mTc-MAA SPECT/CT and

posttreatment scans were reviewed. In 3 cases CL activity was seen on the 99mTc-
MAA SPECT/CT but not on the posttreatment scan. In one case a large calibre CL
artery was mistakenly interpreted as the artery of segment 4 at the pretreatment
angiography and consequently intentionally bypassed at the eventual RE treatment
(Figures 2 and 3 in the original manuscript). In another case the injection position at
the 99mTc-MAA was slightly more proximal in the RHA than at treatment, though
no extra arterial branches were identified in between these 2 injection positions on
the angiography. In the last case the injection positions were similar for the prox-
imal LHA and RHA, only the MHA was injected slightly more distal at treatment
(< 1 cm). In this last case no explanation for the discrepancy could be identified.
In the 13 cases with a negative 99mTc-MAA SPECT/CT and a positive posttreatment
scan catheter positions were similar for the 99mTc-MAA injection and treatment in
all but two cases. In the first case the 99mTc-MAA was injected in the CHA, where-
as the catheter was positioned in 3 distal branches of the LHA and proximal in
the RHA at treatment. In the last case the injection position in the RHA at the
treatment was approximately 1 cm more proximal than at 99mTc-MAA injection.
Hence, no conclusive explanation for the discrepant results between the 99mTc-
MAA SPECT/CTs and positive posttreatment scans could be identified.
- 118 -
SUPPLEMENT 2
CL activity on the posttreatment scan of patients with sequential or
unilobar delivery
A whole liver treatment with a sequential delivery was performed in 5/82 patients,
of whom 3 had CL tumor involvement. In 4/5 cases 90Y-PET/CTs were acquired
Part II Chapter 5
after both treatments. In 3/4 cases the CL was positive for activity on the post-
treatment scan. In 2 cases this was due to both LHA and RHA supply, in one case
only due to RHA supply. One patient with CL tumor involvement had a negative
posttreatment scan (minimal activity in the paracaval portion) after right lobar
treatment, leading to insufficient treatment of the metastasis (Figure 1 in the orig-
inal manuscript). In one case 166Ho-SPECT/CT was performed after a sequential
treatment with injection in the LHA and the segment 6/7 artery during the first
session and injection in the segment 5/8 artery in the second session. CL activity
was only seen after the first treatment, covering the entire CL.
Three of 82 patients underwent only a selective treatment of the right lobe; in 2/3
patients the CL was positive for activity on the posttreatment scan (both without
CL tumor involvement). The case with a negative posttreatment scan did show
some activity in the caudate process after right lobar treatment (< 2/3 of the CL). A
metastasis was located in the Spigelian lobe in this case. Due to progressive disease
the initially planned left lobar treatment was cancelled.
In 2/5 patients with a prior right hemi-hepatectomy no activity was seen in the CL.
- 119 -
C hap ter
PART II 6
Arterial liver anatomy –
Introducing functional concepts and
terminology to break down
the complexity
A.F. van den Hoven

M.S. van Leeuwen
M.N.G.J.A. Braat
J.D. Louie
M.G.E.H. Lam
D.Y. Sze
In preparation
Arterial liver anatomy - functional concepts and terminology
ABSTRACT
Hepatic arterial anatomy is complex. Although peripheral hepatic artery branches
course alongside the corresponding portal vein branches and biliary ducts, within
their Glissonian sheath, vascular territories supplied by proximal hepatic artery
branches do not mirror that of the corresponding portal vein branches. The reason
for this is that hepatic arterial branches can have multiple different sources of ori-
gin, varying orders of branching, and can cross laterally before being enveloped by
Chapter 6 Part II
the Glissonian sheath. This warrants an unprejudiced assessment of the individual

hepatic arterial anatomy on contrast enhanced cross-sectional imaging in all pa-
tients that undergo invasive liver therapy. In this paper, we review knowledge of the
hepatic arterial anatomy, and draw attention to known differences with the portal
venous anatomy. In addition, we define functional concepts and terminology to
help clarify distinct features of the hepatic arterial vasculature and classify/report
its variants in an unambiguous way. This should break down the perceived com-
plexity that presently surrounds hepatic arterial interventions, and improve mul-
tidisciplinary communication during liver tumor board discussions. A three-step
approach is proposed to break down the complexity of arterial anatomical variants:
assess the 1) origin, 2) order of branching and 3) segmental vascularization pattern
of all main hepatic arterial branches. Based on this assessment, the individual he-
patic arterial anatomy can be summarized by “Term for variant [Origin, Segments
vascularized]” for communication purposes. It is, however, recommended to study
the real location of the arterial watershed zones between functionally independent
liver segments instead of relying on Couinaud’s model of segmental liver anatomy,
since the latter is based on the portal venous ramification, represents a simplifica-
tion of anatomic reality, and does not account for pathology influences.
- 122 -
INTRODUCTION
The liver is a fascinating and complex organ. It took a long time before our under-
standing of the liver exceeded recognition of the external surface anatomy, and
functional anatomy, based on internal vascular territories, was uncovered. Al-
though we have learned much about the physiology and pathology of the liver in
the past decades and are able to safely perform increasingly complex hepatobiliary
surgery and interventional procedures, functional anatomy remains a matter of
Part II Chapter 6
continued study and debate. Recently, the need was voiced for a standardized, con-
cise terminology to describe the division of the liver into different functional parts
based on the portal venous ramification.1-5
For some reason, the arterial liver anatomy has received less attention. The well-
known eight segment representation of functional liver anatomy is based on re-
current patterns of portal venous branching observed in corrosion cast studies.6
Although the peripheral hepatic artery branches course alongside the correspond-
ing portal vein branches and biliary ducts, within their Glissonian sheath, vascu-
lar territories supplied by proximal hepatic artery branches do not mirror that of
the corresponding portal vein branches. The reason for this is that hepatic arterial
branches can have multiple different sources of origin, varying orders of branching,
and can cross laterally before being enveloped by the Glissonian sheath.7 This leads
to a great complexity of anatomical variants, for which various terms have been in-
troduced in the literature. Furthermore, it is acknowledged that the portal-defined
segmental liver anatomy model on itself is a simplification of anatomical reality.1
Since the role of intra-arterial liver cancer treatments is continuously increasing,
it is of importance to acknowledge the distinct features of the hepatic arterial vas-
culature and to use standardized, unambiguous, functional terminology to de-
scribe anatomical variants. This should break down the perceived complexity that
presently surrounds hepatic arterial interventions, and improve multidisciplinary
communication during liver tumor board discussions.
The aims of this overview are to summarize current knowledge of hepatic arteri-
al anatomy, and to present functional concepts and terminology that help clarify
distinct features of the hepatic arterial vasculature and classify its variants in an
unambiguous way.
External versus functional liver anatomy
The anatomy of the liver can be described on the basis of its external surface ap-
pearance or the functional distribution of its internal vasculobiliary structures.
A left and right liver lobe can be distinguished, based on the external surface anat-
omy (Figures 1A-B). The falciform ligament, an anterioposterior peritoneal fold
that attaches the liver to the anterior body wall, marks the division on the parietal
- 123 -
surface of the liver. It is continued on the anterior inferior side by the fissure for the
round ligament or ligamentum teres hepatis (the remnant of the umbilical vein),
and on the posterior superior side by the fissure for the ligamentum venosum (the
remnant of the ductus venosus). These fissures form a continuum in the embryo,
enabling the umbilical vein to carry oxygenated blood from the placenta to the
fetus and bypassing the liver through the ductus venosus, which shunts the blood
directly to the inferior vena cava.
Chapter 6 Part II
A B
Galbladder
Left liver lobe Quadrate

lobe
Right liver lobe

Right liver lobe Left liver lobe
Caudate
lobe
Vena
cava
C D
2 Galbladder
5
8
7 4
3 6
4 3
5 1 2
6 7
Vena
cava
Figure 1: External surface anatomy vs. functional anatomy of the liver. A-B) Schematic illustration of the
external surface anatomy, from an anterior (A) and posterior (B) view. A) The falciform ligament divides
the liver on the anterior surface into a right and left liver lobe. B) The most important demarcations of
external liver anatomy form a ‘H’-configuration (black-and-white lines) on the posterior side (visceral
surface) of the liver. The vertical line between the fissure of the ligamentum teres hepatis (also called
the umbilical fissure) and the fissure for the ligamentum venosum constitutes the left limb of the ‘H’.
The right limb is formed by an imaginary line extending from the gallbladder fossa to the inferior vena
cava, e.g. Cantlie’s line. The cross bar of the ‘H’ is formed by the porta hepatis (or hepatic hilum), which
contains the three main vasculobiliary structures of the liver: the hepatic artery, the portal vein and the
biliary duct. On the superior and inferior side of the cross bar, enclosed within the left and right limb of
the ‘H’, lie the caudate lobe (segment 1) and the quadrate lobe (segment 4) respectively. C-D) Schematic
illustration of Couinaud’s model of segmental liver anatomy, from an anterior (C) and posterior (D)
view. The division of the functional right (segments 5-8) and left (segments 2-4) hemi-liver is formed
by the main portal scissura (not shown), which can be approximated by Cantlie’s line.
- 124 -
Of more clinical importance is, however, the division of functionally independent

liver areas that are defined by the ramification of internal vasculobiliary structures
(Figures 1C-D). Building on previous work by Rex8, Segall9, Melnikoff10, Hjortsö11,
Elias and Petty12, the French surgeon Couinaud started mapping the entire internal
branching pattern of the vasculobiliary structures that he observed in corrosion
casts of explanted livers.13 Based on the observation of recurrent patterns in por-
tal venous ramification and the location of the portal scissurae, watershed planes
Part II Chapter 6
between independently vascularized areas in the liver, he developed a simple sche-
matic model that helps to explain general functional liver anatomy. The portal vein
was chosen as a basis for this model, instead of the hepatic artery or biliary duct,
due to the more consistent ramification. Others proposed slightly different mod-
els14-17, but Couinaud’s model of segmental liver anatomy, with minor adjustments
by Bismuth6,18, became the most popular system, and propelled the development of
anatomical liver resections.
According to this model, the main portal vein divides into right and left first or-
der branches that supply two functionally independent hemi-livers, separated by
the main portal scissura. These hemi-livers are then subdivided into different sec-
tors, which themselves constitute multiple segments. The right portal vein divides
into two second order branches supplying the right anterior and posterior sector,
separated by the right portal scissura. Both sectors are in turn subdivided into
superior/inferior segments (segment 5/8 in the anterior sector and segments 6/7
in the posterior sector), irrigated by third order branches, and separated by the
transverse portal scissura. The left portal vein describes an arch towards the round
ligament and divides into three second order branches supplying segments 2, 3
and 4. Segment 4 corresponds to the medial/anterior located quadrate lobe that is
separated from lateral segments 2-3 by the fissure for the ligamentum teres hepatis,
and is sometimes (although not by Couinaud) subdivided into a superior (4a) and
inferior (4b) segment. The posterior/superior located segment 2 is divided from
the more anterior/inferior located segment 3 by the left portal scissura. The au-
tonomous segment 1 corresponds to the caudate lobe, and is usually supplied by
branches from both the left and right portal vein.6
Anatomical landmarks that are visible on cross-sectional imaging and during sur-
gery have been sought to approximate the location of the vertical and horizontal
planes that form the portal scissurae, since these cannot be visualized themselves.
Cantlie’s line, an imaginary line drawn through the fundus of the gallbladder to the
center of the inferior vena cava, named after the Scottish surgeon who discovered
it in 1897, serves as an external landmark for the main portal scissura. The course
of the middle hepatic vein tends to coincide with Cantlie’s line, and thus also
- 125 -
approximates the location of the main portal scissura. The courses of the left he-
patic vein, right hepatic vein and the right portal trunk have been proposed as
indicator for the left, right and transverse portal scissurae respectively.
The introduction of Couinauds’ segmental model has enhanced our understanding
of gross functional liver anatomy and formed the basis for modern liver surgery. It
is also very useful as a tool for topographical communication, enabling specialists
from different disciplines to discuss different kinds of treatment strategies based on
Chapter 6 Part II
the location of liver tumors classified by a consistent system, as seen on cross-sec-

tional imaging. Yet, it is increasingly acknowledged that the model is a simplifica-
tion of anatomical reality, and that the true portal venous ramification pattern and
location of the portal scissurae frequently deviates from this model in individual
patients.1,19-24
Investigations that compared Couinaud’s model to the individual portal venous
ramification on cross-sectional imaging, showed that assessments based on Cou-
inaud’s model may lead to incorrect estimates of segmental shape, localization and
volume22, as well as erroneous preoperative tumor localization25. When reviewing
the specific discrepancies between model and reality, it is noted that the first or-
der division of the liver into two hemi-livers, as well as the approximation of the
main portal scissura by Cantlie’s line and the course of the middle hepatic vein, is
fairly constant. On the contrary, second and third order divisions, as well as the
approximation of the right and transverse portal scissura, show marked individual
variability and frequently deviate from Couinaud’s description. First of all, not only
8 but an average of 20 terminal portal branches (range 9 – 44) can be identified.23
Second, although a right portal scissura can often be identified, it is not vertical
but angled, and thus mostly divides an anteriosuperior and posterioinferior sector.
Furthermore, the right hepatic vein is an inaccurate indicator for the right portal
scissura. Third, no clear transverse scissura, devoid of portal segmental branches,
can be found in the right hemi-liver. Also, a division of segment 4 into an inde-
pendent superior and inferior part is only found in 50 % of studied livers. Fourth,
although the left hepatic vein appears to be a reasonably accurate indicator for the
position of the left portal scissura, especially in its lateral extension, it remains un-
certain due to the challenge to visualize these small portal branches.19
Considering all of the above, it is recommended to investigate the true borders of
the functionally independent liver territories prior to surgery and interventional
procedures.1
- 126 -
DISTINCT FEATURES OF THE HEPATIC ARTERIAL VASCULATURE

There are four distinct features of the hepatic arterial vasculature that set it apart
from the portal venous vasculature. Anatomical variants of the hepatic artery are
very common. In up to 50 % of patients, the anatomy deviates from the classical
description of a celiac axis giving rise to the common hepatic artery (CHA), that
branches off the gastroduodenal artery (GDA), continues as the proper hepatic
artery (PHA) and divides into the left hepatic artery (LHA) vascularizing segments
Part II Chapter 6
2-4 and the right hepatic artery (RHA) vascularizing segments 5-8 (Figure 2). Ar-
terial supply to segment 1 is often not specified in this description, because its
supply is highly variable, usually involving small arterial branches from both the
LHA and RHA.
Figure 2: DSA image of a

classic hepatic arterial anatomy,
obtained during an angiographic
intervention. Abbreviations: DSA
= digital subtraction angiography;
CHA
LGA SA
LHA SA = splenic artery; CA = celiac
axis; LGA = left gastric artery;
CHA = common hepatic artery;
GDA PHA = proper hepatic artery;
RHA PHA GDA = gastroduodenal artery;
CA
LHA = left hepatic artery; RHA =
right hepatic artery.
The first distinct feature of the hepatic arterial vasculature is that arterial branches
can originate at various locations, including vascular systems outside the celiac
axis. An explanation for this phenomenon lies in embryological development.26-28
In the embryological liver, three main arteries exist: the embryological LHA
(eLHA) that originates from the left gastric artery (LGA) and vascularizes segment
2, the embryological middle hepatic artery (MHA) that originates from the celi-
ac axis and vascularizes segments 3-5 and segment 8, and an embryological right
hepatic artery (eRHA) that originates from the superior mesenteric artery (SMA)
and vascularizes segments 6-7. In most instances, the eLHA and eRHA regress, and
- 127 -
the eMHA takes over the arterial blood supply to the entire liver. If one of these
arteries does not regress, an arterial branch with an aberrant origin (i.e., outside the
celiac axis) – an aberrant hepatic artery – persists. According to the first description
by Michels, aberrant hepatic arteries can be divided into accessory and replaced he-
patic arteries.29-30 Replaced hepatic arteries provide the main blood supply to the left
or right liver lobe. Accessory hepatic arteries on the other hand, only supply part of
the right or left liver lobe, and are accompanied by a celiac derived counterpart that
Chapter 6 Part II
supplies the rest of that lobe. Logically, the majority of aberrant left and right hepatic
arteries originate from the LGA and SMA respectively (Figure 3). Other origins that
have been described are the aorta and the GDA.28 The CHA together with the GDA
and all hepatic arteries can also be replaced to the SMA, which is referred to as a
replaced CHA.
A B
MHA
SMA
rRHA CHA
GDA
rLHA
Figure 3: DSA of aberrant hepatic arteries. This
LGA patient has a rRHA originating from the SMA
(A), a MHA originating from the celiac axis
derived CHA (B), and a rLHA from the LGA (C).
CHA
Abbreviations: SA = splenic artery; CA = celiac
CA SA
axis; LGA = left gastric artery; CHA = common
hepatic artery; PHA = proper hepatic artery;
GDA = gastroduodenal artery; rLHA = replaced
left hepatic artery; rRHA = replaced right hepatic
artery.
- 128 -
The second distinct feature of the hepatic arterial vasculature is that the order of
branching from CHA to first order hepatic arterial branches is highly variable. Al-
though the portal vein also shows variants in the branching order, deviant branch-
ing patterns are more frequent in the hepatic arterial vasculature. The most fre-
quently encountered variants are an early branching hepatic artery, e.g. a (part of
the) left or right hepatic artery that originates from the CHA (or celiac axis) prox-
imal to the GDA origin, and a trifurcation/quadrifurcation of the CHA, which is
Part II Chapter 6
essentially a CHA that divides into a GDA and the main hepatic arteries without
a PHA in-between (Figure 4). Variants in the branching patterns of the celiac axis
itself can also occur, but fall outside the scope of this paper.
A B
CHA
LHA
LHA
RHA
CHA
CHA GDA
RHA
GDA
Figure 4: DSA of early branching patterns. A) Trifurcation of the CHA, i.e., absence of a PHA. B) Early
branching LHA from the CHA. Others may argue that the RHA (in B) originates from the GDA.
However, when reasoning from proximal to distal, the short common trunk after the origin of the LHA
is still called the CHA because the GDA has not yet arisen. Abbreviations: CHA = common hepatic
artery; GDA = gastroduodenal artery; LHA = left hepatic artery; RHA = right hepatic artery.
The third distinct feature of the hepatic arterial vasculature is that its segmental
vascular territory often differs from that of the corresponding segmental portal
vein branch. Segment 4 does not consistently belong to the perfusion territory of
the LHA; only in approximately half of cases, the artery supplying segment 4 (A4)
originates from a LHA (or rLHA). The A4 can also originate from the RHA (or
rRHA), from a separate origin of the CHA/PHA, or it can constitute two separate
branches from the LHA and RHA.27,28,31 Hence, the arterial trunk vascularizing seg-
ments 2-3 (A2-3) is the only consistent part of the LHA.
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Segment 1 even has a more peculiar arterial vascularization. It can be divided into
the Spigelian lobe to the left of the inferior vena cava, the paracaval portion to the
right of the cava and extending to the hepatic venous confluence between the mid-
dle and right hepatic veins, and the caudate process that connects inferolaterally
with the right hemi-liver. Arterial vascularization is realized by up to six different
small arterial branches. The artery vascularizing the Spigelian lobe can originate
from the RHA, LHA, A4 or some of their distal branches, whereas the RHA or its
Chapter 6 Part II
posterior sector branch mostly supplies the paracaval and caudate process por-
tions.32-33
The fourth distinct feature of the hepatic arterial vasculature is that it delivers nu-
merous gastrointestinal and pancreatic arterial side-branches. The gastroduodenal
artery has a fairly consistent origin, and typically gives rise to the supraduodenal
artery, right gastroepiploic artery, anterior and posterior superior pancreaticodu-
odenal artery. The latter form functional anastomoses with the anterior and poste-
rior inferior pancreaticoduodenal arteries that originate from the SMA. The right
gastric artery (RGA) has a very variable origin, but predominantly arises from the
LHA, and anastomoses with the LGA along the lesser curvature of the stomach.
The origin of the cystic artery is also highly variable; in the majority of configura-
tions it originates from the RHA. A relatively rare configuration is that of a super-
ficial and deep branch of the cystic artery with two different origins.34
The fifth distinct feature of the hepatic arterial vasculature is its complex micro-
vasculature. Angiographic studies showed that numerous intrahepatic collaterals
in the liver enable redistribution of blood supply after arterial occlusion. Interlobar
anastomoses connect the left and right liver lobe via the caudate lobe vessels, and
intersegmental anastomoses connect segment 4 with segments 2-3 via the umbili-
cal fissure. On an even smaller level, arterial collaterals arise from the distal hepatic
arterial branches that supply the liver capsule and the portal triads with their con-
tent, and communicate with the terminal portal venules.9,35-36
The complexity of the hepatic arterial vasculature lies in the fact that the above
described variants frequently coincide, e.g. aberrant hepatic arteries may be ac-
companied by early branching patterns and an extraordinary segmental vascular-
ization pattern. The main hepatic arteries that are situated on the anatomical left
and right side, thus, do not necessarily vascularize the same liver territory as its
adjacent portal venous counterparts. This warrants an unprejudiced assessment
of the individual hepatic arterial anatomy on contrast enhanced cross-sectional
imaging in all patients that undergo invasive liver therapy.
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FUNCTIONAL CONCEPTS AND TERMINOLOGY

To break down the complexity, assessment of the individual hepatic arterial anat-
omy should be subdivided into 3 levels of potential variants. The first two levels
describe the hepatic arterial configuration, i.e. the way that the hepatic arterial
branches are configured and interrelate. The third level is associated with the arte-
rial segmental vascular territory.
Part II Chapter 6
LEVEL 1: VARIANTS IN THE ORIGIN OF HEPATIC ARTERIAL BRANCHES
Aberrant hepatic arteries constitute a replaced CHA (rCHA), accessory/replaced
LHA (aLHA/rLHA) and RHA (aRHA or rRHA). All kinds of combinations be-
tween aberrant left and right hepatic arteries can be observed.
Aberrant LHAs originate from the LGA and enter the liver through the fissure for
the ligamentum venosum instead of the porta hepatis. This distinct anatomical
course can be used to easily recognize aberrant left hepatic arteries, although it
should be noted that accessory left gastric arteries show a similar course with the
opposite direction of flow.37 Given the inconsistent origin of the A4, segment 4
should not be used to distinguish between replaced and accessory LHAs. Thus, an
aLHA per definition only vascularizes segment 2, whereas a rLHA may vascularize
segment 2-3 or 2-4, the latter being less common.
The majority of aberrant RHAs arise from the SMA, but variants originating from
the aorta or GDA have also been described.28 Aberrant RHAs originating from
the SMA also show a distinct anatomical course; they are situated posterior to the
portal vein in the hepatoduodenal ligament. Replaced RHAs per definition vascu-
larize segments 5-8, but may also vascularize segment 4. Accessory RHAs on the
other hand can vascularize everything from a single up to all-but one segment of
the right hemi-liver.
Although anatomically correct, the use of terms such as gastrohepatic or hep-
atomesenteric trunk should be avoided since these do not provide any functional
information.
LEVEL 2: VARIANTS IN THE HEPATIC ARTERIAL BRANCHING PATTERN

All orders of branching that deviate from CHA – GDA – PHA – main hepatic ar-
terial branches should be considered variants. Early branching patterns also occur
in combination with aberrant hepatic arteries.
The terminology used to describe the parts of the hepatic artery proximal to the
first order hepatic arterial branches is based on the GDA takeoff. The CHA is de-
fined as the arterial trunk proximal to the GDA origin that constitutes at least one
- 131 -
of the major hepatic arterial branches. Thus, if a part of the RHA (or LHA) orig-
inates before the GDA takeoff, it is an early branching RHA (or LHA) from the
CHA or celiac axis (Figure 4B). The term double RHA has previously been used to
describe an early branching RHA. Yet, this term may falsely imply that a duplicate
RHA exists with two branches supplying the same liver territory. Of note, early
branching RHAs can show a retroportal course similar to aberrant RHAs originat-
ing from the SMA.
Chapter 6 Part II
The PHA is defined as a common trunk shared between the LHA (not necessarily
including A4) and RHA in between the GDA origin and first order hepatic arterial
branching. The PHA is absent if the CHA directly divides into the GDA, LHA, (A4)
and RHA (Figure 4A). This variant is termed a trifurcation or quadrifurcation of
the CHA, with the latter also including a separate origin for the branch that vascu-
larizes segment 4. The LHA is usually the first branch to arise from the PHA, and
courses to the left and slightly cranially towards the umbilical fissure. The RHA
starts distal to the offspring of the arterial branches to segment 2-3. Deviations in
the second order branching of the LHA as well as the RHA are numerous, but are
seldom of clinical importance.
LEVEL 3: VARIANTS IN THE ARTERIAL SEGMENTAL

VASCULARIZATION PATTERN
Once the hepatic arterial configuration has been evaluated, the arterial segmental
vascularization pattern should be assessed. That is, it should be clarified which
segments are vascularized by the main hepatic arteries. Of special importance is
the origin of the arterial branch vascularizing segment 4, as well as the segmental
territories supplied by aberrant and early branching hepatic arteries.
If the A4 originates from the LHA, it can be either a proximal branch from the
common trunk shared with the A2-3 or a distal branch that arises at the level of the
arterial branch to segment 3 (A3).12 Conversely, if the A4 originates from the RHA,
it is mostly a proximal branch. The A4 can also constitute two separate branches,
one originating from the LHA and one from the RHA, which may reflect the divi-
sion of segment 4 into a superior (segment 4a) and inferior (segment 4b) part. The
last possible configuration is that of an A4 originating from a separate origin off
the CHA or PHA. In these cases, the A4 is termed a middle hepatic artery (MHA),
to indicate that it is positioned in the anatomic middle, i.e. in between the LHA
and RHA.27-28
In patients with a combination of a rLHA from the LGA and rRHA from the SMA,
a MHA often originates from the celiac axis, and appears as the only terminal he-
patic branch after the origin of the GDA. Otherwise, the celiac axis gives rise to the
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GDA only, and segment 4 is vascularized by the rLHA.

The presence of a rLHA or rRHA can lead to confusion about terminology, since
a real PHA does not exist in these configurations. If segment 4 is not vascularized
by a rLHA, it can be said that a MHA originates from either the CHA or RHA; the
mirror condition can be applied in the presence of a rRHA.
CLASSIFICATION AND REPORTING SYSTEM
Part II Chapter 6
There is a need for a simple and clear reporting system to communicate a patient’s
individual anatomy after assessing level 1 – 3. To that purpose, we introduce such
a system, aiming to standardize anatomical reporting in both clinical care and re-
search.
Box 1: Reporting system for anatomical variants of the hepatic arteries

Notation = Term for variant [Origin, Segments vascularized]
Examples
rRHA [SMA, S5-8]
aRHA [SMA, S5] + rLHA [LGA, S2-3]
aLHA [LGA, S2*]
rRHA [SMA, S5-8] + rLHA [LGA, S2-3] **
RHA [S4-8]
Early br. LHA [CHA, S2]
rCHA [SMA, S2-8*] + trifurcation [CHA]
* These terms could even be reduced, since an aLHA per definition vascularizes S2 only and a rCHA
the S2-8. ** Note that the rRHA and rLHA do not appear to vascularize S4; thus a MHA must arise
from the celiac derived CHA.
The system is explained in Box 1.

Basically, it represents a way to notate the type of variant, its origin and vascular
territory. Multiple of these terms can be combined. This enables the use of a short
notation for complex anatomical variants, by leaving out all the aspects that are
considered ‘standard anatomy’. Table 1 gives an overview of the most commonly
observed hepatic arterial configurations and segmental vascularization patterns.28
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Table 1: Hepatic arterial configurations and segmental vascularization patterns

No aberrant hepatic artery
LHA [S2-4] + RHA [S5-8]
LHA [S2-3 or S2-4] + RHA [S4-8]
LHA [S2-3] + MHA [CHA or PHA, S4] + RHA [S5-8]
rLHA [LGA, S2-3 or S2-4]
Chapter 6 Part II
aLHA [LGA, S2]

rRHA [SMA, S4-8 or S5-8]
rRHA [SMA, S4-8] + RHA [S4-8]
rLHA [LGA, S2-3] + MHA [CHA, S4] + rRHA [SMA, S5-8]
rLHA [LGA, S2-4] + rRHA [S5-8]
aLHA [LGA, S2] + aRHA [SMA, S*]
aLHA [LGA, S2] + rRHA [SMA, S5-8]
rLHA [LGA, S2-3 or S2-4] + aRHA [SMA, S*]
Replaced common hepatic artery
rCHA [SMA, S2-8]
Early br. LHA [CA or CHA, S*]
Early br. RHA [CA or CHA, S*]
Trifurcation or Quadrifurcation [CHA]
This table summarizes the most common hepatic arterial configurations and segmental vasculariza-
tion patterns in the style of the proposed reporting system. Note that numerous sorts of combina-
tions between early branching patterns and aberrant hepatic arteries are also possible. For simplicity,
the origin of aberrant right hepatic arteries has been displayed as the SMA, but other origins such
as the aorta or GDA are also possible. If no origin is recorded, the vessel is ‘normally’ derived from
the celiac axis. * Variable territory of segmental vascularization. Abbreviations: LHA = left hepatic
artery; RHA = right hepatic artery; CHA = common hepatic artery; PHA = proper hepatic artery;
aLHA/rLHA = accessory/replaced LHA; aRHA/rRHA = accessory/replaced RHA; LGA = left gastric
artery; SMA = superior mesenteric artery; CA = celiac axis.
LIMITATIONS AND FUTURE DIRECTIONS

The above outlined distinct features of the hepatic arterial vasculature as well as
the proposed functional concepts, terminology and reporting system should con-
tribute to an enhanced understanding of hepatic arterial anatomy and improve
interdisciplinary communication during liver tumor board meetings. However, it
is important to acknowledge that our current knowledge is still limited.
- 134 -
First, some arterial branches are too small to detect on cross-sectional imaging,
such as contrast enhanced multidetector CT or magnetic resonance imaging, or
even during invasive angiography or surgical dissection. As a result, the arterial
distribution of different parts of segments 1 and 4 still remain a black box.
Second, the segmental vascularization patterns that are outlined in this paper are
based on studies that tracked on contrast enhanced CT which arterial branches
course towards which liver segments.28 In fact, these investigations try to fit the
Part II Chapter 6
individual anatomy of a patient to the well-known model for segmental liver anat-
omy as described by Couinaud, to enable clear communication to the readership.
Thus, the locations of the true portal or arterial scissurae, as they exist in individ-
ual patients, have not been defined. New technological developments in imaging
hardware and software might enable such analyses. Interestingly, a recent analysis
of the portal ramification on contrast enhanced CT showed that, the number of
independent liver segments averages 20 instead of 8, in line with the original work
of Couinaud.1 Another promising method to investigate the arterial perfusion
pattern is the use of catheter-directed, contrast enhanced cone-beam C-arm CT.
This imaging modality can depict the true arterial perfusion pattern by showing
contrast enhancement of liver tissue that is dependent on the target branch that is
selected for selective catheterization and subsequent injection of contrast agent.38
Third, pathology can affect anatomy. The variants discussed in this overview are
also observed in healthy subjects, as they have an embryological basis. Yet, pathol-
ogy (tumors, trauma, infection, thrombosis) can disturb segmental vascularization
patterns through processes of neovascularization, compression or invasion of vas-
cular structures and development of arterioportal or arteriosystemic shunting. In
patients with hypervascular tumors, for example, tumor-feeding vessels are often
recruited from extrahepatic arterial branches39, which alters the arterial perfusion
of the tumor and adjacent healthy liver tissue. Furthermore, the architecture of
arterial vessels themselves can be disturbed by atrophy-inducing liver cirrhosis,
anti-angiogenic drugs, surgery, ablation and embolotheraphy.40-41 For these rea-
sons, it is even more important to critically evaluate the hepatic arterial anatomy of
individual patients before liver surgery or interventions.
- 135 -
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Es HW, et al. (1994) Variations in venous
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and three-dimensional MR imaging in
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healthy volunteers. AJR Am J Roentgenol
9. Segall HN (1923) An experimental investi- 162:1337–1345.
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20. van Leeuwen MS, Noordzij J, Fernandez
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MA, et al. (1994) Portal venous and seg-
10. Melnikoff A (1921) Architektur der intra- mental anatomy of the right hemiliver:
hepatischen gefässe und der gallenwege des Observations based on three-dimensional
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163:1395–1404.
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21. Strunk H, Stuckmann G, Textor J, Willinek 30. Michels N (1966) Newer anatomy of the
W (2003) Limitations and pitfalls of cou- liver and its variant blood supply and col-
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31. Jin G, Yu H, Lim H, Moon J (2008) Ana-
22. Fischer L, Cardenas C, Thorn M, et al. tomical variations of the origin of the seg-
(2002) Limits of couinaud’s liver segment ment 4 hepatic artery and their clinical im-
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32. Lee UY, Murakami G, Han SH (2004) Ar-
Comput Assist Tomogr 26:962–967.
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23. Fasel JHD, Majno PE, Peitgen HO (2010) dorsal liver: A dissection study using con-
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33. Miyayama S, Yamashiro M, Hattori Y, et al.
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24. Fasel JHD, Schenk A (2013) Concepts for caudate lobe of the liver. Cardiovasc Inter-
liver segment classification: Neither old vent Radiol 34:1244–1253.
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The origin of the cystic artery supplying
25. Rieker O, Mildenberger P, Hintze C, et al. hepatocellular carcinoma on digital sub-
(2000) [Segmental anatomy of the liver in traction angiography in 311 patients. Car-
computed tomography: Do we localize the diovasc Intervent Radiol 37:1268-82.
lesion accurately?]. Rofo 172:147–152.
35. Healey JE, Schroy PC (1953) The Intrahe-
26. Couinaud C (1989) Surgical anatomy of the patic distribution of the hepatic artery in
liver revisited: Embryology. Masson, Paris. man. J Int Coll Surg 133 – 148.
27. Wang S, He X, Li Z, et al. (2010) Character- 36. Charnsangavej C, Chuang V, Wallace

ization of the middle hepatic artery and its S (1982) Angiographic classification of
relevance to living donor liver transplanta- hepatic arterial collaterals. Radiology
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28. van den Hoven AF, van Leeuwen MS, Lam 37. van den Hoven AF, Smits MLJ, de Keizer B,
MGEH, van den Bosch MAAJ (2015) He- et al. (2014) Identifying aberrant hepatic ar-
patic arterial configuration in relation to teries prior to intra-arterial radioemboliza-
the segmental anatomy of the liver; obser- tion. Cardiovasc Intervent Radiol 37:1482-
vations on MDCT and DSA relevant to 1493.
38. van den Hoven AF, Prince JF, de Keizer B,
Intervent Radiol 38:100-111.
et al. (2016) Use of c-arm cone beam CT
29. Michels NA. (1953) Collateral arterial path- during hepatic radioembolization: Protocol
ways to the liver after ligation of the hepatic optimization for extrahepatic shunting and
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39. Abdelmaksoud MHK, Louie JD, Kothary 40. Farnsworth RH, Lackmann M, Achen MG,
N, et al. (2011) Embolization of parasitized Stacker SA (2014) Vascular remodeling in
extrahepatic arteries to reestablish intrahe- cancer. Oncogene 33:3496–3505.
patic arterial supply to tumors before yt-
41. Jain RK (2005) Normalization of tumor
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vasculature: An emerging concept in anti-
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angiogenic therapy. Science 307:58–62.
Chapter 6 Part II
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C hap ter
PART II 7
Liver CT during
radioembolization workup:
Comparison of an early
and late arterial phase protocol
A.F. van den Hoven

M.N.G.J.A. Braat
J.F. Prince
P.J. van Doormaal
M.S. van Leeuwen
M.G.E.H. Lam
European Radiology [accepted]

Liver CT during radioembolization workup
ABSTRACT
Objectives
Compare RGA and A4 origin detection rates during radioembolization workup
between early and late arterial phase liver CT protocols, and determine inter-rater
reproducibility.
Methods
100 consecutive patients were included who underwent liver CT between May
2012 – January 2015 with an early or late arterial phase protocol (n = 50 each, 10 vs.
20 s postthreshold delay). RGA and A4 origin detection rates, assessed by 2 raters,
Chapter 7 Part II
and CNR of the hepatic artery relative to the portal vein were compared between
both protocols. Inter-rater reproducibility measures were determined.
Results
The 1st – 2nd rater scored the RGA origin as visible in 58 – 65 % (specific propor-
tion of agreement 82 %, κ = 0.62); A4 origin in 96 – 89 % (specific proportion of
agreement 94 %, κ = 0.54). Origin detection rates were equivalent for the early/late
arterial phases: RGA 59 vs. 57 % (rater #1), 61 vs. 70 % (rater #2); A4 96 vs. 96 %
(rater #1), 87 vs. 91 % (rater #2). Mean CNR was higher in the early arterial phase
protocol (1.7 vs. 1.2, p < 0.001).
Conclusion
A 10-second delay arterial phase protocol does not improve the detection rate of
small intra- and extrahepatic branches, despite increased CNR. The RGA origin
detection rate is currently suboptimal, whereas the A4/MHA origin detection rate
is much higher, with good inter-rater reproducibility.
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INTRODUCTION
Radioembolization has evolved as a safe and effective treatment option in patients
with liver tumors that are not resectable and are refractory to standard system-
ic therapy.1 Since this treatment encompasses the injection of radioactive micro-
spheres via a microcatheter positioned in the hepatic arteries, it is essential to per-
form a thorough assessment of the hepatic arterial anatomy before treatment.2
Interventional radiologists used to depend on the digital subtraction angiography
(DSA) images acquired during the pretreatment angiography for their evaluation
of the vascular anatomy.3 However, since modern multidetector computed tomog-
Part II Chapter 7
raphy (CT) scanners enable high resolution, multiphasic, multiplanar imaging of
the liver, the arterial vasculature can already be evaluated on CT before the pre-
treatment angiography. This has two distinctive advantages. First, CT images can
depict the spatial relation between arterial branches and liver parenchyma or gas-
trointestinal organs in three dimensions, instead of a two-dimensional projection
image. Furthermore, timely assessment of the anatomy enables the establishment
of a treatment strategy ahead of time, and results in increased confidence of the
operator during the treatment procedure.4
A standard triphasic liver CT protocol is used for the evaluation of the liver pa-
renchyma and vasculature during radioembolization workup, encompassing a late
arterial, portal venous and equilibrium phase with postthreshold delays of 20 sec,
55 sec, and 5 min respectively. These imaging delays are optimized for tumor de-
tection and characterization, but it is questionable whether the late arterial phase is
best suited for evaluation of the arterial vasculature. We noticed in clinical practice
that contrast enhancement of the portal vein often obscures the origin of small ar-
terial branches that need to be identified, especially the right gastric artery (RGA)
and segment 4 artery (A4). An early arterial phase with a delay of 10 s may reveal
the RGA and A4 origin better due to a higher contrast to noise ratio (CNR) of the
hepatic artery relative to the portal vein. Furthermore, it remains uncertain how
well the RGA and A4 origins can be visualized on liver CT in the population of
heavily pretreated radioembolization patients, and how reproducible these obser-
vations are when comparing different raters.
Hence, the purpose of this study was to compare RGA and A4 origin detection
rates during radioembolization workup between early and late arterial phase liver
CT protocols, and to determine inter-rater reproducibility.
- 143 -
METHODS
Study design
We performed a prospective development study in accordance with the IDEAL
recommendations.5 Standard triphasic liver CT (from now on referred to as stan-
dard protocol) was already part of our routine workup for radioembolization. To
improve the visualization of small arterial branch origins, we adjusted our liver CT
protocol (from now on referred to as new protocol). The performance of the novel
scan protocol was tested by using a historical cohort of patients previously scanned
with the standard protocol as comparison.
Chapter 7 Part II
The medical ethics committee of our institution approved this study and waived
the need for informed consent for reviewing imaging data on radioembolization
patients in our center.
Study population
A total of 100 patients (50 patients each for both protocols) would be required to
demonstrate a 30 % difference in RGA detection rate (80 % for the new protocol
vs. 50 % for the standard protocol) with a power of 0.90, at an alpha level of 0.05
(sample size calculation with ‘Power and Sample Size Calculation’ version 3.1.2 for
MacOsX).
All patients with unresectable and chemorefractory liver tumors who underwent
a pretreatment liver CT in combination with a 18F-FDG-PET scan on the same CT
scanner, before undergoing a preparatory angiography as part of the radioembo-
lization workup, were eligible for study participation. Starting in December 2013,
50 consecutive patients were selected for the new liver CT protocol. A group of 50
consecutive patients who had been scanned earlier using the standard protocol was
selected for comparison. Patients with a technical scan failure or those without a
preparatory angiography were excluded. Baseline patient characteristics for both
groups were compared to ensure a valid comparison.
Technique, Equipment and Scan Settings
On the day before the examination, all patients received 1000 ml of water-soluable
contrast solution (Telebrix Gastro 300 mg/ml) per os. In the new protocol, Man-
nitol solution (100 ml, 15 %) was given orally before the scan to stimulate gastric
emptying and create a negative contrast with adjacent contrast enhanced vessels.
Subsequently, 150 – 185 ml (depending on body weight) Iopromide 300 mg/ml
contrast agent (Ultravist, Bayern Schering Pharma AG, Berlin Germany) was di-
luted with 50 ml of NaCl solution, and injected in the anticubital vein at a rate of
5 ml/s. All CT scans were acquired on an integrated PET/CT scanner (Biograph
- 144 -
mCT, Siemens Healthcare, Erlangen, Germany) with 40 detector rows, using a ma-
trix size of 512 x 512, rotation time of 0.4 – 0.5 sec, pitch of 0.9 – 1.2, and a fixed
120 kV tube potential.
The standard protocol consisted of a late arterial, portal venous and an equilibrium
phase, which were obtained with a postthreshold (abdominal aorta enhancement >
100 HU) delay of 20, 55 and 300 s respectively. A tube current of 150 mAs was used
in the arterial and equilibrium phase, and 225 mAs for the portal venous phase.
Slice thickness/increment were 0.9/0.7 cm for the arterial phase, and 1.5/1.0 cm for
the portal venous and equilibrium phase.
The new protocol consisted of an arterial phase with a shortened postthreshold de-
Part II Chapter 7
lay of 10 s, and an unchanged timing of the portal venous phase. No equilibrium
phase was acquired.
In this protocol, tube current was dependent on the weight of the patient: 150 mAs
in patients < 85 kg, and 200 mAs in patients ≥ 85 kg. In all phases, slice thickness/
increment was 0.9/0.7 mm.
Image analyses
All images were anonymized and loaded into OsiriX (version 5.8, 32-bit, MacOS
X) for image analyses.
Two independent raters, an abdominal radiologist (MB) and an interventional ra-
diologist (PJvD), were asked to score: visibility of the RGA origin (yes/no), location
of the RGA origin (arrow appointing the region of interest), visibility of the A4/
MHA origin (yes/no), location of the A4/MHA origin/origins (arrow), ability to
distinguish two separate branches to S4a and S4b (yes/no). The raters were in-
structed to score the origin as not visible when in doubt.
The origins were evaluated on the thin slices (1 mm thickness/ 0,7 mm increment).
Use of a maximum intensity projection (MIP) with a reconstructed slice thickness
of 4 mm and/or the use of multiplanar reconstruction was optional. Scans of pa-
tients who had previously undergone surgery in which the RGA was sacrificed or
segment 4 was resected were considered non-evaluable.
The A4 was termed a middle hepatic artery (MHA) when originating in-between
a (r)LHA and (r)RHA, as a branch from the CHA or PHA. No true PHA exists in
patients with an aberrant hepatic artery, therefore, the RGA or A4 origin was called
after the non-aberrant arterial branch if originating distal to the origin of the gas-
troduodenal artery (GDA).4
A third rater (AvdH) scored the individual hepatic arterial anatomy as described
earlier4, and measured the signal-to-noise ratio (SNR) of the hepatic arteries and
portal veins, as well as the contrast-to-noise ratio (CNR) of the hepatic arteries
- 145 -
The A4 was termed a middle hepatic artery (MHA) when originating in-‐between a (r)LHA and
Andor F. van de
(r)RHA, as a branch from the CHA or PHA. No true PHA exists in patients with an aberrant
Verwijderd: S4
hepatic artery, therefore, the RGA or A4 origin was called after the non-‐aberrant arterial branch
Andor F. van de
if originating
Liver CT during d istal to the origin workup
radioembolization of the gastroduodenal artery (GDA).4
Verwijderd: S4
A third rater (AvdH) scored the individual hepatic arterial anatomy as described earlier4, and Andor F. van de
measured the signal-‐to-‐noise ratio (SNR) of the hepatic arteries and portal veins, as well as the Verwijderd: [4
Andor F. van de
contrast-‐to-‐noise ratio (CNR) of the hepatic arteries relative to the portal vein. Circular ROIs with
relative to the portal vein. Circular ROIs with a diameter of 3 – 6 mm were drawn Met opmaak: S
a diameter of 3 – 6 mm were drawn in the hepatic artery and the portal vein at approximately the
in the hepatic artery and the portal vein at approximately the same level in the liver Andor F. van de
same level in the liver hilum on axial slice MIP (8mm reconstructed slice thickness) images of the Verwijderd: [4
hilum on axial slice MIP (8mm reconstructed slice thickness) images of the arterial
arterial phase, and the mean and standard deviation (SD) of the signal (in HU) were noted. The Andor F. van de
phase, and the mean and standard deviation (SD) of the signal (in HU) were noted. Verwijderd:
following equations were used:
The following equations were used: Andor F. van de
Verwijderd:
!"#$ (!") Andor F. van de

𝑆𝑆𝑆𝑆𝑆𝑆 = !"(!") (Equation 1) (Equation 1)
!"(!") Verwijderd:
Andor F. van de

Verwijderd:
!"#$!"#$"%$& !!"#$!"#$%& !"#$ Andor F. van de
(Equation 2)
Chapter 7 Part II
𝐶𝐶𝐶𝐶𝐶𝐶 = (Equation 2)

! ∗(!" ! !
!"#$"%$& !!"!"#$%& !"#$ )
Verwijderd: -‐
!

Descriptive analyses were performed to give an overview of baseline patient char-
acteristics,
and RGA/A4 origin locations. Data with a normal and non-normal dis-
tribution are presented as mean ± standard deviation and median (range).
A two-sided unpaired student’s t-test was used to test for differences in mean arte-
rial and portal SNR, and mean CNR, between the standard and the new protocol.
The proportion of visible origins of the RGA and A4 were compared between the
standard protocol and new protocol by means of a chi-square test. Furthermore,
specific proportion of agreement and kappa statistics were used to indicate in-
ter-rater agreement and reliability for the visibility and location of the RGA ori-
gin as well as the A4 origin. All analyses were performed with R Studio version
0.98.1102 for MacOsX. A p value < 0.05 was considered statistically significant.
RESULTS
Patients and scans

Between December 2013 and January 2015, 58 patients were scanned according to
the new protocol for liver CT, and were found eligible for inclusion in this study.
Eight of these patients were excluded, because the scan was performed on another
CT scanner (n = 6), or because no angiography was performed (n = 2). Between
May 2012 and December 2013, 63 patients had undergone a standard triphasic liv-
er CT. 12 of these patients were not selected for the control group, because the scan
was acquired on another CT scanner (n = 9), no angiography was performed (n =
2), or due to technical failure of the CT scan (n = 1). Both groups were comparable
with regard to baseline patient characteristics and hepatic arterial anatomy (Table
1 and 2).
- 146 -
Table 1: Baseline patient characteristics

Characteristic Entire cohort Standard protocol New protocol
(n = 100) (n = 50) (n = 50)
Age 64 ± 10 years 63 ± 11 years 65 ± 11 years
Gender
Male 54 (54 %) 24 (48 %) 30 (60 %)
Female 46 (46 %) 26 (52 %) 20 (40 %)
BMI 27 ± 4 27 ± 5 27 ± 4
Liver tumor burden
< 25 % 83 (83 %) 42 (84 %) 41 (82 %)
25 – 50 % 12 (12 %) 6 (12 %) 6 (12 %)
Part II Chapter 7
> 50 % 5 (5 %) 2 (4 %) 3 (6 %)
Liver tumor type
CRC 66 (66 %) 31 (62 %) 35 (70 %)
Cholangioca 11 (11 %) 6 (12 %) 5 (10 %)
Uvea melanoma 8 (8 %) 4 (8 %) 4 (8 %)
Mammaca 5 (5 %) 3 (6 %) 2 (4 %)
Other 10 (10 %) 6 (12 %) 4 (8 %)
Previous surgery involving
A4 6 (6 %) 2 (4 %) 4 (8 %)
RGA 5 (5 %) 4 (8 %) 1 (2 %)
The baseline patient characteristics are summarized in this table, for the entire cohort and for both
protocols separately. Values are given in mean ± standard deviation or number of patients (percent-
age of total).
Table 2: Individual hepatic arterial anatomy

Anatomical variant Entire cohort Standard protocol New protocol
(n = 100) (n = 50) (n = 50)
Standard anatomy 54 (54 %) 29 (58 %) 25 (50 %)
Early branching pattern 19 (19 %) 9 (18 %) 10 (20 %)
Early branching LHA 2 (2 %) 1 (2 %) 1 (2 %)
Early branching RHA 1 (1 %) 0 1 (2 %)
Trifurcation of CHA 13 (13 %) 7 (14 %) 6 (12 %)
Quadrifurcation of CHA 3 (3 %) 1 (2 %) 2 (4 %)
Aberrant hepatic arteries 27 (27 %) 12 (24 %) 15 (30 %)
rLHA [LGA, S2-3] 8 (8 %) 2 (4%) 6 (12 %)
rLHA [LGA, S2-4] 2 (2 %) 1 (2 %) 1 (2 %)
aLHA [LGA, S2] 2 (2 %) 1 (2 %) 1 (2 %)
rRHA [SMA, S5-8] 9 (9 %) 5 (10 %) 5 (10 %)
rRHA [SMA, S4-8] 0 0 0
aRHA [SMA, S5+8] 1 (1 %) 0 1 (2 %)
rLHA + rRHA [SMA, S5-8] 1 (1 %) 0 1 (2 %)
rCHA [SMA] 4 (4 %) 3 (6 %) 1 (2 %)
The hepatic arterial configuration is summarized in this table, for the entire cohort and for both
protocols separately. Values are given in number of patients (percentage of total). Aberrant hepatic
arteries are indicated as type of variant [origin, segmental vascularization pattern].
- 147 -
Origin of the RGA

Five scans (standard protocol n = 4, new protocol n = 1) were not evaluable for the
assessment of the RGA origin, due to previous gastric (n = 4) or pancreatic (n =
1) surgery involving the RGA, leaving 46 scans evaluable for the standard proto-
col and 49 scans for the new protocol (see Figure 1 for a clinical example of both
protocols).
Chapter 7 Part II
Figure. 1: Comparison of liver CT images with the standard (A, C) and the new arterial phase protocol
(B, D) in the same patient, acquired on the same scanner. Note that the new protocol is easier to evaluate
due to an increased CNR for the hepatic artery relative to the portal vein, but the origins of the A4 (A, B,
black arrow) and the RGA (C, D, white arrow) are nonetheless visible in both protocols.
- 148 -
The first and second rater scored the origin of the RGA as visible in 55/95 (58 %)
and 62/95 (65 %) respectively (Table 3). The specific proportion of agreement in
visibility of the RGA origin was 78/95 (82 %). The reliability was substantial; Co-
hen’s kappa was 0.62 (confidence limits 0.46 – 0.78). The detection rate of the RGA
origin did not differ significantly between the standard and the new protocol: 57
vs. 59 % (p = 0.96) scored by rater 1, and 70 vs. 61 % (p = 0.52) scored by rater 2.
According to raters 1 – 2, the RGA originated from the LHA in 47 – 51 % of pa-
tients, PHA in 21 – 23 %, CHA in 10 – 13 %, GDA in 5 – 9 %, RHA in 6 – 8 %, A4/
MHA in 3 – 4 %, and SMA in 2 %. Both raters appointed the same RGA origin
location in all cases with a visible RGA origin. Thus, the specific proportion of
Part II Chapter 7
agreement between both raters including the exact origin of the RGA was the same
as the agreement of visibility, 78/95 (82 %).
Table 3: Origin detection of the RGA

Entire cohort Standard protocol New protocol
(n = 95) (n = 46) (n = 49)
Origin of RGA visible?
Rater 1
Yes 55 (58 %) 26 (57 %) 29 (59 %)
No 40 (42 %) 20 (43 %) 20 (41 %)
Rater 2
Yes 62 (65 %) 32 (70 %) 30 (61 %)
No 33 (35 %) 14 (30 %) 19 (39 %)
RGA origins
Rater 1
CHA 7 (13 %) 6 (23 %) 1 (3 %)
GDA 5 (9 %) 3 (12 %) 2 (7 %)
PHA 11 (21 %) 2 (8 %) 9 (31 %)
LHA 27 (51 %) 14 (54 %) 13 (45 %)
A4/MHA 2 (4 %) 0 2 (7 %)
RHA 3 (6 %) 1 (4 %) 2 (7 %)
Rater 2
CHA 6 (10 %) 6 (19 %) 0
GDA 3 (5 %) 2 (6 %) 1 (3 %)
PHA 15 (23 %) 5 (16 %) 10 (33 %)
LHA 30 (47 %) 16 (50 %) 14 (47 %)
A4/MHA 2 (3 %) 0 2 (7 %)
RHA 5 (8 %) 3 (10 %) 2 (7 %)
SMA 1 (2 %) 0 1 (3 %)
The RGA origin and its detection rate is summarized for both raters in this table, for the entire cohort
and for both protocols separately. Values are given in number of patients (percentage of total). No
true PHA exists in patients with an aberrant hepatic artery. Therefore, the RGA was called after the
non-aberrant arterial branch if originating distal to the origin of the gastroduodenal artery (GDA).
- 149 -
Origin of the A4/MHA

Six scans (standard protocol n = 2, new protocol n = 4) were not evaluable for the
assessment of the A4/MHA origin, due to previous liver surgery involving segment
4, leaving 48 scans evaluable for the standard protocol and 46 scans for the new
protocol.
The first and second rater scored the origin of the A4/MHA as visible in 90/94
(96 %) and 84/94 (89 %) respectively (Table 4). The specific proportion of agree-
ment in visibility of the A4/MHA origin between both raters was 88/94 (94 %). The
reliability was moderate; Cohen’s kappa was 0.54 (confidence limits 0.23 – 0.86).
Chapter 7 Part II
Table 4: Origin detection of the A4/MHA

Entire cohort Standard protocol New protocol
(n = 94) (n = 48) (n = 46)
Origin of A4/MHA visible?
Rater 1
Yes 90 (96 %) 46 (96 %) 44 (96 %)
No 4 (4 %) 2 (4 %) 2 (4 %)
Rater 2
Yes 84 (89 %) 42 (87 %) 42 (91 %)
No 10 (11 %) 6 (13 %) 4 (9 %)
A4/MHA origins
Rater 1
CHA 4 (4 %) 1 (2 %) 3 (7 %)
PHA 3 (3 %) 3 (7 %) 0
LHA 51 (57 %) 28 (61 %) 23 (52 %)
rLHA 2 (2 %) 1 (2 %) 1 (2 %)
RHA 25 (28 %) 13 (28 %) 12 (27 %)
rRHA 0 0 0
LHA + RHA 4 (4 %) 0 4 (9 %)
rLHA + RHA 1 (1 %) 0 1 (2 %)
Rater 2
CHA 4 (5 %) 1 (2 %) 3 (7 %)
PHA 4 (5 %) 4 (10 %) 0 (0 %)
LHA 47 (56 %) 26 (62 %) 21 (50 %)
rLHA 1 (1 %) 1 (2 %) 0
RHA 23 (27 %) 10 (24 %) 13 (31 %)
rRHA 0 0 0
LHA + RHA 4 (5 %) 0 4 (10 %)
rLHA + RHA 1 (1 %) 0 1 (2 %)
The A4/MHA origin and its detection rate is summarized for both raters in this table, for the entire
cohort and for both protocols separately. Values are given in number of patients (percentage of total).
- 150 -
The detection rate of the A4/MHA origin did not differ significantly between the
standard and the new protocol: 96 vs. 96 % scored by rater 1, and 87 vs. 91 % (p =
0.79) scored by rater 2.
According to raters 1 – 2, segment 4 was vascularized exclusively by a A4 origi-
nating from the LHA in 56 – 57 % of patients, from the RHA in 27 – 28 %, from
a rLHA in 1 – 2 % and never from a rRHA. A MHA originated from the CHA in
4 – 5 % of patients, and from the PHA in 3 – 5 %. A dual-type A4 originated from
the LHA + RHA in 4 – 5 % of patients, and from a rLHA + RHA in 1 %. The spe-
cific proportion of agreement between both raters including the exact origin of the
A4/MHA was 84/94 (89 %). There was a disagreement between both raters in the
Part II Chapter 7
appointed A4/MHA origin location in 4 patients.
Rater 1 and 2 indicated that they could clearly distinguish two separate arterial
branches to the superior (S4a) and inferior (S4b) part of S4 in 18/94 (19 %) and
10/94 (11 %) of patients. These two branches originated from a different main he-
patic arterial branch (LHA + RHA or rLHA + RHA) in 5 of these patients, and
originated from the same main hepatic arterial branch in the rest of the cases.
SNR and CNR
The mean arterial SNR was not different for both protocols: 7.5 and 7.4 for the
new protocol and the standard protocol respectively (95 % CI for the difference
in means: -1.2 – 1.5; p = 0.83). The mean portal SNR was significantly lower in
the new protocol compared with the standard protocol: 7.4 vs. 9.7 (95 % CI for
the difference in means: -3.2 – -1.3; p = 8.9 x 10-6). This resulted in a significantly
higher mean CNR of the hepatic arteries relative to the portal vein in the standard
protocol: 1.7 vs. 1.2 (95 % CI for the difference in means: 0.4 – 0.7; p = 4.9 x 10-11).
DISCUSSION
The purpose of this study was to compare RGA and A4/MHA origin detection
rates during radioembolization workup between early and late arterial phase liver
CT protocols, and to determine inter-rater reproducibility. The new protocol with
the early arterial phase did not improve the detection rate of small intra- and extra-
hepatic branches, despite a higher CNR of the hepatic arteries relative to the portal
vein. Furthermore, the RGA origin detection was lower than that of the A4 (58 – 65
% vs. 89 – 96 %) in our study. However, when identified, the inter-rater agreement
of the origin localization was high for both the RGA (82 %) and A4 (89 %). The
inter-rater reliability was moderate and substantial, respectively.
- 151 -
The RGA origin detection rate is suboptimal, which may be explained by the of-
ten-small caliber of the RGA. The high inter-rater agreement and moderate reli-
ability nevertheless suggests that when the RGA is visible, origin localization is
not rater dependent. Thus, the necessity to coil embolize the RGA or advance the
microcatheter beyond its origin, to avoid harmful extrahepatic deposition of ra-
dioactive microspheres, can already be evaluated in patients with a visible origin of
the RGA on pretreatment liver CT.
The A4/MHA origin detection rate is much higher, which has several important
benefits. Depending on the hepatic arterial configuration of an individual patient,
it can be decided to use the A4/MHA as a separate site of administration, include
Chapter 7 Part II
it in a more proximal injection position, or coil embolize it to induce intrahepatic

redistribution of blood flow. Furthermore, it allows pretreatment activity calcu-
lations to be performed with knowledge of the segment 4 vascularization. This is
crucial to avoid under or overdosing of segment 4 when performing radioembo-
lization on a single-session basis, and it may contribute to a more reliable distri-
bution of 99mTc-macroaggregated albumin (99mTc-MAA) during a routine pretreat-
ment procedure.6-7 Interestingly, we found that the typical distinction of segment 4
into an upper (4a) and lower segment (4b) as based on the portal vascularization,
could only be made in 11 – 19 % of patients.
The radiologists in our center reported increased ease of use for vascular eval-
uation with an early arterial phase. However, this subjective benefit should be
weighed against poorer evaluation of the liver parenchyma: a 10 s delay is too short
for sufficient enhancement of hypervascular tumors, compromising detection and
response assessment of these tumors. The use of two arterial phases (10 and 20 s
postthreshold delay respectively) may break this tradeoff.
Our study had several limitations. First, our sample size was based on an assump-
tion of a reasonable number of patients two compare both protocol groups, be-
cause specific detection rates for this study population were lacking. Yet, baseline
characteristics were comparable. Furthermore, we allowed raters to use both MIP
and non-MIP images to detect the RGA and A4 origins. For CNR assessment,
we used MIP images only. We believe that this has attributed to the difference in
results for the CNR measurements and origin detection assessments. In clinical
practice radiologists are, however, also not restricted to a specific method to eval-
uate images. In addition, we tried to blind the raters for the type of protocol used
in a scan, but because the difference in CNR was so explicit and the gastric prepa-
ration was slightly different in both protocols, they could still differentiate between
both protocol types. Finally, we only evaluated the origin of the RGA and A4, be-
- 152 -
cause these branches are present in all patients and have important implications.
However, in some patients other small arterial branches are also important such as
the artery to segment 1, extrahepatic branches to the pancreas or duodenum, and
parasitized extrahepatic arteries. Further research needs to clarify whether these
branches and their origin can be visualized on pretreatment CT.
CT hardware and acquisition protocols are continually evolving. So, further im-
provements to liver CT protocols are imminent. Especially, the use of a higher
contrast agent concentration or injection rate, and dual or multi-energy CT are
among promising developments.8-9
Part II Chapter 7
CONCLUSION
A 10-second delay arterial phase protocol does not improve the detection rate of
small intra- and extrahepatic branches, despite increased CNR of the hepatic ar-
teries relative to the portal vein. Ease of use with this protocol needs to be weighed
against suboptimal detection of hypervascular tumors. The RGA origin detection
rate is currently suboptimal, whereas the A4/MHA origin detection rate is much
higher, with good inter-rater reproducibility.
- 153 -
REFERENCES
1. Kennedy A (2014) Radioembolization 6. Van den Hoven AF, Prince JF, van den
of hepatic tumors. J Gastrointest Oncol Bosch MAAJ, Lam MGEH (2014) Hepatic
5:178–189. radioembolization as a true single-session
treatment. J Vasc Interv Radiol 25:1143–
2. Lewandowski RJ, Sato KT, Atassi B, et al.
1144.
(2007) Radioembolization with 90Y micro-
spheres: Angiographic and technical con- 7. Wondergem M, Smits MLJ, Elschot M, et
siderations. Cardiovasc Intervent Radiol al. (2013) 99mTc-macroaggregated albumin
30:571–592. poorly predicts the intrahepatic distribu-
3. Ugurel MS, Battal B, Bozlar U, et al. (2010)
Chapter 7 Part II

Anatomical variations of hepatic arterial
1301.
system, coeliac trunk and renal arteries: An
analysis with multidetector CT angiogra- 8. Rengo M, Bellini D, De Cecco CN, et al.
phy. Br J Radiol 83:661–667. (2011) The optimal contrast media policy
in CT of the liver. Part I: Technical notes.
Acta radiol 52:467–472.
patic arterial configuration in relation to 9. Rengo M, Bellini D, De Cecco CN, et al.
the segmental anatomy of the liver; obser- (2011) The optimal contrast media policy
vations on MDCT and DSA relevant to in CT of the liver. Part II: Clinical protocols.
radioembolization treatment. Cardiovasc Acta radiol 52:473–480.
5. McCulloch P, Cook JA, Altman DG, et al.

(2013) IDEAL framework for surgical in-
novation 1: The idea and development stag-
es. BMJ 346:f3012.
- 154 -
C hap ter
PART II 8
Use of C-arm cone beam CT during
hepatic radioembolization: Protocol
optimization for extrahepatic
shunting and parenchymal
enhancement
A.F. van den Hoven

J.F. Prince
B. de Keizer
E.J.P.A Vonken
R.C.G. Bruijnen
H.M. Verkooijen
M.G.E.H. Lam

Use of C-arm cone beam CT during hepatic radioembolization
ABSTRACT
Purpose
To optimize a C-arm CT protocol for radioembolization (RE), specifically for ex-
trahepatic shunting and parenchymal enhancement.
Materials and methods
A prospective development study was performed per IDEAL recommendations.
A literature based protocol was applied in patients with unresectable and chemo-
refractory liver malignancies undergoing an angiography before radioemboliza-
tion. Contrast and scan settings were adjusted stepwise and repeatedly reviewed
in a consensus meeting. Afterwards, two independent raters analyzed all scans. A
third rater evaluated the SPECT/CT scans as a reference standard for extrahepatic
Chapter 8 Part II
shunting and lack of target segment perfusion.

Results
Fifty scans were obtained in 29 procedures. The first protocol, using a 6 s delay and
10 s scan, showed insufficient parenchymal enhancement. In the second protocol,
the delay was determined by timing parenchymal enhancement on DSA power in-
jection (median 8 s, range 4 – 10 s): enhancement improved, but breathing artifacts
increased (from 0 to 27 %). Since the third protocol with a 5 s scan decremented
subjective image quality, the second protocol was deemed optimal. Median CNR
(range) was 1.7 (0.6 – 3.2), 2.2 (-1.4 – 4.0), and 2.1 (-0.3 – 3.0) for protocol 1, 2 and
3 (p = 0.80). Delineation of perfused segments was possible in 57, 73, and 44 % of
scans (p = 0.13). In all C-arm CTs combined, the negative predictive value was 95
% for extrahepatic shunting and 83 % for lack of target segment perfusion.
Conclusion
An optimized C-arm CT protocol was developed that can be used to detect extra-
hepatic shunts and non-perfusion of target segments during radioembolization.
- 158 -
INTRODUCTION
C-arm cone beam computed tomography (CT) can be used to acquire, reconstruct
and display high-resolution 3D images of selective contrast-enhanced vessels and
the surrounding soft-tissue. Hence, it can provide valuable information on vascular
anatomy and tissue perfusion during intra-arterial liver-directed treatments, such
as transarterial chemoembolization (TACE) or radioembolization. However, the
specific purpose for C-arm CT imaging may differ from treatment to treatment.
During TACE, C-arm CT is performed to identify the lesion of interest and all
tumor-feeding arteries, to plan and navigate to the intended injection position,
and to confirm adequacy of the injection position by evaluating contrast enhance-
ment of the targeted tumor.1-4 In contrast, during radioembolization, C-arm CT is
used to map the hepatic arterial anatomy, to identify extrahepatic branches, and
Part II Chapter 8
to rule out extrahepatic shunting or non-perfusion of a target volume.5-6 The lat-
ter allows for additional measures to be taken before the administration of tech-
netium-99m-labelled macro-albumin aggregates (99mTc-MAA) and acquisition of
single-photon emission computed tomography (SPECT). Since extrahepatic depo-
sition of 99mTc-MAA is reported in 10 – 20 % of patients after a workup solely based
on digital subtraction angiography (DSA)7-8, C-arm CT could significantly reduce
the number of angiography procedures that need to be repeated.
As these imaging purposes differ, they require other acquisition protocols, with
appropriate timing of the contrast injection and scan delay. Thus far, an optimal
acquisition protocol that enables the use of a single-run C-arm CT for radioembo-
lization purposes has yet to be established. Furthermore, even though C-arm CT is
increasingly performed, evidence for its added diagnostic value in radioemboliza-
tion is still scarce. Thus, a clear need exists for the development and validation of a
C-arm CT protocol for radioembolization.
The Innovation, Development, Exploration, Assessment, Long-term Study (IDE-
AL) recommendations describe how to perform a study with these aims.9 These
guidelines were initially formulated to provide a framework for a responsible step-
wise evaluation of surgical innovations, but they also apply to complex interven-
tions in the field of interventional radiology.10 The first stage (‘Stage 1: Idea’) of
evaluation is to perform a proof of concept study for a novel idea in a few selected
patients. The next stage (‘Stage 2a: Development’) is the early development stage,
in which prospective development studies should be performed in 10 – 100 pa-
tients to determine which technique has the best chance for procedural success,
treatment efficacy, and safety. It is a crucial stage that differs the most from the
pharmacological evaluations in the phase I – IV trial paradigm. “IDEAL supports
- 159 -
prospective rather than retrospective studies at this stage, with sequential reporting
of all cases and outcomes without omissions, and with clear explanations of when
and how technique, design, or indications were changed.”11 If these studies provide
convincing evidence for safety and short-term benefits, the innovation enters the
exploration stage (‘Stage 2b: Exploration’). The goal of this stage is to learn as much
as possible about the safety and benefits of the procedure as patients and opera-
tors vary. Large, prospective, observational studies with registry data collection
are particularly suited for this purpose. The last two stages (‘Stage 3: Assessment’
and ‘Stage 4: Long term study’) of evaluation are quite similar to pharmacological
phase III and IV trials. Large (multicenter) randomized controlled trials are indis-
pensable to assess comparative effectiveness of the innovation versus the current
standard of care, and surveillance studies, preferably integrated in national patient
Chapter 8 Part II
registries, are needed to assess long-term safety and effectiveness outcomes.12

The use of C-arm CT during radioembolization is still in ‘Stage 2A: Development’.
Accordingly, the purpose of this study was to develop a C-arm CT protocol op-
timized for the detection of extrahepatic shunting and non-perfusion of a target
volume during radioembolization.
MATERIALS AND METHODS

Study Design
A prospective development study was performed in accordance with phase 2A of
the IDEAL recommendations, consisting of two parts: Part (1) prospective, step-
wise, optimization of our C-arm CT protocol in clinical practice, and Part (2)
blinded analysis of C-arm CT image quality and its diagnostic value.
C-arm CTs were already part of clinical practice during radioembolization pro-
cedures in our center, but the added value was limited to vascular mapping only,
and the scan protocol was dependent on the operator. With the aim to reduce the
number of repeat procedures for extrahepatic shunting or missed target segments,
the protocol was optimized and then modified based on clinical experience. The
medical ethics committee of the University Medical Center Utrecht waived the
need for informed consent for reviewing imaging data in patients undergoing ra-
dioembolization in our center.
Reporting was done in agreement with the Strengthening the Reporting of Obser-
vational Studies in Epidemiology (STROBE) and the research reporting standards
for radioembolization.13-14
- 160 -
Study population
All patients undergoing a pretreatment angiography during workup for radioem-
bolization were eligible for C-arm CT acquisition, and thus for participation in
our study. These patients had unresectable and chemorefractory liver malignancies
(either primary tumors or metastasized), liver-dominant disease, a life expectancy
exceeding three months, WHO performance status > 2, hepatic tumor load ≤ 70
% of the liver volume, and unimpaired hepatic, renal and hematological functions.
Mirroring clinical practice, operators could refrain from acquiring a C-arm CT, if
they deemed the additional contrast load too high in patients with previous aller-
gic reactions, or when C-arm CT was considered of no added value in a particular
patient (for example in an ultra-selective injection position during segmental treat-
ment of a single tumor).
Part II Chapter 8
Technique, equipment and scan settings
The workup for radioembolization was performed following current standards
of practice.15 At baseline, patients received a 18F-FDG-PET scan combined with a
multiphasic liver CT to: (1) rule out contraindications such as celiac axis stenosis,
main portal vein thrombosis, or dominant extrahepatic disease, (2) localize the
liver tumors, (3) assess the individual hepatic arterial anatomy, and (4) determine
a patient-based treatment strategy.16 During the pretreatment angiography, the
hepatic arterial vasculature was selectively catheterized by femoral approach with
a standard 5F guiding catheter (Celiac, Cobra or Simmons shape), 2.7F Progreat
microcatheter (Terumo, Leuven, Belgium) and a 0.014-inch Transend guide wire
(Boston Scientific, Natick, MA, USA). The celiac axis, common/proper hepatic ar-
tery, and left/middle/right hepatic arteries were selectively catheterized in all pa-
tients. The left gastric artery and superior mesenteric artery were only selectively
catheterized when an aberrant hepatic artery was demonstrated on the pretreat-
ment CT. Power injection DSA was used to search for potential sources of extrahe-
patic shunting. Coil embolization of extrahepatic branches was restricted to cases
in which it was absolutely necessary to avoid extrahepatic shunting. Eventually, the
microcatheter was positioned in the target vessel(s), and a C-arm CT acquisition
was performed. A non-sequential, whole-liver approach with two or more selective
injection positions was used in patients with bilobar disease. A lobar/segmental
approach was used in patients with tumors confined to a single lobe or segment.
An Allura Xper FD20 (Philips, Best, The Netherlands) system, equipped with the
XperCT and EmboGuide options was used for the C-arm CT acquisitions. The
abdomen fast high dose (HD) or abdomen fast low dose (LD) settings were used.
Depending on the setting, 312 (LD) or 624 (HD) images were acquired in a scan
time of 5 (LD) or 10 (HD) s during a 240° rotation (Table 1).
- 161 -
Table 1: Differences between scan settings

Parameters Abdomen Fast High Dose Abdomen Fast Low Dose
Rotation time 10.4 s 5.2 s
Number of images 624 312
Maximum rotation speed 20° per second 41° per second
Delay was defined as the time period between start of the contrast injection and
start of the scan. Acquisition time was defined as the sum of the delay and scan
time. Contrast agent (ioxidanol 270 mg/ml, Visipaque 270; GE Healthcare) was
diluted 1:1 with 0.9 % NaCl solution to reduce beam-hardening artifacts and to
limit the contrast burden. The injection of contrast agent was continued during the
Chapter 8 Part II
entire acquisition time in order to obtain images with contrast enhancement of the
vascular tree and liver parenchyma. Injection rates were similar to those typically
used in the common, proper, left and right hepatic artery during power injector
DSA.
The C-arm CT images were reviewed in the angio suite, and additional measures
were taken if deemed necessary. Consequently, a total of 150 MBq 99mTc-MAA was
administered, and SPECT/CT images were acquired on a Symbia T16 scanner (Sie-
mens Healthcare, Erlangen, Germany).
Part 1: Protocol optimization in clinical practice
Based on a literature review by two authors (AvdH, JP), a first protocol was defined.
Starting from October 2013, all C-arm CTs were performed using this protocol.
After a predefined number of 5 patients, image quality and usefulness were sub-
jectively assessed, and the need to alter one of the acquisition parameters was dis-
cussed in a consensus meeting between three investigators (AvdH, JP, EJV). This
process was repeated until a protocol was found with sufficient image quality, al-
lowing for both visualization of the arterial tree and detection of missed target
segments and extrahepatic shunting. After optimization, further C-arm CTs were
performed with that particular protocol, to expand the study population.
Part 2: Retrospective analysis of image quality and diagnostic value
Consequently, a retrospective analysis of image quality and diagnostic value was
performed. For this purpose, scans were anonymized and randomized. For evalu-
ation, Osirix (v.5.8 32-bit for MacOS X) was used. Reconstructions were made in
the axial plane, using a window level of 60 HU and window width of 350 HU, with
maximum intensity projections of 5 mm. Two raters (AvdH, JP) independently
- 162 -
determined: the vessel from which contrast was injected, the ability to discrimi-
nate between the perfused and non-perfused liver territory (categorized as “Yes”,
“Partially”, and “No”), the presence of breathing artifacts, whether the Field of View
(FOV) contained the whole liver, presence of extrahepatic shunting and the culprit
vessel, presence of a non-perfused liver segment and if so, which one(s). Extra-
defined as a sharply defined area of contrast enhancement in the gastric wall, pancreas, duodenum or
hepatic shunting was defined as a sharply defined area of contrast enhancement
bowel (excluding the gallbladder wall as an extrahepatic location). Discrepancies between the two raters
defined as a sharply defined area of contrast enhancement in the gastric wall, pancreas, duodenum or
in the gastric wall, pancreas, duodenum or bowel (excluding the gallbladder wall
defined
during as aa ssharply
ubsequent defined area m
consensus of eeting.
contrast enhancement in the gastric wall, pancreas, duodenum or
bowel (excluding the gallbladder wall as an extrahepatic location). Discrepancies between the two raters
were resolved
as an extrahepatic location). Discrepancies between the two raters were resolved
were For
resolved dbowel (excluding the gallbladder wall as an extrahepatic location). Discrepancies between the two raters
quantitative uring aanalyses,
subsequent both cronsensus
aters drew six Volumes of Interest (VOIs), three in the perfused liver lobe
meeting.
during a subsequent consensus meeting.
For qand
uantitative were r
three in atnalyses, esolved
he non-‐perfused. d uring
both raters a
Each s
drew ubsequent
VOI wV
six as pclaced
onsensus
olumes an marea
eeting.
oif n Interest (oVOIs),
f the liver
three that
in tw as
he representative
perfused liver lobe for the
For quantitative analyses, both raters drew six Volumes of Interest (VOIs), three in
hree in the For
and tenhancement quantitative
non-‐perfused.
of Eaach
the liver lobe, nalyses,
V bas
OI wa
with oth raters
placed
size drew
in
between an 1
area sand
ix Voolumes
f 10
the cm 2 oto
liver f Itnterest
hat was
allow (rVOIs),
for three
epresentative
proper in tfhe
estimation or tphe
erfused
of the liver lobe
the perfused liver lobe and three in the non-perfused. Each VOI was placed in an
signal standard
enhancement and t hree i
of the deviation n t he
liver lobe, (SD). n on-‐perfused.
with Mean E ach
a size Hounsfield V OI
between 1 Units w as
and 10 p laced
(HU)
cmand
2 i n a n
to SD
allow a rea o
of the f t he l
signal in
for proper iver t hat w as r
the VOI were
estimation epresentative
noted.
of the for the
area of the liver that was representative for the enhancement of the liver lobe, with
Part II Chapter 8
The
signal standard enhancement
three VOIs were (SD).
deviation combined of Mean
the liver
by lobe, with
averaging
Hounsfield a size
the
Units three
(HU) between
mean
and SD 1
of and
HU the 10
values. cm 2 to
The in
signal SDs allow
the VOI for
were proper
combined
were noted. estimation
using of the
a size between 1 and 10 cm2 to allow for proper estimation of the signal standard
Equation
The three VOIs signal standard deviation (SD). Mean Hounsfield Units
1. were combined by averaging the three mean HU values. The SDs were combined using (HU) and SD of the signal in the VOI were noted.
deviation (SD). Mean Hounsfield Units (HU) and SD of the signal in the VOI were
Equation
1. The three VOIs were combined by averaging the three mean HU values. The SDs were combined using
noted. The three VOIs were combined by averaging the three mean HU values. The
Equation 1.
SDs were=combined
𝑆𝑆𝑆𝑆!"#$%!"# 1 ∗ (𝑆𝑆𝑆𝑆 using
! Equation
!
! +𝑆𝑆𝑆𝑆! +𝑆𝑆𝑆𝑆! )
!1.
[Equation 1]
3
𝑆𝑆𝑆𝑆!"#$%!"# = ! 1
! !
3 ∗ (𝑆𝑆𝑆𝑆! +𝑆𝑆𝑆𝑆! +𝑆𝑆𝑆𝑆! ) [Equation 1]
𝑆𝑆𝑆𝑆!"#$%!"# = 1 3 ∗ (𝑆𝑆𝑆𝑆! ! +𝑆𝑆𝑆𝑆! ! +𝑆𝑆𝑆𝑆! ! )
[Equation 1]
[Equation 1]
For calculation of the signal-‐to-‐noise ratio (SNR), the following formula was used17:
Andor F. van den Hove
For c alculation o f the signal-‐to-‐noise ratio (SNR), the following formula was used17:
For calculation of the signal-to-noise ratio (SNR), the following formula was usedAndor
17
: Verwijderd: S
F. van den Hoven 23
For calculation of the signal-‐to-‐noise
!"#$ (!") ratio (SNR), the following formula was used17: Andor F. van den Hove
𝑆𝑆𝑆𝑆𝑆𝑆 = [Equation 2] Verwijderd: S Andor F. v
!"(!")
!"#$ (!") Verwijderd:
[Equation 𝑆𝑆𝑆𝑆𝑆𝑆 = [Equation 2] 2]
Andor F. van denVerwijderd Hoven 23
!"(!") !"#$ (!") Andor F.
Verwijderd:
van den Hove
𝑆𝑆𝑆𝑆𝑆𝑆 = [Equation 2] Andor F. v
Verwijderd: N
The contrast-‐to-‐noise-‐ratio (CNR) was calculated to !"(!") demonstrate differences between the perfused and Andor F. van denVerwijderd Hoven 23
The contrast-to-noise-ratio (CNR) was calculated to demonstrate differences be- Andor F. van den Hove
Verwijderd: N Andor F. v
non-‐perfused liver territories
The contrast-‐to-‐noise-‐ratio relative
(CNR) was to the to
calculated background
demonstrate noise in the liver
differences between parenchyma, by using
the perfused and the Verwijderd: R
tween the perfused and non-perfused liver territories relative to the background F. van denVerwijderd Andor Hoven 23
non-‐perfused The
following liver
formula contrast-‐to-‐noise-‐ratio
territories
18 : (CNR) was calculated to demonstrate
relative to the background noise in the liver parenchyma, by differences between the
using the perfused Andor F. van den Hove
and
Verwijderd: R
noise in the liver parenchyma, by using the following formula : 18 Andor F. v
Verwijderd: [17]

following formula non-‐perfused
18: liver territories relative to the background noise in the liver parenchyma, by using Andor F. van denVerwijderd
the Hoven 23
Verwijderd: [17] Andor F. v
following f ormula 18:
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀!"#$%&"' − 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀!"!!!"#$%&"' Verwijderd: C
𝐶𝐶𝐶𝐶𝐶𝐶 = Andor F. van denVerwijderd Hoven 23
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 − 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 Andor F. van den Hove
Verwijderd: C
1 !"#$%&"' ! !"!!!"#$%&"' ! Andor F. v
𝐶𝐶𝐶𝐶𝐶𝐶 = 2 ∗ (𝑆𝑆𝑆𝑆!"#$%&"' 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀
+ 𝑆𝑆𝑆𝑆!"!!!"#$%&"'
− 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀
) Verwijderd:
Andor F. van denVerwijderd Hoven 23
1 ∗𝐶𝐶𝐶𝐶𝐶𝐶 ! !"#$%&"' ! !"!!!"#$%&"'
2 (𝑆𝑆𝑆𝑆!"#$%&"' = + 𝑆𝑆𝑆𝑆!"!!!"#$%&"' ) Verwijderd: Andor F. v
The average of both raters was 1 ∗ used
(𝑆𝑆𝑆𝑆 as !
CNR + to
𝑆𝑆𝑆𝑆 test for !
differences
) between the Andor
Verwijderd: N
F. van den Hoven 23
2 !"#$%&"' !"!!!"#$%&"' Verwijderd
The average of both raters was used as CNR to test for differences between the three protocols. All image Verwijderd: Andor F. van den Hove
N Andor F. v
three protocols. All image quality analyses were performed on a scan basis. Verwijderd: R

quality analyses were performed on a scan basis.
The average of both raters was used as CNR to test for differences between the three protocols. All image Andor F. van denVerwijderd Hoven 23
SPECT/CT images were retrospectively reviewed by a nuclear medicine physician Andor F. van den Hove
Verwijderd: R Andor F. v
quality The average of both raters was used as CNR to test for differences between the three protocols. All image
analyses were performed on a scan basis.
SPECT/CT images were retrospectively reviewed by a nuclear medicine physician (BdK) with experience Verwijderd: [18]
(BdK) with experience in the field of radioembolization (indication, patient man- Andor F. van denVerwijderd Hoven 23
in the field quality analyses were (pindication,
of radioembolization erformed opn a scan
atient mbanagement,
asis.
SPECT/CT images were retrospectively reviewed by a nuclear medicine physician (BdK) with experience administration and evaluation). He was Verwijderd: [18]
agement, administration and evaluation). He was blinded for the outcome of the Andor F. van den Hove Andor F. v
blinded
in the SPECT/CT images were retrospectively reviewed by a nuclear medicine physician (BdK) with experience
field of for the outcome of the
radioembolization two raters
(indication, evaluating
patient the C-‐arm
management, CT. The rater
administration was
and asked to evaluate
evaluation). He was the Verwijderd
two raters evaluating the C-arm CT. The rater was asked to evaluate the presence Andor
Verwijderd: RE
F. van den Hoven 23
presence in t he
of outcome f
extrahepatic ield o f r adioembolization
deposition ( indication,
in evaluating
the gastric p
wall, atient m
pancreas, anagement,
duodenum a dministration
rater was or bowel, a nd e valuation).
and total the H e w as
blinded for the
of of the
extrahepatic two raters
deposition the
in theC-‐arm CT. The
gastric wall, pancreas, asked
or lack
to evaluate
duodenum bowel, of
and
Verwijderd: RE Andor F. v
presence
99mTc-‐MAA blinded
activity for
of extrahepatic the of
one outcome
in deposition the in of segments.
the
liver the two wall,
gastric raters
This evaluating
pancreas, the C-‐arm
duodenum
served as reference or CT. The
bowel,
test to rater
and
evaluate was
total asked
the lack of to evaluate the
diagnostic Verwijderd
accuracy
99mTc-‐MAA of presence
C-‐arm
activity of of
CT.
in one extrahepatic
Negative
the liver deposition
predictive
segments. in served
values
This the gastric
(NPV) were
as wall, pancreas,
determined
reference duodenum
for
test to the or
extrahepatic
evaluate bowel, and
shunting
diagnostic total lack of
and
99mTc-‐MAA activity in one of the liver segments. This served as reference test to evaluate the diagnostic
non-‐perfusion
accuracy of C-‐arm of a Negative
CT. target volume. The dvalues
predictive iagnostic value
(NPV) analyses
were were performed
determined on a procedure
for extrahepatic shunting band
asis. For
oaccuracy
f a target of C-‐arm TCT.
he dNegative
iagnostic predictive -(NPV)
values 163 -were determined for extrahepatic
a procedure to be evaluable, C-‐arm CTs had to be acquired in all catheter positions in which
non-‐perfusion volume. value analyses were performed on a procedure basis.
99mF or shunting and
Tc-‐MAA
non-‐perfusion of a target volume. The diagnostic value analyses were performed
a procedure to be evaluable, C-‐arm CTs had to be acquired in all catheter positions in which
was injected. on
99m a procedure basis. For
Tc-‐MAA
was i njected. a procedure to be evaluable, C-‐arm CTs had to be acquired in all catheter positions in which 99mTc-‐MAA
total lack of 99mTc-MAA activity in one of the liver segments. This served as ref-
erence test to evaluate the diagnostic accuracy of C-arm CT. Negative predictive
values (NPV) were determined for extrahepatic shunting and non-perfusion of a
target volume. The diagnostic value analyses were performed on a procedure basis.
For a procedure to be evaluable, C-arm CTs had to be acquired in all catheter po-
sitions in which 99mTc-MAA was injected.
Statistics
Differences in CNR between the three protocols were tested using an ANOVA.
A Fisher-Freeman-Halton exact test was used to compare the subjective score for
discriminating ability between protocols. A p value < 0.05 was considered statis-
tically significant. All statistical analyses were performed with R version 3.0.1 for
Windows.
Chapter 8 Part II
RESULTS
Study population
A flowchart of this study is displayed in Figure 1. From October 2013 until Febru-
ary 2014, we performed 37 pretreatment angiographies in 32 patients in our insti-
tute. During 31 angiography procedures, a total of 62 C-arm CTs were obtained in
28 different patients. The majority of C-arm CTs were performed during the first
pretreatment angiography (n = 26), 4 were performed during repeat procedures,
and 1 during the second pretreatment angiography for the treatment of a different
liver lobe (n = 1).
Twelve C-arm CTs had to be excluded for the following reasons: the field of view
was incorrect (n = 4 scans), the injection parameters were unknown (n = 4), the
catheter was displaced during contrast injection (n = 1), the wrong acquisition set-
tings were used (n = 1), the scan was made after treatment (n = 1), and no contrast
was injected (n = 1). For two procedures, these scans were the only C-arm CTs
available; these two patients were excluded, leaving a total of 50 scans acquired
during 29 procedures in 26 patients for analysis. The patients included in this study
had a median age of 64 years (range 45 – 80 years), and 16 of 26 (62 %) were male.
They were treated for primary or metastatic liver tumors, with the following pri-
mary tumor types: colorectal cancer (n = 10, 37 %), hepatocellular carcinoma (n
= 6, 23 %), cholangiocarcinoma (n = 2, 8 %), breast cancer (n = 2, 8 %), other (n
= 6, 24 %). Median tumor burden was 14 % (range 0 – 66 %), WHO performance
score was 0 in 18 patients (69 %), 1 in 3 patients (12 %), 2 in 1 patient (4 %) and not
reported in 4 patients (15 %). Child Pugh score was A5 in the majority of patients
(n = 24, 92 %), A6 in one patient (4 %) and not reported in another patient (4 %).
- 164 -
Part II Chapter 8
Figure 1: Detailed flowchart of the selection process, showing the number of scans, procedures and
patients. * The number of unique patients is 26. Two patients were scanned with more than one protocol.
- 165 -
Part 1: Protocol optimization in clinical practice

For the first protocol, a fixed delay of 6 s was chosen based on a literature review,
combined with the high dose scan setting of 10 s. After the first protocol was ap-
plied during 5 procedures (8 C-arm CTs, 5 unique patients), the degree of paren-
chymal contrast enhancement was deemed insufficient. To improve the parenchy-
mal enhancement, it was decided to use a variable delay. This delay was determined
by assessing the time to parenchymal enhancement on power injection DSA, using
an identical injection rate and catheter position (Figure 2). This method adjusts for
differences between liver lobes and between patients.
Chapter 8 Part II
Figure 2: Example of how the C-arm CT scan

delay was determined on power injection DSA in
the right hepatic artery. A) Start of the DSA run.
Only vascular contrast enhancement is visible.
B) Midway the DSA run. Parenchymal contrast
enhancement of the right liver lobe (white arrows
indicate the border of the right liver lobe) is
starting to show. C) At the end of the DSA run,
maximal parenchymal contrast enhancement is
reached. The time between the first and last run is
used as delay for the C-arm CT scan.
- 166 -
For the second protocol, a variable delay (median 8 s, range 3-10 s) and 10 s high
dose scan setting were used. This protocol was used during 10 procedures (17 scans
in 9 patients). Parenchymal contrast enhancement had improved substantially in
comparison with the first protocol. However, the relatively long scan time was as-
sociated with breathing artifacts (from 0 to 27 %).
In the third protocol, used during 7 procedures (12 scans in 7 patients), a 5 s low
dose scan setting was applied to reduce breathing artifacts, in combination with a
variable delay (median 8 s, range 4-10 s). It did show considerably less breathing
artifacts, and parenchymal contrast enhancement was acceptable. Still, this proto-
col was not favored over the second protocol, because the low dose scan settings
had led to deterioration of the overall image quality.
The second protocol was subsequently used in another 7 procedures (13 scans in 7
Part II Chapter 8
patients), bringing it to a total use in 17 procedures (30 scans in 16 patients).
Part 2: Retrospective analysis of image quality and diagnostic value
For image quality analysis, eight of these scans were obtained with protocol 1, 30
scans with protocol 2, and 12 scans with protocol 3.
The results of the image quality analysis are summarized in Table 2. The median
CNR (range) for discrimination between the perfused and non-perfused liver ter-
ritories was 1.7 (0.6 – 3.2) for protocol 1, 2.2 (-1.4 – 4.0) for protocol 2, and 2.1
(-0.3 – 3.0) for protocol 3 (p = 0.80). The subjective score for discriminating ability
was Yes – Partially – No, in 57 – 29 – 14 % of evaluable scans for protocol 1, 73 – 27
– 0 % of scans for protocol 2, and 44 – 33 – 22 % of scans for protocol 3 (p = 0.13).
Nine scans (2x protocol 1, 4x protocol 2, 3x protocol 3) could not be evaluated for
the discriminating ability due to the absence of a non-perfused territory. Breathing
artifacts were reported in none of the scans for protocol 1, 8 of 30 scans (27 %) for
protocol 2, and 1 of 12 (8 %) scans for protocol 3.
For diagnostic accuracy analysis, 25 of 29 (86 %) procedures were evaluable: a
C-arm CT was not obtained in all injection positions in 2 procedures, a dissection
hampered SPECT/CT acquisition in 1 procedure, and C-arm CTs were not assess-
able due to breathing artifacts in 1 procedure.
In 21 of 25 procedures (84 %, Table 3a), the retrospective C-arm CT analysis re-
vealed no extrahepatic shunting. In one of the 21 procedures, SPECT/CT analysis
demonstrated extrahepatic deposition of 99mTc-MAA. This extrahepatic deposi-
tion occurred near the implanted coils in the right gastric artery and could not
be detected on the C-arm CT (Figure 3). The negative predictive value for extra-
hepatic shunting was 95 %. It should be noted that during 3 procedures (14 %),
extrahepatic shunting had already been observed on C-arm CT in clinical practice.
- 167 -
Chapter 8 Part II
Table 2: Summary of protocols and outcomes

Protocol # Subjective discriminating ability
Delay Scan Scan Number of CNR, Yes, Partially, No, Not evaluable,
time (s) setting Scans median (range) n scans (%) n scans (%) n scans (%) n scans
1. 6s 10 Fast HD 8 1.7 (0.6 – 3.2) 4 (57 %) 2 (29 %) 1 (14 %) 1
2. Variable1 10 Fast HD 30 2.2 (-1.4 – 4.0) 19 (73 %) 7 (27 %) 0 (0 %) 4
1
3. Variable 5 Fast LD 12 2.1 (-0.3 – 3.0) 4 (44 %) 3 (33 %) 2 (22 %) 3
The protocol settings, number of scans per protocol, objective (CNR) and subjective ability to discriminate between perfused and non-perfused liver territories are
displayed in this table.1 Estimated by contrast enhanced DSA series where time between infusion and liver parenchyma enhancement is used as the delay time for
C-arm CT. Abbreviations: CNR = contrast-to-noise ratio, HD = high dose, LD = low dose.
- 168 -
Table 3a: Diagnostic outcomes – gastrointestinal shunting Table 3b: Diagnostic outcomes – non-perfused target volumes
99m 99m
Gastrointestinal Tc-MAA SPECT/CT Non-perfused target Tc-MAA SPECT/CT

shunting Present Absent Total volume Present Absent Total
Present 3 1 4 Present 5 2 7
C-arm CT Absent 1 20 21 C-arm CT Absent 3 15 18
Total 4 21 25 Total 8 17 25
Negative predictive value 95.2 % Negative predictive value 83.3 %
Two by two table displaying the presence and absence of gastrointestinal Two by two table displaying the presence and absence of non-perfused
shunting on C-arm CT (experimental test) and 99mTc-MAA SPECT/CT target volumes on C-arm CT (experimental test) and 99mTc-MAA SPECT/
(reference standard). The numbers represent the number of procedures. CT (reference standard). The numbers represent the number of procedures.
Part II Chapter 8
Figure 3: A) Extrahepatic deposition of 99mTc-MAA activity in the region of the coil embolized right
gastric artery on a fusion SPECT/CT image (white arrow). B) On C-arm CT imaging, no extrahepatic
shunting was noted, due to the extensive coil-related beam hardening artifacts (white arrow).
In two of these patients, an extrahepatic branch (pancreatic/duodenal branch from

the RHA, collateral between cystic artery and the gastroduodenal artery) was suc-
cessfully coil embolized, before the administration of 99mTc-MAA. In the other pa-
tient, the catheter was positioned distal to the extrahepatic branch (gastric branch
originating from the LHA). Success was confirmed by a repeated C-arm CT scan
without extrahepatic shunting (see Figure 4 for an example).
In our retrospective evaluation, C-arm CT showed extrahepatic shunting in 4 of
25 procedures (16 %), located in the duodenal region (n = 3) or stomach wall (n =
1). The SPECT/CT analysis confirmed extrahepatic deposition in 3 of these proce-
dures (Figure 5).
Of the 25 procedures that were assessable for the perfusion of target liver territo-
ries, 7 (28 %) showed one or more unperfused target segments in the C-arm CT
analysis (Table 3b). Five of those 7 procedures also showed a lack of perfusion on
99m
Tc-MAA (Figure 6). In the two remaining patients, segments 1 and 4 showed
no contrast enhancement on C-arm CT, but 99mTc-MAA activity was visible on
SPECT/CT. Both patients had markedly hypervascular tumors with a heteroge-
neous contrast and 99mTc-MAA activity distribution. Furthermore, in 3 of 18 pro-
cedures with adequate perfusion on C-arm CT, lack of 99mTc-MAA activity was
found on SPECT/CT (in segments 1-4b, segment 7, and segments 1-5 + 8) in the
retrospective analysis. The negative predictive value for non-perfusion was 83 %.
- 169 -
Chapter 8 Part II
Figure 4: A) DSA from the LHA. B) C-arm CT performed from the LHA shows extrahepatic shunting
in the gastric wall (white arrow). The small extrahepatic branch indicated by the white arrow in (A) was
the culprit vessel. C) The catheter was positioned more distal in the LHA. D) C-arm CT performed
from the new injection position did not show extrahepatic shunting anymore.
Figure 5: Comparison of C-arm CT and SPECT/CT in a patient with extrahepatic shunting. A) C-arm
CT shows extrahepatic shunting in the duodenal region (black arrow), caused by a collateral branch
from the cystic artery. B) Corresponding extrahepatic 99mTc-MAA activity in the duodenal region on
SPECT/CT (white arrow).
- 170 -
Figure 6: Comparison of C-arm CT (A) and SPECT/CT (B) in a patient with right lobar infusion of
Part II Chapter 8
Tc-MAA. The right part of segment 1 is perfused (black arrow), but the left part is non-perfused
99m
(white arrow). Note the free pertechnetate in the stomach on SPECT/CT (B).
DISCUSSION
In this study, an acquisition protocol for C-arm CT imaging has been developed
that meets specific needs during radioembolization procedures.
We have shown that a continuous infusion of contrast agent, a variable scan delay
based on the time to parenchymal enhancement on DSA, and a 10 second high
dose scan setting resulted in images that contain both contrast enhancement of
the arterial tree and liver parenchyma, show gastrointestinal shunting, and provide
sufficient contrast between perfused and non-perfused liver territories, all in a sin-
gle C-arm CT run. It is expected that optimization of these acquisition parameters
increases the detection rate of angiographic failures, providing an opportunity to
take additional measures and prevent unnecessary repeat procedures.
In our series, the negative predictive values for extrahepatic shunting and non-per-
fusion were 95 % and 83 % respectively, which is in line with the results of two
previous studies. In 2009, Louie et al., performed a study in 42 patients who under-
went radioembolization for primary and metastatic liver tumors. In a total of 22 of
42 patients (52 %), extrahepatic shunting or incomplete tumor perfusion on C-arm
CT affected the treatment plan. In the majority (14/22 patients), these findings
were not detected on DSA. Extrahepatic shunting was demonstrated on C-arm
CT in 8 patients (19 %), and only in 1 on SPECT/CT. According to the authors,
this incongruence can be explained by the limited spatial resolution of SPECT/CT.
- 171 -
Interestingly, 1 patient with extrahepatic shunting on C-arm CT developed a gas-

tric ulcer upon follow-up, as a complication of extrahepatic yttrium-90 micro-
sphere deposition.5
Later, Heusner et al. assessed the accuracy of C-arm CT for the detection of ex-
trahepatic shunting before radioembolization in 30 patients with primary and
metastastic liver tumors in a similar type of study. Using 99mTc-MAA SPECT/CT
as reference standard, they found a negative predictive value of 96 %, and C-arm
CT detected extrahepatic shunting that was not visible on DSA in 10 % of their
patients.6
Other studies reported that arterial and parenchymal enhancement images can
also be acquired in two separate C-arm CT scans using two different delay times,
or by means of a customized dual-phase C-arm CT setting that allows back-to-
Chapter 8 Part II
back acquisitions of two scans with a single contrast injection.3,19 In our opinion, it
is easier to continue the contrast infusion during the entire acquisition time (delay
+ scan time). This also provides the benefit that potential extrahepatic shunting
and the culprit vessel can be identified in the same image.
Now the technical aspects have been refined and the feasibility of C-arm CT as a
diagnostic tool is demonstrated, there is a window of opportunity to rigorously
test its diagnostic value in accordance with ‘Stage 2B: Exploration’ and ‘Stage 3:
Assessment’ of the IDEAL recommendations. C-arm CT is not likely to replace
the infusion of 99mTc-MAA, for the latter is also used for the evaluation of lung
shunting and dosimetric evaluation. Nevertheless, C-arm CT may come to play
an important role in evaluating the pretreatment angiographies, since it allows for
timely intervention to prevent repeat angiographies. Furthermore, C-arm CT is, as
an adjunct to a multiphasic pretreatment CT, indispensable in the development of
a single-day treatment algorithm for radioembolization. 20
The current study suffers from a relatively small sample size, as is common in the
developmental phase of a new technique. To prevent bias, all consecutive cases
were described and their reasons for inclusion/exclusion mentioned. Also, there
was no predefined plan for the modifications to the scan protocol, it was adjusted
by the needs identified by the consensus meeting. Furthermore, there is no clear
end point for an optimal scan protocol, so other studies may improve on this pro-
posal. For our diagnostic accuracy evaluation, it was not possible to assess the false
positive rate for C-arm CT, since additional measures were taken when extrahe-
patic shunting was detected during the preparatory angiography. Besides, the op-
erator was allowed to refrain from using C-arm CT. In theory, this may introduce
selection bias. However, in most cases there was a reason to refrain from C-arm CT
- 172 -
(e.g., contrast allergy). Finally, 99mTc-MAA SPECT/CT was used as a reference stan-
dard, but this modality also has limitations. Its limited spatial resolution and room
for registration errors between SPECT and CT volumes can make the detection of
extrahepatic deposition a challenging task. Furthermore, 99mTc-MAA SPECT/CT is
an imperfect predictor for the posttreatment yttrium-90 microsphere distribution.
Therefore, future investigations should determine the definite role of C-arm CT
and 99mTc-MAA SPECT/CT in the workup for radioembolization.
In conclusion, we have developed an optimized C-arm CT protocol that can be

used to detect extrahepatic shunts and non-perfusion of target segments during
radioembolization. Its use is currently in the developmental phase, and needs to be
further evaluated in the near future.
Part II Chapter 8
- 173 -
REFERENCES
1. Iwazawa J, Ohue S, Mitani T, et al. (2009) 8. Smits MLJ, van den Hoven AF, Rosenbaum
Identifying feeding arteries during TACE of CENM, et al. (2013) Clinical and laboratory
hepatic tumors: Comparison of C-arm CT toxicity after intra-arterial radioemboliza-
and digital subtraction angiography. AJR tion with 90Y-microspheres for unresectable
Am J Roentgenol 192:1057–1063. liver metastases. PLoS One 8:e69448.
2. Iwazawa J, Ohue S, Hashimoto N, et al. 9. McCulloch P, Altman DG, Campbell WB,

(2010) Detection of hepatocellular carci- et al. (2009) No surgical innovation without
noma: Comparison of angiographic C-arm evaluation: the IDEAL recommendations.
CT and MDCT. AJR Am J Roentgenol Lancet 374:1105–1012.
195:882–887.
10. Franklin JM, Gebski V, Poston GJ, Sharma
3. Loffroy R, Lin M, Yenokyan G, et al. (2013) RA (2014) Clinical trials of interventional
Intraprocedural C-arm dual-phase cone- oncology-moving from efficacy to out-
Chapter 8 Part II
beam CT: Can it be used to predict short- comes. Nat Rev Clin Oncol 12:93-104.
term response to TACE with drug-eluting
11. McCulloch P, Cook JA, Altman DG, et al.
beads in patients with hepatocellular carci-
noma? Radiology 266:636–648.
novation 1: The idea and development stag-
4. Tognolini A, Louie JD, Hwang GL, et al. es. BMJ 346:f3012.
(2010) Utility of C-arm CT in patients with
12. Cook J a, McCulloch P, Blazeby JM, et al.
hepatocellular carcinoma undergoing tran-
shepatic arterial chemoembolization. J Vasc
novation 3: Randomised controlled trials in
the assessment stage and evaluations in the
5. Louie JD, Kothary N, Kuo WT, et al. (2009) long term study stage. BMJ 346:f2820.
13. Von Elm E, Altman DG, Egger M, et al.
(2014) The strengthening the reporting
zation. J Vasc Interv Radiol 20:606–613.
of observational studies in epidemiology
6. Heusner TA, Hamami ME, Ertle J, et al. (STROBE) statement: Guidelines for re-
(2010) Angiography-based C-arm CT for porting observational studies. Int J Surg
the assessment of extrahepatic shunting be- 1453–1457.
fore radioembolization. Rofo 182:603–608.
14. Salem R, Lewandowski RJ, Gates VL, et al.
7. Dudeck O, Wilhelmsen S, Ulrich G, et al. (2011) Research reporting standards for ra-
(2012) Effectiveness of repeat angiographic dioembolization of hepatic malignancies. J
assessment in patients designated for ra- Vasc Interv Radiol 22:265–278.
dioembolization using yttrium-90 micro-
spheres with initial extrahepatic accumu-
lation of technitium-99m macroaggregated
radioembolization. Cardiovasc Intervent
albumin: a single center’s experience. Car-
Radiol 36:613–622.
- 174 -
16. van den Hoven AF, van Leeuwen MS, Lam 19. Lin M, Loffroy R, Noordhoek N, et al.
MGEH, van den Bosch MAAJ (2015) He- (2011) Evaluating tumors in transcatheter
patic arterial configuration in relation to arterial chemoembolization (TACE) using
the segmental anatomy of the liver; obser- dual-phase cone-beam CT. Minim Invasive
vations on MDCT and DSA relevant to Ther Allied Technol 20:276–281.
20. Van den Hoven AF, Prince JF, van den
Bosch MAAJ, Lam MGEH (2014) Hepatic
17. Bushberg J, Seibert J, Leidholdt E, Boone radioembolization as a true single-session
JM (2012) The essential physics of medical treatment. J Vasc Interv Radiol 25:1143–
imaging, third edition. Lippincott Wiliams 1144.
& Wilkins, Philadelphia.
18. Suchá D, Willemink MJ, de Jong PA, et al.
Part II Chapter 8
(2014) The impact of a new model-based
iterative reconstruction algorithm on
prosthetic heart valve related artifacts at
reduced radiation dose MDCT. Int J Car-
diovasc Imaging 30:785–793.
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PART III
NOVEL TREATMENT
STRATEGIES
C hap ter
PART III 9
Hepatic radioembolization as
a true single-session treatment
A.F. van den Hoven

J.F. Prince
M.G.E.H. Lam
Journal of Vascular and Interventional Radiology 2014

Hepatic radioembolization as a true single-session treatment
We read with great interest the article by Gates et al. entitled “Outpatient Single-Ses-
sion Yttrium-90 Glass Microsphere Radioembolization”.1 The authors are the first to
demonstrate the feasibility of performing yttrium-90 (90Y) glass microsphere radi-
oembolization (RE) on an outpatient, single-day basis for the treatment of primary
and metastatic cancer.
We learn that a careful evaluation of the hepatic arterial anatomy and determina-
tion of the target volume on cross-sectional imaging allow for dosimetry before
treatment and increased time efficiency of the preparatory angiography. In addi-
tion, advanced imaging techniques, such as high injection rate digital subtraction
angiography and C-arm computed tomography can be used to rule out inadvertent
extrahepatic shunting.
Although radioembolization was conducted on a single-day basis, the authors still
performed separate preparatory and treatment angiography, with planar scintigra-
phy acquisition in between. In their treatment algorithm, 99mTc-MAA scintigraphy
Chapter 9 Part III
was performed only to calculate the lung shunt fraction (LSF). However, this step
was the most important obstacle to implementing single-session radioemboliza-
tion on a larger scale. This finding raises the question: is it necessary to perform a
99m
Tc-MAA infusion?
We reviewed our clinical data on LSF based on 99mTc-MAA planar scintigraphy in
160 consecutive patients who underwent a preparatory angiography for 90Y radio-
embolization during the period 2009 – 2013 in our institute. Only three patients (2
%), all with markedly hypervascular liver metastases (uveal melanoma or urothe-
lial cell carcinoma), could not receive therapy because of an unacceptable LSF (26,
31, and 39 %). In the 128 patients eventually receiving treatment in 153 proce-
dures, preparatory angiography demonstrated a median LSF of 6 % (range 1 – 20
%). According to current guidelines, treatment activity should be reduced when
the LSF > 10 % to prevent radiation-induced pneumonitis by maintaining the lung
dose < 30 Gy.2 Administration of median net 90Y activity of 1.3 GBq (range, 0.07
– 2.3 GBq) resulted in a median lung absorbed dose of 3.4 Gy (range, 0.1 – 11.9
Gy). LSF was > 10 % in 26 of 153 (17 %) cases. However, in these 26 patients, the
initially prescribed, unreduced treatment activity would have resulted in a median
lung absorbed dose of 9.2 Gy (range, 2.0 – 20.4 Gy), and a median cumulative dose
of 10.1 Gy (range, 5.8 – 12.8) in patients who received sequential lobar treatment.
Even though LSFs may be > 10 % and < 20 %, absorbed lung doses seldom exceed
the critical value of 30 Gy in clinical practice, especially not when 90Y radioembo-
lization is performed as lobar or segmental treatment.
- 180 -
Assessment of the LSF may be redundant in a selected patient population. Patients

with hypovascular liver metastases and a limited burden of disease, such as most
patients with colorectal cancer liver metastases (CRLM), may not need calculation
of LSF before treatment. These patients constitute most patients eligible for radio-
embolization and seldom have a significant LSF. In our population, the median LSF
was 6 % (range, 0.9 – 20 %) in 77 90Y radioembolization procedures in 71 patients
with CRLM (median tumor burden, 11 %; range, 1 – 50 %). Without reduction of
the prescribed activity, the median lung absorbed dose would have been 5.0 Gy
(range 0.6 – 20.4).
Planar scintigraphy of 99mTc-MAA is currently used as the reference test. However,
it is questionable whether the LSF is accurately quantified and predicted by pla-
nar 99mTc-MAA scintigraphy. 99mTc-MAA particle size varies greatly. Small particles
may be able to pass the liver capillaries, while the larger radioactive microspheres
cannot. Furthermore, leaching of 99mTc pertechnetate from the macro-albumin ag-
Part III Chapter 9

gregates (visible by thyroid activity) seems to correlate with the calculated LSF.3
Perhaps this is caused by a mechanism leading to both leaching of pertechnetate
and disintegration of MAA into smaller particles. As a result, 99mTc-MAA scintigra-
phy may overestimate the real LSF. This was recently shown by using holmium-166
(166Ho) poly(L-lactic acid) microspheres scout dose as comparator to 99mTc-MAA.4
In addition to high-energy beta radiation, 166Ho-microspheres emit low-energy
gamma radiation, enabling quantitative SPECT.
Based on our data, in addition to the study results of Gates et al., we hypothesize
that a true single-session treatment is feasible in patients with CRLM, since no
significant LSF is anticipated in these patients.
- 181 -
REFERENCES
1. Gates VL, Marshall KG, Salzig K, et al. 3. Lambert B, Mertens J, Sturm EJ, et al.
(2014) Outpatient single-session yttri- (2010) 99mTc-labelled macroaggregated al-
um-90 glass microsphere radioemboliza- bumin (MAA) scintigraphy for planning
tion. J Vasc Interv Radiol 25:266–270. treatment with 90Y microspheres. Eur J
Nucl Med Mol Imaging 37:2328–2333.
2. Dezarn WA, Cessna JT, DeWerd LA, et al.
(2011) Recommendations of the american 4. Elschot M, Nijsen JFW, Lam MGEH, et al.
association of physicists in medicine on (2014) (99m)Tc-MAA overestimates the ab-
dosimetry, imaging, and quality assurance sorbed dose to the lungs in radioemboliza-
procedures for 90Y microsphere brachyther- tion: A quantitative evaluation in patients
apy in the treatment of hepatic malignan- treated with 166Ho-microspheres. Eur J Nucl
cies. Med Phys 38:4824. Med Mol Imaging 41:1965–1975.
Chapter 9 Part III
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C hap ter
PART III10
Posttreatment PET/CT confirmed
intrahepatic radioembolization
performed without coil embolization,
by using the anti-reflux surefire
infusion system
A.F. van den Hoven

J.F. Prince
M. Samim
A. Arepally
B. A. Zonnenberg
M.G.E.H. Lam

Radioembolization performed without coil embolization by using the SIS
ABSTRACT
Intra-arterial radioembolization with yttrium-90 microspheres is a safe and effec-
tive treatment option for patients with unresectable liver tumors. Pretreatment coil
embolization of extrahepatic vessels is recommended to avoid extrahepatic depo-
sition of radioactive microspheres. A novel infusion system with an expandable
tip, the Surefire Infusion System (SIS), has recently been developed to minimize
reflux. We report three cases of radioembolization with the use of the SIS. In all
cases, yttrium-90 radioembolization was performed successfully without coil em-
bolization of extrahepatic vessels. In all patients, positron emission tomography/
computed tomography confirmed intrahepatic biodistribution of the microspheres
in all targeted liver segments, and no extrahepatic deposition. With the use of the
SIS, the need for coil embolization of extrahepatic vessels might be eliminated, and
treatment may be extended to patients who were previously deemed unfit.
Chapter 10 Part III
- 186 -
INTRODUCTION
Intra-arterial radioembolization with yttrium-90 (90Y) microspheres is a safe and
effective treatment option for patients with unresectable primary and metastastic
liver cancer.1 During this procedure, microspheres tagged with the radioactive iso-
tope 90Y are administered into the hepatic artery. The microspheres then become
lodged in the microvasculature around the tumor, inducing an embolization effect
and emitting high-energy beta radiation to the tumor.
During treatment, three safety aspects have to be addressed to prevent complica-
tions caused by extrahepatic deposition of radioactive microspheres. First, depo-
sition of microspheres in the gastrointestinal tract, such as the duodenal or gastric
wall, can lead to ulceration.2-3 Therefore, extrahepatic branches of the hepatic artery
may be selectively embolized using coils (coil embolization), to prevent deposition
of radioactive microspheres to the gastrointestinal tract.4 It is recommended to
confirm the absence of extrahepatic activity by single-photon emission computed
Part III Chapter 10

tomography/computed tomography (SPECT/CT), performed after the administra-
tion of technetium-99m-labelled macro-albumin aggregates (99mTc-MAA) during
a pretreatment angiography.5-6 Second, liver tumors induce arteriovenous shunt-
ing to the lung parenchyma. Radioembolization can induce radiation pneumoni-
tis when treatment is provided despite a large lung shunt fraction.7 Therefore, a
quantitative assessment of the lung shunt fraction should be performed in advance.
Third, during the administration of resin 90Y microspheres, reflux of microspheres
can occur as a result of stasis of flow or vascular spasm. Therefore, preservation of
antegrade flow in the hepatic artery should be monitored during administration,
and the administration should be discontinued when stasis occurs.3,8 After the
administration of 90Y microspheres, a posttreatment 90Y bremsstrahlung SPECT
scan or 90Y positron emission tomography (PET) can be performed to exclude un-
anticipated extrahepatic deposition and assess the intrahepatic distribution of 90Y
microspheres.9 In a recent study, it has been demonstrated that the posttreatment
imaging quality of 90Y-PET is superior over bremsstrahlung SPECT for the assess-
ment of the microsphere distribution.10
A novel infusion system, the Surefire Infusion System (SIS), has recently been de-
veloped (Surefire Medical Inc., Westminster, CO, USA). The FDA- and CE-mark-
ing-approved 3.0F (internal diameter 0.027 inches, range of vessel size 4 – 6 mm)
microcatheter has a funnel-shaped expandable tip that dynamically expands
during reverse flow to minimize reflux of radioactive microspheres while also al-
lowing for antegrade flow (Figure 1). Placing the microcatheter distal to extrahe-
patic branches would exclude the need for coil embolization, while at the same
time reflux is prevented. Recently, it has been advocated that the SIS also causes
- 187 -
B
Chapter 10 Part III
Figure 1: Schematic representation of the Surefire infusion system. A) Infusion through a standard
microcatheter does not prevent reflux (curved arrow). B) Infusion through the Surefire infusion system,
with the expanded tip preventing reflux. C) Physiologic blood flow past the Surefire infusion system is
continued.
protection against extrahepatic deposition through the induction of hepatopetal

flow in extrahepatic arterial branches.11 According to the authors, this is caused by
a decrease in blood pressure in the distal vascular compartment when the SIS tip is
expanded. Subsequently, a reversal in the direction of flow in the gastroduodenal
artery occurs, as this artery forms an anastomosis between the celiac axis and the
superior mesenteric artery.12
- 188 -
In this case report, we describe our experience using this novel microcatheter in
patients with unresectable liver tumors. Intra-arterial administration of 90Y mi-
crospheres was performed exclusively with the SIS, without coil embolization of
extrahepatic arterial branches. In all patients, 99mTc-MAA SPECT/CT and 90Y-PET/
CT were performed to exclude extrahepatic deposition and to demonstrate the
intrahepatic biodistribution of 90Y microspheres in all targeted liver segments (re-
ferred to as adequate intrahepatic biodistribution).
CASE REPORT
Case 1
The first patient was a 63-year-old man with an unresectable, multifocal hepatocel-
lular carcinoma. The largest lesion was located in liver segment 7 and several small-
er lesions were located in segments 2, 3, 4 and 6. Previously, the patient was treated
with transarterial chemoembolization (TACE), for which selective embolization of
Part III Chapter 10

the right gastric artery was performed (Figure 2A). Follow-up imaging after TACE
revealed progressive disease. Subsequently, the patient was considered eligible for
90
Y radioembolization treatment after review by a multidisciplinary tumor board.
After the left hemi-liver had been treated with 90Y microspheres (SIR-Spheres, SIR-
TeX, Lane Cove, Australia), with the use of a conventional microcatheter, it was
decided to perform treatment of the right hemi-liver with the use of the Surefire
microcatheter. The latter is reported in this case report.
A pretreatment angiographic procedure was performed, in which 146 MBq 99mTc-
MAA were administered through the SIS, to simulate the distribution of the radio-
active 90Y microspheres. The SIS was selectively positioned in the common branch
of the right hepatic artery, distal to the origin of the segment 4 artery and cystic
artery. After the pretreatment procedure, SPECT/CT was performed, on which no
extrahepatic deposition of 99mTc-MAA was observed. A lung shunt fraction of 5.5
% was calculated.
During the treatment procedure, the 3.0F Surefire microcatheter was positioned in
the same position as during the pretreatment procedure (Figure 2B).
90
Y microspheres, with an activity of 729 MBq, were administered. PET/CT
demonstrated an adequate intrahepatic biodistribution of 90Y microspheres in the
right hemi-liver (segments 5-8) with focal activity accumulation at tumor sites,
and no extrahepatic depositions (Figure 5A). The patient experienced no symp-
toms of the postembolization syndrome and was discharged from hospital one day
after treatment.
- 189 -
Figure 2: Angiographic images of case 1 (patient A). A) Anatomical configuration. B) Expanded tip
of Surefire microcatheter prevents reflux during administration (* = no contrast in the CA and S4A).
GDA = gastroduodenal artery; RGA = right gastric artery (previously coiled during TACE); LHA = left
hepatic artery; S4A = segment 4 artery; CA = cystic artery; RHA = right hepatic artery.
Chapter 10 Part III
Case 2
The second patient was a 77-year-old man with a sigmoid carcinoma and synchro-
nous liver metastases. Previously the patient had been treated with a resection of
the primary tumor and segmentectomy of liver segments 4 and 5. Furthermore,
there was a large tumor located in segment 7, with a diameter of 3 cm. This tumor
was treated twice using radiofrequency ablation. Follow-up imaging 1 week after
the last radiofrequency ablation procedure revealed residual tumor at the rim of
the ablation zone. The patient was deemed suitable for 90Y-radioembolization treat-
ment by a multidisciplinary tumor board.
The SIS was positioned in the posterior branch of the right hepatic artery, proximal
to the postsurgical stricture (Figure 3A), to target the tumor in segment 7. After a
successful pretreatment procedure with infusion of 99mTc-MAA, no extrahepatic
deposition was observed, and a lung shunt fraction of 1.4 % was calculated.
During the treatment procedure, 822 MBq 90Y microspheres was administered
(Figure 3B) through the 3.0F Surefire microcatheter. During both the pretreatment
and treatment procedures, intravenous nitroglycerine (Nitro Pohl 200 μg) was
administered to treat moderate vasospasm occurring proximal to the level of the
postsurgical stricture. Posttreatment PET/CT demonstrated an adequate intrahe-
patic biodistribution of 90Y microspheres, exclusively in segments 6 and 7, prefer-
entially at the tumor site (Figure 3C). The patient experienced no symptoms of the
postembolization syndrome and was discharged the day after treatment.
- 190 -
Figure 3: Angiographic images of case 2 (patient B). A) Anatomical configuration. The (replaced) left
hepatic artery originates from the left gastric artery. B) Expanded tip of Surefire microcatheter prevents
reflux during administration (* = no contrast in the AB RHA). GDA = gastroduodenal artery; AB RHA
= anterior branch of the right hepatic artery; PB RHA = posterior branch of the right hepatic artery.
Part III Chapter 10

Case 3
The third patient was a 66-year-old man with liver metastases from an esophageal
carcinoma. The patient had not previously received locoregional treatment of the
liver metastases. One liver lesion was located in segment 8, and one lesion was
located on the border of segments 8 and 5. After the patient was deemed eligible
for radioembolization, a pretreatment angiographic procedure was initially per-
formed with the use of a conventional catheter. During routine coil embolization
of the gastroduodenal artery, the tip of the last coil dislocated into the adjacent
right gastric artery (Figure 4A). As a result, it was no longer possible to selectively
catheterize the right gastric artery. Consequently, the right gastric artery was in-
sufficiently occluded. The conventional catheter was placed distally in the left and
right hepatic artery, and 99mTc-MAA was administered. However, SPECT/CT re-
vealed extrahepatic activity in the stomach despite the distal catheter positioning,
confirming the insufficient coil embolization of the right gastric artery.
Therefore, it was decided to repeat the pretreatment angiographic procedure with
the SIS. During this procedure, the SIS was placed selectively in the left and right
hepatic artery to adequately target the liver lesions. After a successful pretreatment
procedure with infusion of 99mTc-MAA, no extrahepatic deposition was observed,
and a lung shunt fraction of 1 % was calculated.
During the treatment procedure 90Y microspheres, with activities of 540 and 1,220
MBq were administered through the 3.0F Surefire in the left (Figure 4B) and right
(Figure 4C) hepatic arteries, respectively (Figures 4B-C). Nitroglycerine (Nitro Pohl
500 μg) was given intravenously, to resolve occurring vasospasm. Posttreatment
- 191 -
A B
C Figure 4: Angiographic images of case 3 (patient

C). A) Anatomical configuration. B) Expanded tip
of Surefire microcatheter in the LHA, preventing
reflux during administration (* = no contrast in the
RGA). C) Expanded tip of Surefire microcatheter in
the RHA, preventing reflux during administration
Chapter 10 Part III
(* = no contrast in the first branch of the RHA).

The tip of the last coil in the GDA is dislocated into
the RGA. GDA = gastroduodenal artery; RGA =
right gastric artery; RHA = right hepatic artery;
LHA = left hepatic artery.
A B
Figure 5: Posttreatment PET/CT. A) Case 1. B) Case

2. C) Case 3. Note the intrahepatic biodistribution
of 90Y microspheres in all targeted liver segments.
- 192 -
PET/CT again revealed an adequate intrahepatic biodistribution of 90Y micro-

spheres in the whole liver and no extrahepatic depositions (Figure 5C). The patient
experienced no symptoms of postembolization syndrome and was discharged the
day after treatment.
DISCUSSION
In this case report, we described the successful treatment of three patients with
intra-arterial 90Y-radioembolization by using the SIS, without coil embolization.
In case 1 and 2, targeting of specific liver segments was achieved with the SIS in a
superselective injection position. In case 3, treatment became possible in a patient
who could not have been treated with a conventional microcatheter. To verify that
the Surefire microcatheter prevented reflux of radioactive microspheres while al-
lowing for adequate treatment targeting, both SPECT/CT and PET/CT were per-
formed after the administration of 99mTc-MAA and 90Y microspheres, respectively.
Part III Chapter 10

These imaging modalities confirmed the absence of extrahepatic deposition and
demonstrated an adequate intrahepatic biodistribution of 90Y microspheres, con-
firming a safe and efficient administration.
The SIS is designed to eliminate reflux of diagnostic and therapeutic agents to ex-
trahepatic arterial branches, through dynamic expansion of the expandable tip
during reverse flow. The tip consists of a polymer wall with hydrophilic coating to
prevent passage of small particles. The tip also contains three radiopaque markers
to indicate its expansion on fluoroscopy.
The use of the SIS may have several advantages. By eliminating the need for coil
embolization of extrahepatic arterial branches, treatment may be extended to pa-
tients who were previously considered unsuitable for 90Y-radioembolization as a
result of inaccessible extrahepatic branches originating from one of the hepatic
arteries. This is illustrated by case three. In this patient, SPECT/CT initially re-
vealed extrahepatic activity in the gastrointestinal tract after selective administra-
tion of 99mTc-MAA with a conventional microcatheter. This was due to incomplete
coil embolization of the right gastric artery, which was not accessible for selective
catheterization and subsequent coil embolization. Consequently, this inhibits safe
administration of 90Y microspheres with a conventional microcatheter. However,
the Surefire microcatheter enabled treatment through its expandable tip, that ade-
quately prevented reflux of radioactive microspheres.
Another potential benefit of the SIS is that it may increase the infusion efficien-
cy through a reduction of (resin microsphere) backflow. Arepally et al. recently
investigated the infusion efficiency of the Surefire microcatheter during renal ar-
tery embolization with radiopaque tantalum beads in swine. Administration of the
- 193 -
tantalum beads with the Surefire microcatheter lead to a statistically significant

increase (p < 0.05) in infusion efficiency (defined as the percentage of infusate de-
livered to the target vessel), when compared to a standard diagnostic catheter (72
vs. 99.9 %, respectively).13 Whether this will lead to an increased concentration of
microspheres in tumorous tissue is still unclear.
Serious complications like radiation-induced gastric ulceration, gastritis, and pan-
creatitis can occur when reflux leads to gastrointestinal deposition of radioactive
microspheres.6 Therefore, it is recommended to coil embolize extrahepatic branch-
es of the hepatic artery, including the gastroduodenal artery and right gastric ar-
tery, when using a standard microcatheter during radioembolization.8 However,
the use of the SIS during radioembolization enables safe administration of radioac-
tive microspheres without the need for coil embolization, without compromising
the intrahepatic biodistribution of microspheres in the targeted liver territory. In
all three presented cases, final pretreatment 99mTc-MAA SPECT/CT did not reveal
Chapter 10 Part III
any extrahepatic activity, and posttreatment 90Y PET/CT confirmed an adequate

intrahepatic distribution of 90Y microspheres.
During the deployment of the expendable SIS tip, moderate vasospasm occurred
in two patients, which was adequately treated with intravenous nitroglycerine. No
other adverse events related to the use of this novel microcatheter occurred. These
findings are in line with the first experience in man with the SIS, described by
Louie et al..14 Nevertheless, the use of this microcatheter during radioembolization
without coil embolization of extrahepatic arterial branches still has to be evaluated
on its safety aspects with a variety of possible injection positions and anatomical
variations.
The indications for the use of the SIS during radioembolization have yet to be de-
termined. In cases 1 and 2, the use of a conventional microcatheter was also fea-
sible. In these cases, the SIS was used to demonstrate that selective liver segments
can be adequately targeted with the use of the SIS. In case 3, treatment was only
possible with the use of the SIS. We believe that the SIS will be especially useful in
patients with an arterial configuration that does not permit safe administration of
90
Y microspheres with a conventional microcatheter, when extrahepatic arterial
branches close to the preferred site for treatment administration cannot be coil
embolized.
It should be noted that the SIS is more expensive than a conventional microcath-
eter. However, a fair cost analysis is complex and would have to include the price
of a conventional microcatheter plus the embolic devices (e.g., regular coils) used
to prevent extrahepatic deposition of microspheres, and should also take time ef-
ficiency into account.
- 194 -
In summary, using the novel SIS, three patients with liver malignancies were suc-
cessfully treated with selective intra-arterial 90Y-radioembolization, without coil
embolization of extrahepatic arterial branches. One patient could not have been
treated without the use of the SIS. Posttreatment 90Y PET/CT confirmed safe and
efficient treatment in all three patients.
Part III Chapter 10
- 195 -
REFERENCES
1. Vente MAD, Wondergem M, van der Tweel microsphere brachytherapy: A consensus
I, et al. (2009) Yttrium-90 microsphere ra- panel report from the radioembolization
dioembolization for the treatment of liver brachytherapy oncology consortium. Int J
malignancies: A structured meta-analysis. Radiat Oncol Biol Phys 68:13–23.
Eur Radiol 19:951–959.
9. Gates VL, Esmail AAH, Marshall K, et al.
2. Yip D, Allen R, Ashton C, Jain S (2004) Ra- (2011) Internal pair production of 90Y per-
diation-induced ulceration of the stomach mits hepatic localization of microspheres
secondary to hepatic embolization with using routine PET: Proof of concept. J Nucl
radioactive yttrium microspheres in the Med 52:72–76.
treatment of metastatic colon cancer. J Gas-
10. Elschot M, Vermolen BJ, Lam MGEH, et
troenterol Hepatol 19:347–349.
al. (2013) Quantitative comparison of PET
3. Lam MGEH, Banerjee S, Louie JD, et al. and Bremsstrahlung SPECT for imaging
(2013) Root cause analysis of gastroduo- the in vivo yttrium-90 microsphere distri-
denal ulceration after yttrium-90 radio- bution after liver radioembolization. PLoS
Chapter 10 Part III
embolization. Cardiovasc Intervent Radiol One 8:e55742.

36:1536–1547.
11. Rose SC, Kikolski SG, Chomas JE (2013)
4. Kennedy A, Coldwell D, Sangro B, et al. Downstream hepatic arterial blood pres-
(2012) Radioembolization for the treat- sure changes caused by deployment of the
ment of liver tumors general principles. Am surefire antireflux expandable tip. Cardio-
J Clin Oncol 35:91–99. vasc Intervent Radiol 36:1262–1269.
5. Ahmadzadehfar HSA, Reichmann K, 12. Song S, Chung J, Kwon J, Joh J (2002) Col-
Muckle M, et al. (2011) Imaging of Y90 lateral pathways in patients with celiac axis
distribution with PET/CT and bremsstrah- stenosis: Angiographic–spiral CT correla-
lung SPECT/CT after radioembolization: A tion. Radiographics 22:881–893.
patient based study. J. Nucl. Med. 52(Sup-
13. Arepally A, Chomas J, Kraitchman D, Hong
plement 1):92.
K (2013) Quantification and reduction of
6. Riaz A, Lewandowski RJ, Kulik LM, et al. reflux during embolotherapy using an anti-
(2009) Complications following radioem- reflux catheter and tantalum microspheres:
bolization with yttrium-90 microspheres: Ex vivo analysis. J Vasc Interv Radiol
A comprehensive literature review. J Vasc 24:575–580.
14. Louie JD (2012) First in man experience
7. Wright CL, Werner JD, Tran JM, et al. with the surefire infusion system – a ded-
(2012) Radiation pneumonitis following icated microcatheter system to eliminate
yttrium-90 radioembolization: Case report reflux during embolotherapy. Soc Interv
and literature review. J Vasc Interv Radiol Radiol Annu Sci Meet
23:669–674.
8. Kennedy A, Nag S, Salem R, et al. (2007)

Recommendations for radioembolization
of hepatic malignancies using yttrium-90
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C hap ter
PART III11
Innovation in catheter design
for intra-arterial liver cancer
treatments results in favorable
particle-fluid dynamics
A.F. van den Hoven

M.G.E.H. Lam
S. Jernigan
G.D. Buckner
Journal of Experimental & Clinical Cancer Research 2015

Innovation in catheter design results in favorable particle-fluid dynamics
ABSTRACT
Background
Liver tumors are increasingly treated with radioembolization. Here, we present
first evidence of catheter design effect on particle-fluid dynamics and downstream
branch targeting during microsphere administrations.
Materials and Methods
A total of 7 experiments were performed in a bench-top model of the hepatic
arterial vasculature with recreated hemodynamics. Fluorescent microspheres
and clinically used holmium microspheres were administered with a standard
microcatheter (SMC) and an anti-reflux catheter (ARC) positioned at the same
level along the longitudinal vessel axis. Catheter-related particle flow dynamics
were analyzed by reviewing video recordings of UV-light illuminated fluorescent
microsphere administrations. Downstream branch distribution was analyzed
by quantification of collected microspheres in separate filters for two first-order
branches. Mean deviation from a perfectly homogenous distribution (DHD) was
used to compare the distribution homogeneity between catheter types.
Results
The SMC administrations demonstrated a random off-centered catheter
Chapter 11 Part III
position (in 71 % of experiments), and a laminar particle flow pattern with an

inhomogeneous downstream branch distribution, dependent on catheter position
and injection force. The ARC administrations demonstrated a fixed centro-luminal
catheter position, and a turbulent particle flow pattern with a more consistent and
homogenous downstream branch distribution. Quantitative analyses confirmed a
significantly more homogeneous distribution with the ARC; the mean DHD was
40.85 % (IQR 22.76 %) for the SMC and 15.54 % (IQR 6.46 %) for the ARC (p =
0.047).
Conclusion
Catheter type has a significant impact on microsphere administrations in an in
vitro hepatic arterial model. A within-patient randomized controlled trial has been
initiated to investigate clinical catheter-related effects during radioembolization
treatment.
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BACKGROUND
Primary liver tumors (hepatocellular carcinoma, intrahepatic cholangiocarcinoma)
and liver metastases affect a great number of cancer patients worldwide, and
advanced disease stages are generally associated with poor prognosis.1-4 Only
a minority of patients are eligible for potentially curative surgery, and the
efficacy of palliative systemic therapy is dependent on tumor type.5-8 In the last
decade, image-guided treatment techniques have evolved as another therapeutic
option, and minimally invasive, transcatheter treatments such as transarterial
chemoembolization and intra-arterial radioembolization have found their way to
patients with irresectable and chemorefractory disease.9-10
During radioembolization treatment, radioactive microspheres are administered
through a catheter placed in the hepatic arterial vasculature. Since liver tumors
are almost exclusively vascularized by the hepatic artery, and healthy liver tissue
receives the majority of its blood supply from the portal vein, arterial blood flow
should preferentially transport the microspheres towards tumorous tissue, where
they lodge in the distal vessels surrounding tumors and emit tumoricidal high-
energy β-radiation, while relatively sparing healthy liver tissue.11 Yet, individual
tumors may receive subtherapeutic doses of radioactivity as a result of the complex
interplay between tumor vascularization, particle-fluid dynamics and catheter
Part III Chapter 11

placement.12-14
So far, the standard end-hole microcatheter (SMC) has been the undisputed device
of choice for microsphere administrations. However, a novel catheter type has
recently been developed specifically for transcatheter liver cancer treatments. This
anti-reflux catheter (Surefire Infusion System, Surefire Medical Inc., Westminster,
Co, USA) features a dynamically expandable tip that prevents reflux of particles
in reverse flow conditions, while preserving normal antegrade blood flow.15 In
addition, the catheter orifice is fixed in the center of the vessel lumen (centro-
luminal position). These marked differences may affect fluid-particle dynamics
during microsphere administrations, and have a significant impact on tumor
targeting during radioembolization.
Remarkably, fluid-particle dynamics are still inadequately understood, and the
potential effects of catheter design and position remain unknown. The aim of this
study is to enhance our understanding of this complex interplay by comparison of
microsphere administrations with an ARC and SMC in the controlled environment
of an experimental vascular model. In addition, we elaborate on potential clinical
benefits that may be associated with favorable catheter characteristics.
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METHODS
Experiments
Table 1 shows an overview of the methods for all experiments performed in this
study. The microsphere type, catheter position, injection technique and vascular
model varied between experiments to address specific questions and test both
catheter types across a variety of situations (see the specific methods section for a
more detailed description). These parameters were, however, kept identical between
the SMC and ARC administrations within the same experiments to warrant a
valid comparison of the catheter types. The main objective of experiments 1 – 3
with the fluorescent microspheres was to document the particle outflow pattern
for qualitative analysis. For experiments 4 – 7 with the holmium microspheres,
the main objective was to extend the quantitative data on the consistency and
homogeneity of the down-stream branch distribution with clinically validated
microspheres. Secondary objectives were to assess the effect of injection force on
downstream branch targeting, and to evaluate random cross-sectional catheter
positioning.
Table 1: Description of experiments

Chapter 11 Part III
Experiment Microspheres Catheter Catheter Injection Vascular

type position technique model
SMC
1 Fluorescent Distal PHA Manual 1
ARC
SMC
2 Fluorescent Proximal PHA Automatic 1
ARC
SMC
3 Fluorescent Proximal PHA Automatic 1
ARC
SMC RHA,
4 Holmium Automatic 2
ARC proximal to S4A
SMC RHA,
ARC proximal to S4A
SMC RHA,
ARC proximal to S4A
SMC RHA,
ARC proximal to S4A
This table gives an overview of the experiments performed. Abbreviations: SMC = standard
microcatheter; ARC = anti-reflux catheter; PHA = proper hepatic artery; RHA = right hepatic artery;
S4A = segment 4 artery.
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In vitro hepatic arterial model

An in vitro hepatic arterial model was created to replicate hemodynamics and
vessel geometry during microsphere administrations in the human hepatic arterial
vasculature. The use of this model has been described before.16 Central to this system
was a rigid planar model fabricated by 3D printing. Two different models were used:
a transparent model for the fluorescent microsphere administrations (experiments
1 – 3) to optimize the visibility of the microsphere flow, and a non-transparent
model with a piece of surgical tubing inserted at the intended injection position
to optimize vessel sealing by the ARC (experiments 4 – 7, Figure 2). The geometry
of both models was obtained from the branching pattern of three-dimensional CT
imaging. The models consisted of a main bifurcation into left hepatic artery (LHA)
and right hepatic artery (RHA), with the LHA terminating in six vessels (1.0 mm
ID), and the RHA and segment 4 arterial (S4A) branch terminating in a total of ten
vessels (1.0 mm ID). Hemodynamics was regulated by a closed-loop, dynamically
pressurized system. At the proximal side of the vascular model, a fluid supply
reservoir was connected to two parallel configured, computer-controlled pumps,
a gear pump (Greylor Corporation, Cape Coral, FL) and a custom-made positive
displacement pump that induced pulsatile pressurization of the hepatic arterial
model to resemble the cardiac cycle. A blood pressure profile with a systolic/
Part III Chapter 11

diastolic value of 140/60 mm Hg and 60 cycles/min was chosen as target (Figure 1),
based on previous simulations of the hepatic arterial blood flow.17 One-way valves
in the fluid lines near the pumps prevented backflow. The distal vessels drained into
open collection reservoirs, mounted on USB-interfaced laboratory scales. Pumps
connected to the collection reservoirs intermittently recirculated the fluid back to
the fluid supply reservoir. Real time mass measurements were used to quantify the
intravascular flow rates. All terminal vessels ran through pinch valves that were
iteratively adjusted to keep the flow rates at target level and increase peripheral
resistance. A target flow velocity of 10 ml/min for each vessel (total flow rate 160
ml/min) was chosen for all administrations. This choice was based on reported
flow rates of the right hepatic artery with a range of 29 – 225 mL/min, constituting
60 % of the total hepatic arterial flow, yielding a range of 48.3 – 375.0 mL/min for
the proper hepatic artery.18-20 To replicate blood viscosity, with a reported value of
3.49 cP at systolic shear rates21 (ex vivo measurements corrected for hematocrit
level), a 25/75 % glycerin/water solution was used. Adequate fluid viscosity (3.48
± 0.42 cP at a shear rate of 150 s-1) was confirmed by measurements taken with a
HAAKE™ Viscotester™ 550 (ThermoFisher Scientific, Waltham, MA).
- 203 -
Figure 1: Recreated pressure profile

of the hepatic arterial vasculature.
The change in blood pressure (in mm
Hg) is displayed for one cardiac cycle
(per non-dimensional time unit with
t = time point in cardiac cycle, and
T = period of one cardiac cycle).
Chapter 11 Part III
Figure 2: Photograph of the experimental

hepatic arterial model (model #2). For
practical reasons, the model is oriented
upside down (different to orientation in
a patient). Abbreviations: PHA = proper
hepatic artery; LHA = left hepatic
artery; S4A = segment 4 artery; RHA =
right hepatic artery.
Catheter positioning
After achieving a constant flow velocity of 10 ml/min, the catheter was introduced
into the model through a port proximal to the hepatic arterial model. The tip
of the SMC (Progreat 2.7 Fr., Terumo Europe, Leuven, Belgium) and the ARC
- 204 -
(Surefire Infusion System mT, Surefire Medical Inc., Westminster, Co, USA) were
positioned at a target location on the longitudinal axis of the vessel. Different
target locations were chosen to test both catheter types in various geometrical
configurations. For the first experiment, this location was at 2 mm distance to the
LHA/RHA bifurcation, for the second and third experiment a 5 mm distance was
chosen (representative for a whole liver treatment with a proper hepatic artery
injection). For the experiments with holmium microspheres in the second model
(experiments 4 – 7), the catheters were positioned in the surgical tubing inserted in
the RHA before the branching of the S4A (representative for a lobar treatment with
a right hepatic artery injection). The position of the SMC in the cross-sectional
vessel plane was a result of random placement, affected by the entire vessel
geometry (Figure 3A). Deviation of the SMC tip position was noted. The tip of the
ARC was deployed just before the injection.
Part III Chapter 11
Figure 3: Catheter positions during fluorescent microsphere administrations. Photographs of the

catheter positions in the geometry of the recreated hepatic arterial model, corresponding to the
fluorescent microsphere administrations in Figure 4. A) Note the SMC tip deviation towards the right
side. B) Fixed centro-luminal position of the ARC. Abbreviations: LHA = left hepatic artery; RHA =
right hepatic artery; PHA = proper hepatic artery. NB: the model is oriented up-side down.
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Microsphere injections
A 200 mg dose of fluorescent red polyethylene microspheres (Cospheric LLC,
Santa Barbara, Ca, USA) with a density of 1.20 g/cc and size of 27 – 32 μm was
used for experiments 1 – 3. Fluorescent illumination of these microspheres is
induced at a wavelength of 300 – 550 nm. 600 mg non-irradiated, 165Ho loaded
poly (L-lactic acid) microspheres (QuiremSpheres, Quirem Medical Inc., Utrecht,
The Netherlands) with a density of 1.40 g/cc and size of 30 μm (range 20 – 50
μm) were used for experiments 4 – 7. Both microsphere types were prepared
for administration according to manufacturers instructions. The fluorescent
microspheres were suspended in a tween surfactant solution (Tween 20) to
prevent aggregation, and administered with 30 ml of water, whereas the holmium
microspheres were suspended in an isotonic phosphate buffer, and administered
with 30 ml of 0.9 % NaCl solution.
For the first experiment only, microspheres were injected by manual operation
of a 30 cc syringe, using an intermittent short pulse pattern, similar to clinical
practice. For a brief period of time, injection force was varied from minimal (pulse
injection rate 0.3 ml/sec), to nominal (0.6 ml/sec), and ultimately excessive (1.2
ml/sec), in order to evaluate the impact of injection force on downstream branch
distribution. The time points of different injection force were recorded. During the
other experiments (experiments 2 – 7), an automatic syringe pump was used with
Chapter 11 Part III
standardized settings for injection (pulses of 0.5 ml, 1 s interval between pulses, 5
ml/min) to eliminate all variability for an unbiased comparison between SMC and
ARC administrations. Intravascular flow continued for 15 min after the beginning
of administration.
Qualitative analysis of catheter-related flow patterns
All fluorescent microsphere administrations were filmed using a mounted
high definition camera, under UV-light illumination to assess catheter-related
flow patterns qualitatively. The video recordings of all fluorescent microsphere
administrations with the SMC and ARC were reviewed side-by-side to facilitate
the comparison of particle flow patterns for each catheter type.
Quantitative analysis of microsphere distribution
The distal vessels of the first-order branches (LHA/RHA for experiments 1 – 3,
and S4A/RHA for experiments 4 – 7) drained into separate filters of Dutch-weave
stainless steel with a rating of 10 μm (validated in-house for successful filtering
of microspheres). These filters were weighed on a precision scale (AB135-S/
FACT laboratory scale, Mettler-Toledo Inc., Columbus, Ohio, USA) prior to
administration, and again post-administration after 12 hours of heating at
190 – 250°F in a digitally controlled Thermolyne 1500 furnace (ThermoFisher
- 206 -
Scientific, Waltham, Mass., USA) to evaporate the residual water and glycerin. The
measured change in mass was used to quantify the microspheres collected. The
distribution over the main branches was subsequently determined by calculating
the proportional weight change per filter as a function of the total weight change
for both filters. In order to compare the distribution homogeneity across catheter
types, the deviation from a perfect homogenous distribution (50 : 50 %), abbreviated
as DHD, was calculated in percentage points (for example, a 10 : 90 % distribution
results in a DHD of 40 %).
Statistics
DHD was considered a continuous outcome variable. Data were summarized in
median, range, and interquartile range (IQR) values (non-normally distributed).
Differences in DHD between administrations with both catheter types were tested
by means of a Wilcoxon signed-rank test for paired continuous data. Sample size
calculation based on exploratory statistics after experiments 1 – 5 demonstrated
that two additional experiments should be sufficient to demonstrate a statistically
significant difference in DHD, with a power of 0.90 at an alpha-level of 0.05. A p
value < 0.05 was considered statistically significant. All statistics were performed
in R version 3.1.1 for Mac OS X.
Part III Chapter 11

RESULTS
Fluorescent microsphere administration demonstrates catheter-
dependent flow pattern
A clear qualitative difference in particle outflow pattern between the two catheters
was observed, consistently over all experiments (Figure 4, and supplemental Movie
S1). The SMC administrations showed an ordered, streamlined outflow pattern,
consistent with laminar flow. In contrast, the ARC administrations had a chaotic,
broad-based outflow pattern, consistent with turbulent flow.
Injection force affects downstream branch targeting with a standard
end-hole microcatheter
Random positioning of the SMC in the cross-sectional vessel plane resulted in slight
deviations towards the right side. Review of the administration videos revealed that
the LHA received minimal dosage with the SMC, and the second-order branch
targeting differed remarkably when using minimal, nominal or excessive injection
force (Figures 5A-C). The ARC administrations showed a more homogeneous
first-order branch distribution, but the RHA was still preferentially targeted. No
evident difference in second-order branch targeting was noted between periods of
minimal, nominal and excessive applied injection force (Figures 5D-F).
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Chapter 11 Part III
- 208 -
Figure 4: Catheter-related particle flow-dynamics. Composite figure of the fluorescent microsphere administrations with the SMC (A) and ARC (B). Images of
fluorescent microsphere administrations were created by overlaying frames from a representative part of the experiment 3 video (Movie S1), to show the typical
catheter-related particle flow pattern. The background of images (A) and (B) was edited in Adobe Photoshop to emphasize an area of interest. A) Off-centered SMC
position, laminar outflow pattern and absence of microsphere flow towards the LHA. B) Centro-luminal ARC position, turbulent outflow pattern (note the eddy
current adjacent to the ARC tip) and more homogenous microsphere distribution over the LHA and RHA.
- 209 -
Figure 5: Effect of injection force on downstream branch targeting. This figure highlights the effect of injection force on downstream branch targeting. The images are
constructed from the video recordings from experiment 1 (similar to Figure 4). The upper row (A – C) displays the administrations with the SMC, and the lower row
(D – F) displays the ARC administrations. Periods of minimal (A, D), nominal (B, E) and excessive (C, F) injection force were recorded. Injection force seems to have
a more significant impact on the downstream distribution with the SMC than with the ARC. A) SMC administration with minimal force only targets the right second-
order branch. (B – C) Injection with nominal or excessive force also leads to targeting of the left second-order branch, but the LHA is not targeted at all. Note that
the flow pattern seems to change from laminar to turbulent (A – C). D) ARC administration with minimal force leads to preferential targeting of the RHA. However,
microspheres are still visible in the second order branches of the LHA. (E – F) The ARC administration with nominal and excessive force leads to a homogenous
distribution over all first and second-order branches.
Part III Chapter 11

Chapter 11 Part III
Table 2: Microsphere distribution
Experiment Off-centered SMC ARC Deviation from

SMC position? administrations administrations homogeneous distribution
LHA/S4A RHA LHA/S4A RHA SMC ARC
1 Yes (right side) 3.66 % 96.34 % 17.55 % 82.45 % 46.34 % 32.45 %

2 Yes (right side) 0.64 % 99.36 % 37.52 % 62.48 % 49.36 % 12.48 %
3 Yes (right side) 0% 100 % 49.45 % 50.55 % 50.00 % 0.55 %
4 Yes (left side) 89.68 % 10.32 % 65.63 % 34.37 % 39.68 % 15.63 %
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5 No 41.87 % 58.13 % 57.42 % 42.58 % 8.13 % 7.42 %
6 Yes (left side) 90.95 % 9.05 % 32.82 % 67.18 % 40.95 % 17.18 %
7 No 39.50 % 60.50 % 35.46 % 64.54 % 10.50 % 14.54 %
The microsphere distribution results are summarized in this table. The distribution over LHA or S4A and RHA are shown for both catheter types. *The column LHA/
S4A targeting refers to LHA for experiments 1 – 3, and S4A for experiments 4-7. The deviation from homogeneous distribution (DHD) is the distance to a perfect
homogenous distribution (50 – 50 %) in percentage points. Abbreviations: LHA = left hepatic artery; S4A = segment 4 artery; RHA = right hepatic artery; SMC =
standard microcatheter; ARC = anti-reflux catheter.
Downstream branch targeting is more consistent and homogenous

with an anti-reflux catheter
Random cross-sectional positioning of the standard microcatheter resulted in
catheter tip deviations towards the right vessel wall during experiments 1 – 3,
towards the left vessel wall during experiments 4 and 6, and a centered position
during the experiments 5 and 7. The results of the quantitative analysis are
summarized in Table 2. The downstream branch distribution was significantly
more homogenous with the ARC than with the SMC (Wilcoxon signed-rank test,
V = 26, p = 0.047). The median DHD was 40.85 % (range 8.13 – 50 %, IQR 22.76 %)
for the SMC, and 15.54 % (range 0.55 – 32.45 %, IQR 6.46 %) for the ARC across all
experiments. Furthermore, the homogeneity and consistency of the downstream
distribution seemed dependent on cross-sectional catheter position for the SMC.
Only the experiments with a centered cross-sectional SMC position (experiments
5 and 7) showed a relatively homogeneous distribution (DHD 8.13 and 10.50 %
respectively). The distribution was skewed (DHD range 39.68 - 50 %) towards the
catheter tip direction for experiments with an off-centered cross-sectional SMC
position (experiments 1 – 4 and 6).
DISCUSSION
Part III Chapter 11

In this report, we present the first evidence that a SMC and ARC differ substantially
with regard to cross-sectional catheter position, particle outflow pattern, and
downstream branch distribution during the administration of microspheres in an
in vitro hepatic arterial model.
The use of a SMC has long been standard clinical practice for radioembolization
procedures. This may be explained by its convenient use, and the fact that potential
problems with random cross-sectional catheter position or inadequate downstream
branch targeting are not easily visualized during angiographic procedures. In our
study, administrations with an SMC exhibited a laminar particle flow pattern.
Under normal conditions, arterial blood flow is laminar. This means that blood
flows in streamlines parallel to the vessel wall, without lateral mixing.22 The
microspheres seemed to drift along these ordered streamlines. The downstream
distribution therefore becomes dependent on random cross-sectional catheter
positioning. The SMC induced a homogenous downstream branch distribution,
only in the experiment in which it was reasonably centered. In the other 5 of 7
experiments, the SMC was off-centered, and a very heterogeneous downstream
branch distribution was observed, with one of the targeted main branches receiving
only 0 – 10 % of injected microspheres. Interestingly, qualitative video analysis of
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the first experiment also suggests that the downstream branch distribution may
be dependent on injection force. We theorize that this is related to the difference
between particle release velocity and blood flow velocity. Low force injection
results in particle release velocities lower or equal to the local blood flow velocity.
Therefore, microspheres follow the streamline into which they are released.17,23-25
On the contrary, high injection force results in a particle release velocity exceeding
the local blood flow velocity, which allows microspheres to cross streamlines
laterally.
In radioembolization treatment, it is important to achieve adequate coverage of
the entire tumor bearing liver tissue26-27; therefore, a homogenous distribution
over first-order branches is a minimum requirement. If the tumors are confined
to a specific part of the liver, a more distal catheter position is often chosen28,
limiting the influence of flow on microsphere distribution. Furthermore, particle
distribution is generally assumed to be consistent over repeated administrations
with the catheter placed at the same position in the longitudinal axis of the vessel.
In current practice, the administration of 90Y microspheres is simulated in the
week(s) before treatment by injection of technetium-99m macroaggregated
albumin (99m-Tc-MAA) particles from the same longitudinal catheter position,
to rule out extrahepatic microsphere deposition or significant liver-to-lung
Chapter 11 Part III
shunting.29 Various studies demonstrated that the 99mTc-MAA distribution does

not accurately predict the posttreatment intrahepatic microsphere distribution.30-32
Inconsistencies are often ascribed to marked differences in particle characteristics
such as size, density, and embolic effect33, but the results of our study suggest that
random differences of the cross-sectional SMC position between procedures may
also play an important role.
The ARC administrations revealed a turbulent particle flow pattern. The
expandable tip likely breaks up the laminar columns in the antegrade flow; and
once the flow has passed the tip, flow swirls (so called eddy currents) to create a
chaotic, turbulent flow pattern into which microspheres are released. Combined
with the fixed centro-luminal position of the catheter orifice, this leads to a more
predictable and more homogenous microsphere distribution. This may have
important implications for radioembolization.
For one, tumor targeting may be improved by using the ARC. The ultimate goal
is to realize an adequate radioactive dose delivery to all tumors in the liver. Two
studies demonstrated that inadequate treatment of at least one tumor occurs
frequently in patients treated with radioembolization, which may explain some
of the inconsistencies in reported tumor response rates.12-13,34 Although tumor
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vascularization may complicate matters in practice, we expect that a more

homogenous downstream branch targeting is paramount to achieve adequate
tumor coverage, which should in turn translate in to improved treatment efficacy.
Furthermore, a more consistent microsphere distribution over repeated
administrations may increase the predictability of the treatment effect. In this light,
the combination of the self-centering ARC and holmium-166 (166Ho) microspheres
is especially interesting. Holmium-166 microspheres have been developed and
clinically validated as an alternative to 90Y microspheres for radioembolization, with
the added value of γ-radiation based SPECT imaging, and the option to administer
a scout dose of identical 166Ho microspheres before treatment instead of 99m-Tc-
MAA.12,35 Administering identical particles during the scout dose procedure in the
same longitudinal and axial catheter position as during treatment, may be the key
to accurately predict the intrahepatic distribution of the therapeutic microspheres.
An accurate prediction would enable tailoring of the treatment strategy towards
individual patients. Current treatment activity calculations for 90Y microspheres are
based on empirically determined thresholds for a maximum tolerable whole liver
absorbed dose, assuming a perfectly homogenous microsphere distribution ratio,
i.e. a tumor to non-tumor (T/N) ratio of 1.14 This worst-case scenario approach
has been adopted, because it is currently not possible to accurately determine the
Part III Chapter 11

individual T/N ratio prior to treatment. If the scout dose distribution truly reflects
the posttreatment distribution, a minimal effective tumor dose can be targeted,
while respecting a maximal tolerable healthy liver dose. Consequently, patients
with a favorable T/N ratio on scout dose imaging may be treated more aggressively
to enhance treatment efficacy, while a more careful approach could be selected for
patients with an unfavorable T/N ratio to minimize toxicity.
Clinical studies on the use of the ARC have mainly focused on its anti-reflux
characteristics, which obviates the need to coil embolize gastrointestinal
branches during treatment workup, enabling a simpler and less time-consuming
workflow.15,36-37 In another study, it has been shown that the deployment of the
ARC tip decreases blood pressure in the down-stream vascular compartment, but
the consequences of this phenomenon remain uncertain.38 Pasciak et al. recently
performed the first clinical study in which down-stream particle distribution
was compared between ARC and SMC administrations, using a within-patient
controlled study design. This study suggested that the use of the ARC improves
selective tumor targeting, with healthy liver uptake decreasing by 24 – 89 %
and tumor uptake increasing by 33 – 90 %.39 These results should, however, be
interpreted with caution since 99mTc-MAA was used to compare the intrahepatic
particle distribution, instead of therapeutic 90Y microspheres.
- 213 -
Disadvantages of the ARC include a more complex catheterization compared with

the SMC, and the risk of vasospasm after deployment of the catheter tip. Therefore,
interventional radiologists should familiarize themselves with the special technique
that is required for its use. A vasoactive drug such as nitroglycerine can be used to
prevent or remedy vasospasm.37
The controlled environment of the experimental model enabled us to enhance our
understanding of the interplay between catheter design/positioning, injection force,
and fluid-particle dynamics through observation and quantitative experiments.
Clinical hemodynamics were replicated as closely as possible by using pulsatile flow
with a flow rate, pressure profile and fluid viscosity based on previously published
in vivo measurements, in a 3D printed vascular branching model. Nevertheless, it
is impossible to match the complexity of clinical reality. Clear differences include a
more complex three-dimensional geometry of the hepatic arterial vasculature, the
presence of multiple tumors that affect blood flow, the elasticity and responsiveness
of arterial blood vessels, and the potential occurrence of blood flow stasis during
administration of microspheres. Some of these factors, such as preferential tumor
vascularization, may potentially reduce the catheter-related differences that were
observed. However, considering the fact that evident differences were observed
in a model with a relatively simple geometry that should facilitate a homogenous
Chapter 11 Part III
down-stream branch distribution, we expect other factors to exaggerate these

differences in clinical practice.
We have initiated a clinical trial to validate the findings of this study in vivo,
and determine the catheter-related effects on patient outcome (clinical trials.gov
identifier: NCT02208804). In short, we will perform a phase II trial in 25 patients
with irresectable, chemorefractory, and liver-dominant colorectal liver metastases.
All patients will receive a pretreatment procedure during which a scout dose of
166
Ho microspheres will be administered, followed by a therapeutic procedure on
the same day. The effects of both catheter types will be compared within subjects,
by randomly allocating the ARC to the administrations in the left or right hepatic
artery, and using the SMC on the other side. This approach is justified, since the
left and right hemi-livers are functionally independent, and treatment effects are
limited to those areas. The primary endpoint is the T/N ratio of the radioactivity
concentration on posttreatment SPECT. Secondary endpoints include absorbed
tumor dose and healthy liver tissue dose, tumor response, the predictive value of
the scout dose distribution, infusion efficiency, dose-response relationship, clinical
toxicity and overall survival. The sample size is based on an expected factor 1.25-
fold difference in T/N ratio (deemed clinically relevant): a median T/N ratio 2.0 for
the ARC administrations versus 1.6 for the SMC administrations.
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CONCLUSIONS
Using an ARC during microsphere administrations in a surrogate hepatic arterial
model was associated with a favorable particle outflow pattern, a fixed centro-
luminal catheter position, and a significantly more homogeneous downstream
branch distribution, compared with the use of a SMC. These effects may have
important implications for liver tumor treatments with radioembolization, which
will be subject of investigation in a within-patient randomized controlled trial.
Part III Chapter 11
- 215 -
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Outcomes in biliary malignancy. J Surg 12. Smits MLJ, Elschot M, van den Bosch
Oncol 110:585–591. MAAJ, et al. (2013) In vivo dosimetry
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3. Siriwardena AK, Mason JM, Mullamitha
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Ho-microspheres for treatment of liver
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18. Hübner GH, Steudel N, Kleber G, et 26. van den Hoven AF, Smits MLJ, de Keizer
al. (2000) Hepatic arterial blood flow B, et al. (2014) Identifying aberrant
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Hepatol 32:893–899. Radiol 37:1482-1493.
19. Hirata M, Akbar SMF, Horiike N, Onji M 27. Salem R, Lewandowski RJ, Sato KT,
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29. Ahmadzadehfar H, Sabet A, Biermann
21. Lowe GD, Fowkes FG, Dawes J, et al. (1993) K, et al. (2010) The significance of 99mTc-
Blood viscosity, fibrinogen, and activation MAA SPECT/CT liver perfusion imaging
of coagulation and leukocytes in peripheral in treatment planning for 90Y-microsphere
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30. Wondergem M, Smits MLJ, Elschot M,
22. Ku DN (1997) Blood flow in arteries. Annu et al. (2013) 99mTc-macroaggregated
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23. Kennedy AS, Kleinstreuer C, Basciano CA,
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Dezarn WA (2010) Computer modeling of
54:1294–1301.
yttrium-90-microsphere transport in the
hepatic arterial tree to improve clinical 31. Dhabuwala A, Lamerton P, Stubbs RS (2005)
outcomes. Int J Radiat Oncol Biol Phys Relationship of 99mtechnetium labelled
76:631–637. macroaggregated albumin (99mTc-MAA)
uptake by colorectal liver metastases to
24. A. Basciano C, Kleinstreuer C, S. Kennedy
response following selective internal radiation
A (2011) Computational fluid dynamics
therapy (SIRT). BMC Nucl Med 5:7.
modeling of 90Y microspheres in human
hepatic tumors. J Nucl Med Radiat Ther 32. Ulrich G, Dudeck O, Furth C, et al. (2013)
01:2–7. Predictive value of intratumoral 99mTc-
macroaggregated albumin uptake in
25. Richards AL, Kleinstreuer C, Kennedy AS,
patients with colorectal liver metastases
et al. (2012) Experimental microsphere
scheduled for radioembolization with
targeting in a representative hepatic artery 90
Y-microspheres. J Nucl Med 54:516–522.
system. IEEE Trans Biomed Eng 59:198–
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33. Van de Wiele C, Maes A, Brugman E, 37. Fischman AM, Ward TJ, Patel RS, et al.
et al. (2012) SIRT of liver metastases: (2014) Prospective, randomized study
Physiological and pathophysiological of coil embolization versus surefire
considerations. Eur J Nucl Med Mol infusion system during yttrium-90
Imaging 39:1646–1655. radioembolization with resin microspheres.
J Vasc Interv Radiol 25:1709-1716.
34. van den Hoven AF, Smits MLJ, Rosenbaum
CENM, et al. (2014) The effect of intra- 38. Rose SC, Kikolski SG, Chomas JE (2013)
arterial angiotensin II on the hepatic Downstream hepatic arterial blood
tumor to non-tumor blood flow ratio for pressure changes caused by deployment
radioembolization: A systematic review. of the surefire antireflux expandable tip.
PLoS One 9:e86394. Cardiovasc Intervent Radiol 36:1262–1269.
35. Smits MLJ, Nijsen JFW, van den Bosch 39. Pasciak AS, Mcelmurray JH, Bourgeois
MAAJ, et al. (2012) Holmium-166 AC, et al. (2015) The impact of an
radioembolisation in patients with antireflux catheter on target volume
unresectable, chemorefractory liver particulate distribution in liver-directed
metastases (HEPAR trial): A phase 1, dose- embolotherapy : A pilot study. J Vasc Interv
escalation study. Lancet Oncol 13:1025– Radiol 26:660-669.
1034.
36. Morshedi MM, Bauman M, Rose SC,

Kikolski SG (2015) Yttrium-90 resin
microsphere radioembolization using
Chapter 11 Part III
an antireflux catheter: An alternative to

traditional coil embolization for nontarget
protection. Cardiovasc Intervent Radiol
38:381-388.
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SUPPLEMENT
Movie S1: Catheter-related particle flow dynamics: SMC versus ARC. This video fragment shows a part
(first 35 s) of the fluorescent microsphere administration with the SMC (left side) and ARC (right side)
in the third experiment. [Available online at: http://jeccr.biomedcentral.com]
Part III Chapter 11
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C hap ter
PART III12
Study protocol of the surefire
infusion system versus standard
microcatheter use during
holmium-166 radioembolization
(SIM) trial – A within-patient RCT
A.F. van den Hoven

J.F. Prince
R.C.G. Bruijnen
H.M. Verkooijen
G.C. Krijger
M.G.E.H. Lam
Submitted
Study protocol of the SIM trial
ABSTRACT
Background
An anti-reflux catheter (ARC) may increase the tumor absorbed dose during
radioembolization by elimination of particle reflux and its effects on hemodynamics.
Since the catheter is fixed in a centro-luminal position, it may also increase the
predictive accuracy of a scout dose administration before treatment. The purpose
of the SIM trial is to compare the effects of ARC use during radioembolization with
holmium-166 (166Ho) microspheres in patients with colorectal liver metastases
(CRLM), with the use of a standard end-hole microcatheter.
Methods/Design
A within-patient randomized controlled trial (RCT) will be conducted in 25
patients with unresectable chemorefractory liver-dominant CRLM. Study
participants will undergo a 166Ho-scout dose procedure in the morning, and
a therapeutic procedure in the afternoon. The ARC will be randomly allocated
to the left/right hepatic artery, and a standard microcatheter will be used in the
contralateral artery. SPECT/CT imaging will be performed for quantitative
analyses of the microsphere distribution directly after the scout and treatment
procedure. Baseline and follow-up investigations include 18F-FDG-PET + liver
CT, clinical and laboratory examinations. The primary endpoint is the comparison
of tumor to non-tumor (T/N) activity ratio in both groups. Secondary endpoints
include comparisons of mean absorbed dose in tumors and healthy liver tissue,
infusion efficiency, the predictive value of 166Ho-scout dose for tumor response. In
Chapter 12 Part III
the entire cohort, a dose-response relationship, clinical toxicity and overall survival
will be assessed. The sample was determined for the expectation that the ARC will
increase the T/N ratio by 25 % (mean T/N ratio 2.0 vs. 1.6).
Discussion
The SIM trial is a within-patient RCT that will assess whether Ho
166
radioembolization treatment can be optimized by using an ARC.

Trial Registration
The SIM trial is registered at clinicaltrials.gov (NCT02208804).
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INTRODUCTION
Hepatic radioembolization (RE) has evolved to a standard-of-care therapy for
patients with irresectable and chemorefractory colorectal cancer liver metastases
(CRLM). During this treatment, radioactive microspheres are injected in the
hepatic arteries to irradiate liver tumors from within, leading to local disease
control.1 However, treatment efficacy and predictability of the treatment effect can
still be optimized, since the radiation dose to individual tumors is often inadequate
and this cannot be predicted beforehand due to the lack of a reliable surrogate
particle (scout dose) for routinely used yttrium-90 (90Y) microspheres.2
Holmium-166 (166Ho) microspheres have been developed and clinically validated as
a new microsphere for radioembolization.3 Besides β-radiation these microspheres
also emit low-energy γ-radiation and have paramagnetic characteristics, allowing
for visualization and quantitative assessment of the microsphere distribution on
SPECT and MRI.4 Furthermore, identical 166Ho microspheres can be administered
as a scout dose to predict the distribution of the therapeutic microspheres.3,5
Another promising development is the availability of an anti-reflux catheter (ARC,
Surefire Infusion System, Surefire Medical Inc., Westminster, Colorado, USA),
aiming to increase the infusion efficiency and safety, by prevention of reflux.6-8 The
effects on hemodynamics induced by this catheter may improve the microsphere
uptake ratio between tumorous and non-tumorous liver tissue (T/N ratio). The
expanded catheter tip decreases blood pressure down-stream of the tip, which is
believed to lower the resistance that injected microspheres need to overcome in
Part III Chapter 12

order to reach the tumor vasculature.9 Furthermore, the catheter tip converts blood
flow from a laminar into a turbulent pattern, which reduces the chance of missing a
target branch by proper mixing of the microspheres in the vascular compartment.
In addition, the catheter is fixed into a centro-luminal catheter position during
infusion which may further increase the accuracy of the 166Ho-scout dose as a
predictor for the therapeutic 166Ho microspheres distribution.2
In this paper, we describe the study protocol of a prospective, comparative,
clinical trial with the aim to investigate whether the ARC can be used to improve
tumor targeting as well as the predictability of the treatment effect during 166Ho-
radioembolization.
METHODS
Hypothesis
We hypothesize that the use of the ARC increases the posttreatment T/N activity
ratio and improves the predictive value of 166Ho-scout dose distribution, in
comparison with the use of a SMC.
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Study design
The SIM trial is a single-center, open-label, phase II, within-patient randomized
controlled trial (RCT). The medical ethics committee of the University Medical
Center Utrecht has approved the trial, and its conduct is in compliance with
the Helsinki declaration. It is has been registered at clinicaltrials.gov before
commencement (NCT02208804).
As opposed to a conventional RCT design, patients act as their own controls; liver
lobes (right versus left lobe) are the experimental units in this study. Patients with
bilateral, irresectable, chemorefractory, liver-dominant CRLM will undergo two
sequential procedures on the same day, during which a scout-dose and a therapy
dose of 166Ho microspheres will be administered in the left and right hepatic artery.
These separate injections can be regarded as two separate treatments of functionally
independent liver lobes. The use of the ARC will be randomly allocated (1:1) to the
left or right functional liver lobe and a standard microcatheter (SMC) will be used
in the contralateral side. The same catheter type will be used on the same side
during the scout and therapy procedures.
Study population
All patients with irresectable, chemorefractory, and liver-dominant CRLM are
eligible for participation in this trial if they meet the following inclusion criteria:
histopathologically confirmed diagnosis of adenocarcinoma of the colon or rectum,
hepatic metastases with measurable morphological appearance (≥ 1 cm) on cross
Chapter 12 Part III
sectional imaging located in both the right and left hepatic arterial perfusion
territory, irresectable and liver-dominant disease (i.e. pathological locoregional
lymph nodes and up to 5 lung lesions < 1 cm are accepted), progressive disease after
standard second line systemic treatment or no further systemic treatment options
due to severe side effects or unwillingness of the patient, age ≥ 18 years. Adequate
follow-up must be expected and written informed consent must be obtained before
enrolment in the study.
Exclusion criteria are: world health organization (WHO) performance score > 2,
inadequate bone marrow function (hemoglobin < 6.0 mmol/l, leukocyte count
< 3.0 x 109/l, platelet count < 75 x 109/l), inadequate liver function (bilirubin >
35 µmol/l, aspartate aminotransferase / alanine aminotransferase > 5 x upper
limit of normal) or inadequate renal function (creatinine > 1.5 x upper limit of
normal), prior hemihepatectomy, compromised biliary system (biliary stent
or hepaticojejunostomy), Child Pugh score B7 or worse, active hepatitis B or
C, main portal vein thrombosis or previous portal vein embolization, severe
celiac axis stenosis, unsuitable hepatic arterial anatomy, treatment with systemic
- 224 -
chemotherapy within four weeks prior to radioembolization, previous participation

in a study classified as class III by a radiation safety committee, bleeding diathesis,
pregnancy or breast feeding, or any condition that prevents from safe treatment
with radioembolization.
Investigations and Interventions
The flowchart in Figure 1 shows how the investigations and interventions in the
SIM trial compare to standard radioembolization practice with 90Y microspheres.
SIM Trial Conventional 90Y-RE
Clinical & laboratory

Pretreatment investigations + imaging
Eligible patients
Randomization catheter type

SIS/SMC => LHA/RHA
Administration of Administration of
166
Ho scout dose 99m
Tc-MAA
Scout procedure
Part III Chapter 12

SPECT/CT SPECT/CT
Successfull
scout procedure
Same day 1-2 weeks later
Administration of Administration of
Ho therapy dose
166 90
Y therapy dose
Treatment
SPECT/CT PET/CT
Clinical & laboratory

Posttreatment
investigations + imaging
Figure 1: Flowchart of the investigations and interventions in the SIM trial. The study procedures
are compared to standard radioembolization practice with 90Y microspheres (90Y-RE). Note that
in the SIM trial, the same particle is used during the scout and therapy procedure, and patients
receive all procedures on the same day.
- 225 -
arterial anatomy, treatment with systemic chemotherapy within four weeks prior to
radioembolization, previous participation in a study classified as class III by a radiation safety
Andor F. van den Hoven 2
committee, bleeding diathesis, pregnancy or breast feeding, or any condition that prevents from
Verwijderd: RE
safe treatment with radioembolization.

Verwijderd: RE
Investigations and Interventions
The flowchart in Figure 1 shows how the investigations and interventions in the SIM trial
Baseline investigations
compare to standard radioembolization practice with 90Y microspheres.
Patients

will first undergo pretreatment investigations as part of our routine
radioembolization
Baseline investigations workup:
whole-body 18F-FDG-PET/CT to rule out extensive
extrahepatic metastases; dual-phase (arterial + portal phase) liver CT to rule out
Patients will first undergo pretreatment investigations as part of our routine radioembolization
other contraindications for radioembolization, localize the liver tumors and assess
workup: whole-‐body 18F-‐FDG-‐PET/CT to rule out extensive extrahepatic metastases; dual-‐phase
Verwijderd: RE
the(arterial
hepatic + arterial anatomy;
portal phase) laboratory
liver CT investigations
to rule out and physical
other contraindications examination to
for radioembolization,
assess vital functions and general condition of the patient.
localize the liver tumors and assess the hepatic arterial anatomy; laboratory investigations and
Verwijderd: RE
physical examination
Treatment planning to assess vital functions and general condition of the patient.

Eligible patients will be asked to provide informed consent to participate in the study.
Treatment
Next, the interventional planning radiologist and nuclear medicine physician will make an
individualized treatment plan (incl. identification of the target vessels for selective
Eligible patients will be asked to provide informed consent to participate in the study. Next, the
infusion, identification of extrahepatic branches and determining the need for coil
interventional radiologist and nuclear medicine physician will make an individualized treatment
embolization), based on the anatomy of the hepatic arterial vasculature visualized

plan (incl. identification of the target vessels for selective infusion, identification of extrahepatic
onbranches and determining the need for coil embolization), based on the anatomy of the hepatic
pretreatment CT images. In all procedures, two selective injection positions (in
thearterial
left and vasculature visualized on pretreatment CT images. In all procedures, two selective
right hepatic artery) will be used to treat the whole liver on the same
injection positions (in the left and right hepatic artery) will be used to treat the whole liver on the
day. In patients with a variant hepatic arterial configuration, intrahepatic arterial
same day. In patients with a variant hepatic arterial configuration, intrahepatic arterial branches
branches (for example the segment 4 artery) may be coil embolized to induce
(for example the segment 4 artery) may be coil embolized to induce redistribution of blood flow
redistribution of blood flow through intrahepatic collaterals, and enable the use of
through intrahepatic collaterals, and enable the use of two selective injection positions.
two selective injection positions.
The total amount of 166Ho activity (AHo166) required to deliver a whole liver absorbed dose of 60
The total amount of 166Ho activity (AHo166) required to deliver a whole liver absorbed
Gy – the maximum tolerable radiation dose previously determined in a phase I dose-‐escalation
dose of 60 Gy – the maximum tolerable radiation dose previously determined in a
study – is calculated using the formula:
phase I dose-escalation study – is calculated using the formula:
Chapter 12 Part III

60 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺
𝐴𝐴𝐴𝐴!"!"" 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 = 𝑥𝑥𝑥𝑥 𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡𝑡𝑡 (𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾)
15.87 𝑥𝑥𝑥𝑥 10!! 𝐽𝐽𝐽𝐽 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀

Liver
Liver weight
weight (in (in
Kg) iKg) is determined
s determined by multiplying bythe multiplying
volume of the the
liver (volume of bthe
measurement ased liver
on
(measurement based
CT) with the density of lon
iver CT)
tissue with
(1.06 theg/cm density
3). The sof liver
cout tissuea(1.06
procedure lways cg/cm
onsist ).
3
of The scout
250 M Bq
procedure
in 60 mg of always consist
microspheres of 250
(density 1.4 gMBq
/cm3), tinhis 60 mgis ofsubtracted
activity microspheres from the (density 1.4in g/
activity given
cmthe
3
), treatment
this activity is subtracted from the activity given in the treatment
procedure. The treatment activity for each perfusion territory is fractionated procedure.
The treatment
based activity
on its liver volume. for each
If coil perfusion
embolization of aterritory is fractionated
n intrahepatic based
branch is planned, the on its liver
volume of
volume. If coil
its perfusion embolization
territory is included of in an
the intrahepatic branchto istake
side that is anticipated planned,
over the the volume
blood supply. of its
perfusion territory is included in the side that is anticipated to take over the blood
supply.
Scout and therapy procedures
All patients will be admitted to hospital (University Medical Center Utrecht, The
Netherlands) and will undergo a 166Ho-scout procedure the next morning, followed
by the 166Ho-therapeutic procedure in the afternoon when the scout procedure was
performed successfully.
- 226 -
During the 166Ho-scout procedure, digital subtraction angiography (DSA) and

C-arm CT imaging will be performed to confirm adequacy of the intended injection
position(s), and rule out potential extrahepatic shunting. Coil embolization of
side-branches will only be performed when inevitable to warrant safe treatment.
Nitroglycerine 200 μg is given per intra-arterial catheter to prevent vasospasm.
Ultimately, a scout dose (250 MBq) of 166Ho microspheres will be administered
through the anti-reflux catheter (ARC) and the SMC in the target vessels.
Next, a SPECT scan combined with a portal venous phase liver CT will be acquired
and evaluated to rule out extrahepatic deposition of 166Ho microspheres, assess the
intrahepatic biodistribution, as well as the liver-to-lung shunt. In the absence of
extrahepatic deposition and a significant liver-to-lung shunt, patients will undergo
the therapeutic procedure in the afternoon. In the case of an unsuccessful scout
procedure, the patient will be planned for a repeat procedure if possible.
During the therapeutic procedure, the calculated treatment activity of 166Ho
microspheres will be administered in the same position(s) as during the scout
procedure. Patients are discharged the day after treatment. The posttreatment
SPECT (combined with a dual-phase liver CT) is obtained approximately five days
after treatment to reduce the influence of detector dead time.
Follow-up investigations
A telephonic consultation will be scheduled at two weeks after treatment to
evaluate the patient’s general condition, and ask for the occurrence of adverse
events. One month after treatment, patients will undergo physical examination
Part III Chapter 12

and laboratory investigations for toxicity assessment. At three months follow-up,
this is complemented by a whole-body 18F-FDG-PET + dual-phase liver CT for
tumor response assessment, after which the study follow-up is completed.
Study objectives
The primary objective is to assess the difference in posttreatment T/N activity ratio
on SPECT/CT between administration with the ARC and SMC.
Secondary objectives include comparison of the following endpoints between
administrations with the ARC and SMC: mean tumor and healthy liver absorbed
dose on SPECT/CT, percentage of calculated treatment activity administered
(infusion efficiency), predictive value of the 166Ho-scout dose distribution, and
posttreatment tumor response. Furthermore, the presence of a dose-response
relation between tumor absorbed dose and posttreatment tumor response will be
evaluated.
- 227 -
Outcome assessment
In every target vessel’s perfusion territory, the absorbed dose on 166Ho-SPECT
reconstructions will be determined for the metastases and the healthy liver tissue.4
Consequently, a posttreatment T/N activity ratio will be calculated for each
perfusion territory by dividing the number of counts in tumorous and healthy liver
tissue.
The predictive value of the scout dose will be assessed by comparison of the
distribution of the scout dose with the treatment dose. The analysis will be based
on tumor and healthy liver absorbed doses on SPECT/CT analysis.
Infusion efficiency is defined as the percentage of the prepared treatment activity
that is infused. The 166Ho activity that is not infused will be determined by measuring
the administration system (vial, lines and catheters) with a dose calibrator.
Response analysis will be performed in accordance with the Response Evaluation
Criteria in Solid Tumors (RECIST) version 1.110, for each functional liver lobe
separately. Disease control rates (percentage of liver lobes with complete response,
partial response or stable disease) will be determined by CT evaluation at three
months posttreatment. Metabolic tumor response will be determined by assessing
the change (relative to baseline) in total lesion glycolysis values on 18F-FDG-
PET imaging. During the response assessment, observers will be blinded for the
catheter type used.
The relationship between tumor absorbed dose on SPECT/CT, and tumor response
on both CT and 18F-FDG-PET will be characterized on the level of perfusion
Chapter 12 Part III
territories.
Common Terminology Criteria for Adverse Events v 4.03 will be used to describe
laboratory and clinical toxicity for the entire cohort, with specific attention for
device-related adverse events per catheter type such as the occurrence of reflux,
vasospasm or arterial dissections.
The municipal administration will be consulted to assess the overall survival,
measured from treatment onwards.
Statistical considerations
Sample size calculation
A subgroup analysis of the T/N activity ratios in seven patients with CRLM,
previously treated with 166Ho-radioembolization using a SMC3, showed a mean
T/N ratio of 1.6 (standard deviation 0.57). Sample size calculation, based on a
2-sided paired t-test for the comparison of T/N activity concentration ratios at
an alpha-level of 0.05 and power of 0.90, showed that at least 23 patients need to
be included to detect a difference of 0.4 in mean T/N ratios (with an estimated
- 228 -
standard deviation 0.57) in the ARC arm (estimated mean T/N ratio 2.0) and
SMC arm (estimated mean T/N ratio 1.6). This corresponds to a 25 % increase
(considered clinically relevant) in favor of the ARC arm. A rounded number of
25 patients will therefore be treated in this trial. Sample size calculations were
performed with the computer program ‘PS: Power and Sample Size Calculation’
version 3.0 for MacOsX.
Randomization
A computer generated stratified permuted block randomization with varying
block sizes will be used. Difference in tumor burden (< 10 % or ≥ 10 %) between
the two target volumes in the liver will be used as stratification factor to eliminate
the potential influence of tumor burden on the comparison of T/N activity ratios
between catheter types.
A comparison of continuous outcome measures between ARC and SMC infusions,
such as the mean T/N activity concentration and mean decrease in total lesion
glycolysis at three months posttreatment, will be performed by means of a paired
t-test. Categorical outcome measures, such as infusion efficiency and disease
control rates at three months posttreatment, will be compared with a McNemar’s
test. The value of the 166Ho-scout dose distribution will be assessed per catheter
type. Correlation and agreement with the 166Ho-therapy dose distribution will be
evaluated with a linear regression analysis (R2) and Bland-Altman analysis (limits
Part III Chapter 12

of agreement) respectively. The dose-response relationship will be evaluated by
linear regression analysis. Survival analysis by the Kaplan Meier method will be
used to estimate the median overall survival time for the entire cohort.
A two-sided p value < 0.05 will be considered statistically significant.
DISCUSSION
In patients with advanced colorectal cancer, liver metastases are the primary cause
of morbidity and mortality. Unfortunately, only a minority of patients is a candidate
for surgical resection with curative intent. Patients with irresectable disease will
first receive palliative systemic therapy. Though, despite major advances in systemic
treatment, the 5-year overall survival rate remains below 10 %.11
Current standard of care in the systemic treatment of metastatic colorectal cancer is
based on cytotoxic fluoropyrimidines, oxaliplatin and irinotecan, as well as targeted
therapy with the VEGF-targeted monoclonal antibody bevacizumab.12-16 There is
no clear preference for sequential exposure to these drugs during consecutive lines
of treatment or upfront combination therapy.17,18 When disease progression or
- 229 -
intolerable toxicity occurs during first line treatment, patients will subsequently
receive another regimen as second line treatment, with the choice of the regimen
depending on the first chemotherapeutic agents. In the Netherlands, the first line
regimen of choice is CAPOX-B (capecitabine, oxaliplatin and bevacizumab). When
disease progression occurs during this oxaliplatin-based therapy, an irinotecan-
based regimen, e.g. FOLFIRI (leucovorin, 5-FU and irinotecan) or irinotecan
monotherapy, is indicated as second line therapy. Patients with a RAS wild-type
tumor may benefit from additional (third line) treatment with an EGFR-targeted
monoclonal antibody (panitumumab or cetuximab).
Liver directed therapy such as radioembolization is increasingly applied as an
alternative to achieve local disease control, which positively affects overall survival.
Currently, two types of 90Y microspheres are used in worldwide clinical practice:
resin (SIR-Spheres, SIRTeX, Lane Cove, Australia) and glass (TheraSphere; BTG,
Ottawa, Ontario, Canada) 90Y microspheres. In salvage patients with colorectal
liver metastases, who have no regular treatment options left and an average life
expectancy of less than six months, median overall survival after radioembolization
treatment with 90Y microspheres is around 12 months when given as monotherapy
or in combination with chemotherapy.1 Besides, treatment is generally well
tolerated, with typical clinical toxicity being limited to mild symptoms of fatigue,
abdominal pain, nausea, vomiting and/or fever during the first two weeks after
treatment.19
Despite these benefits of radioembolization, there is still room for improvement.
Chapter 12 Part III
Unintentional deposition of radioactive microspheres in other tissues than the

liver may cause serious treatment complications. Therefore, a safety procedure
is performed in the week(s) before the actual treatment. During this procedure,
coil embolization of extrahepatic branches may be performed and a strategic
catheter position is chosen before administering a (harmless) scout dose of
technetium-99m-labelled macro-aggregated albumin (99mTc-MAA). Afterwards,
SPECT/CT and planar nuclear scintigraphy are obtained to exclude the presence
of extrahepatic activity and significant liver-to-lung shunting. The treatment
procedure is typically performed 1 – 2 weeks later, with the administration of 90Y
microspheres from identical catheter positions, followed by posttreatment imaging
with bremsstrahlung SPECT/CT or 90Y-PET/CT.20
As a second topic of possible improvement, the intrahepatic distribution of
therapeutic 90Y microspheres cannot be accurately predicted in advance. The
scout dose of 99mTc-MAA particles differs markedly in embolic effect, size, weight,
and number of particles infused21, and therefore fails to predict the intrahepatic
- 230 -
distribution of 90Y microspheres in most cases.22-24 Besides, imaging of the 90Y

microspheres biodistribution itself is already a challenge due to the lack of
γ-radiation emission. Traditionally, bremsstrahlung SPECT/CT has been used
for posttreatment imaging, but it suffers from a low spatial resolution. Internal-
pair production based 90Y-PET/CT has become available as an alternative for
quantitative imaging, but the low count rate and inherent noise limit its applicability
in daily clinical care.25-27
Third, it is generally assumed that the preferential arterial vascularization of liver
tumors will lead to a selective targeting of tumorous tissue following intra-arterial
infusion of radioactive microspheres. It is known from pathological examinations
of livers treated with 90Y-radioembolization, that radioactive microspheres
cluster preferentially within the peripheral tumor vasculature. The concentration
of microspheres can be up to 200 times greater in the tumor periphery than in
the tumor center and the healthy liver tissue.28 Various studies have investigated
dose-response relationships in radioembolization. The majority of these studies
found strong associations between T/N ratios, absorbed radiation doses,
tumor response and overall survival.23,29-35 Yet, the degree of tumor targeting, as
expressed by the T/N microsphere uptake ratio, shows marked inter-individual
variability in practice, with a reported range of 0.6 – 25.9.36 This heterogeneity
in T/N uptake ratios is likely a result of various factors, including differences in
tumor angiogenesis, microsphere characteristics, catheter position, and flow-
bound distribution physics.21.29 A recent investigation demonstrated that up to
Part III Chapter 12

60 % of patients with liver metastases treated with 166Ho-radioembolization had
at least one tumor that received less than or an equal amount of radioactivity as
compared to the surrounding healthy liver tissue (T/N ≤ 1).4 Flamen et al., also
reported similar findings, with 38 % of the metastatic liver lesions in their study
having an unfavorable T/N uptake ratio (< 1) after radioembolization with 90Y
microspheres.35 Since unfavorable T/N uptake ratios cannot be predicted and only
become apparent after treatment, timely adjustments in treatment technique are
not yet feasible.
The highly variable tumor targeting is an important clinical problem that may at
least explain some of the inconsistencies in reported tumor response rates after
radioembolization.1,37 Considering the reported dose-response relationship, it
can be expected that improved T/N ratios will positively affect tumor response
after radioembolization. It may also reduce hepatotoxicity, since healthy liver
tissue absorbed dose has previously been correlated to biochemical toxicity.33
Improvement of T/N ratios is especially important in CRLM, since metastases
- 231 -
from this tumor type are relatively hypovascular compared with other tumor types
(such as neuroendocrine tumors or uvea melanoma), and generally exhibit low
T/N ratios.
The above outlined shortcomings of current radioembolization practice are being
addressed in the SIM trial, for which trial accrual has started as of November
2014. The distinctive imaging capacities and availability of an identical scout dose
of 166Ho microspheres, combined with the promising effects on particle-fluid
dynamics facilitated by the ARC, may result in an optimized treatment technique
of radioembolization in patients with CRLM.
Chapter 12 Part III
- 232 -
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2. van den Hoven AF, Lam MGEH, Jernigan S,
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3. Smits MLJ, Nijsen JFW, van den Bosch
MAAJ, et al. (2012) Holmium-166 10. Eisenhauer EA, Therasse P, Bogaerts J, et al.
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5. Prince JF, van Rooij R, Bol GH, et al.
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(2015) Safety of a scout dose preceding
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14. Saltz LB (2008) Second- and third-
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D, Hong K (2013) Quantification and
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7. van den Hoven AF, Prince JF, Samim
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17. Koopman M, Antonini NF, Douma J, et 24. Wondergem M, Smits MLJ, Elschot M, et
al. (2007) Sequential versus combination al. (2013) 99mTc-macroaggregated albumin
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colorectal cancer (CAIRO): A phase radioembolization. J Nucl Med 54:1294–1301.
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(2013) Assessment of acquisition protocols
18. Seymour MT, Maughan TS, Ledermann for routine imaging of Y-90 using PET/CT.
JA, et al. (2007) Different strategies of EJNMMI Res 3:11.
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26. Kao YH, Steinberg JD, Tay YS, et al. (2013)
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27. Elschot M, Vermolen BJ, Lam MGEH, et al.
19. Smits MLJ, van den Hoven AF, Rosenbaum
(2013) Quantitative comparison of PET and
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21. Van de Wiele C, Maes A, Brugman E,
29. Gulec SA, Mesoloras G, Dezarn WA,
et al. (2012) SIRT of liver metastases:
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22. Dhabuwala A, Lamerton P, Stubbs RS (2005) function of tumor to liver flow ratio. J
Relationship of 99mtechnetium labelled Transl Med 5:15.
macroaggregated albumin (99mTc-MAA)
30. Lau WY, Leung WT, Ho S, et al. (1994)
uptake by colorectal liver metastases to
Treatment of inoperable hepatocellular
response following selective internal radiation
carcinoma with intrahepatic arterial
therapy (SIRT). BMC Nucl Med 5:7.
yttrium-90 microspheres: A phase I and II
23. Ulrich G, Dudeck O, Furth C, et al. (2013) study. Br J Cancer 70:994–999.
Predictive value of intratumoral 99mTc-
31. Walrand S, Lhommel R, Goffette P, et al.
macroaggregated albumin uptake in
(2012) Hemoglobin level significantly
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impacts the tumor cell survival fraction
scheduled for radioembolization with
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32. Garin E, Lenoir L, Rolland Y, et al. 35. Flamen P, Vanderlinden B, Delatte P,

(2012) Dosimetry based on 99mTc- et al. (2008) Multimodality imaging
macroaggregated albumin SPECT/CT can predict the metabolic response of
accurately predicts tumor response and unresectable colorectal liver metastases to
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patients treated with 90Y-loaded glass labeled resin microspheres. Phys Med Biol
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33. Lam MGEH, Goris ML, Iagaru AH, CENM, et al. (2014) The effect of intra-
et al. (2013) Prognostic utility of 90Y arterial angiotensin II on the hepatic
radioembolization dosimetry based on tumor to non-tumor blood flow ratio for
fusion 99mTc-macroaggregated albumin- radioembolization: A systematic review.
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(2015) Fusion dual-tracer SPECT-based radioembolization for the treatment of liver
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Part III Chapter 12
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PART IV
EVALUATION
OF TREATMENT
TOXICITY AND
EFFICACY
C hap ter
PART IV 13
Clinical and laboratory toxicity
after intra-arterial radioemboli-
zation with 90Y microspheres for
unresectable liver metastases
*MLJ Smits
*A.F. van den Hoven
C.E.N.M. Rosenbaum
B.A. Zonnenberg
M.G.E.H. Lam
J.F.W. Nijsen
M. Koopman
(* Shared first authors)

PLoS ONE 2013
Clinical and laboratory toxicity after intra-arterial radioembolization with 90Y microspheres
ABSTRACT
Objective
To investigate clinical and laboratory toxicity in patients with unresectable liver
metastases, treated with yttrium-90 (90Y) radioembolization.
Methods
Patients with liver metastases treated with 90Y-radioembolization, between
February 1st 2009 and March 31st 2012, were included in this study. Clinical
toxicity assessment was based on the reporting in patient’s charts. Laboratory
investigations at baseline and during a four month follow-up were used to assess
laboratory toxicity according to the Common Terminology Criteria for Adverse
Events version 4.02. The occurrence of grade 3 – 4 laboratory toxicity was stratified
according to treatment strategy (whole liver treatment in one session versus
sequential sessions). Response assessment was performed at the level of target
lesions, whole liver and overall response in accordance with RECIST 1.1 at 3 and
6 months posttreatment. Median time to progression (TTP) and overall survival
were calculated by Kaplan-Meier analysis.
Results
A total of 59 patients, with liver metastases from colorectal cancer (n = 30),
neuroendocrine tumors (NET) (n = 6) and other primary tumors (n = 23) were
included. Clinical toxicity after 90Y-radioembolization treatment was confined to
grade 1 – 2 events, predominantly postembolization symptoms. No grade 3 – 4
clinical toxicity was observed, whereas laboratory toxicity grade 3 – 4 was observed
in 38 % of patients. Whole liver treatment in one session was not associated with
Chapter 13 Part IV
increased laboratory toxicity. Three months disease control rates for target lesions,
whole liver and overall response was 35, 21 and 19 % respectively. Median TTP was
6.2 months for target lesions, 3.3 months for the whole liver and 3.0 months for
overall response. Median overall survival was 8.9 months.
Conclusion
The risk of severe complications or grade 3 – 4 clinical toxicity in patients with liver
metastases of various primary tumors undergoing 90Y-radioembolization is low.
In contrast, laboratory toxicity grade 3 – 4 can be expected to occur in more than
one-third of patients without any clinical signs of radiation-induced liver disease.
- 240 -
INTRODUCTION
Intra-arterial radioembolization with yttrium-90 microspheres
(90Y-radioembolization) is an increasingly applied treatment option for patients with
unresectable primary or secondary hepatic malignancies, refractory to systemic
therapies. The treatment consists of intra-arterial administration of microspheres
tagged with or containing yttrium-90 (90Y), a radioisotope that emits high-energy
beta radiation. In contrast to the normal liver parenchyma, which mainly relies on
the portal vein, intrahepatic malignancies mainly depend on the hepatic artery for
their blood supply.1 As a consequence, these tumors can be selectively targeted by
instillation of 90Y microspheres in the hepatic artery.
There is growing evidence for an overall beneficial effect of 90Y-radioembolization
regarding time to progression, overall survival and quality of life in salvage
patients with either primary or metastatic hepatic malignancies.2-4 The effect of
90
Y-radioembolization in terms of tumor response varies widely, with disease control
rates (complete response + partial response + stable disease) ranging from 56 – 100
%.4 Given the wide variety in tumor response rates, great effort is put into optimal
patient selection through the identification of prognostic factors for a favorable
outcome after 90Y-radioembolization.5-7 Improved selection may increase the efficacy
of this therapy and prevent patients from futile treatment and unnecessary toxicity.
Although minimally invasive, 90Y-radioembolization is not without adverse effects.
Common adverse effects related to 90Y-radioembolization are symptoms of the
postembolization syndrome, comprising fatigue, nausea, vomiting, abdominal pain,
loss of appetite and fever.7-10 In general, these symptoms appear on the day of treatment
and last up to three days after treatment.11 More serious complications can occur
when an excessive radiation dose is applied to non-target tissue. An excessive dose to
Part IV Chapter 13
the healthy liver parenchyma, which can be due to either a high overall administered
activity or an unfavorable tumor to non-tumor activity distribution ratio, can cause
radiation-induced liver disease (RILD). Alternatively, distribution of microspheres
in organs other than the liver could cause serious morbidity and even mortality (e.g.
radiation pneumonitis or gastric ulceration). These severe complications occur in
less than 10 % of patients.12-14
Laboratory toxicity in terms of elevated liver function tests and liver enzymes can be
expected after 90Y-radioembolization. It is important to monitor laboratory toxicity,
because this may be an early indicator for RILD. Relatively little is known, however,
about the normal range of laboratory toxicities following 90Y-radioembolization
in patients who do not develop RILD. The primary objective of this study was to
investigate clinical and laboratory toxicity in patients with liver metastases, treated
with 90Y-radioembolization. Secondary objectives were assessment of tumor response
and overall survival.
- 241 -
Patient selection
Records of all liver metastases patients who were not participating in a clinical
trial and had received a pretreatment angiographic procedure for treatment with
90
Y-radioembolization at our institute between February 1st 2009 and March 31st 2012
were retrospectively analyzed. Patients that were eligible for 90Y-radioembolization
had unresectable liver dominant metastases and had progressive disease under
systemic treatment, or were no longer treated systemically due to contraindications.
The Medical Ethics Committee of the University Medical Center Utrecht waived
the need for informed consent and approved this study.
Procedure
90
Y-radioembolization was carried out over two sessions: a pretreatment diagnostic
angiography and a treatment angiography. Patients were admitted to the hospital
on the evening before angiography. They received 1.5 L per 24h NaCl 0.9 %
intravenously for pre- and posthydration. Pretreatment diagnostic angiography
started with selective visceral catheterization (celiac axis and superior mesenteric
artery) in order to obtain an angiographic map of the patient’s vascular anatomy.
Specific extrahepatic vessels were coil embolized to prevent 90Y microspheres
that were injected into one of the hepatic arteries, to be distributed to visceral
organs other than the liver. Arteries that were actively searched for and embolized
using coils included the gastroduodenal artery, the right gastric artery, and
pancreaticoduodenal vessels and any other relevant arteries depending on the
patient’s specific anatomy. Subsequently, 150 MBq technetium-99m-labelled
Chapter 13 Part IV
macro-albumin aggregates (99mTc-MAA) were injected into the hepatic artery to

simulate the 90Y microspheres distribution. Next, single photon emission computed
tomography (SPECT) and planar nuclear imaging were performed. In order to
assess whether part of the dose was deposited in abdominal organs other than the
liver, the SPECT images were analyzed after fusion with computed tomography
(CT). Planar nuclear imaging was used to calculate the lung shunt fraction; patients
with a lung shunt < 10 % received the full dose of 90Y microspheres, when lung
shunt fraction was between 10 – 15 % or 15 – 20 % the dose of 90Y microspheres
was reduced with 20 % and 40 %, respectively.15 Lung shunt fractions of > 20 %
implied that no treatment could be given. If radioactivity was detected in non-
target organs, such as pancreas, duodenum or stomach, further angiographic
investigation was performed with additional coiling and/or a more distal injection
position of 99mTc-MAA.16 Patients stayed one night in the hospital for observation.
- 242 -
Treatment angiography was performed within two weeks after the pretreatment
angiography. Patients were readmitted to hospital the day before angiography, where
they again received pre- and posthydration. One hour before angiography, patients
received a single intravenous dose of dexamethason (10 mg) and ondansetron (8
mg). The dose of radioactive resin microspheres (SIR-Spheres®, SIRTeX, Lane Cove,
Australia) for each individual patient was calculated according to the body surface
area method provided by the manufacturer.15 The tumor volume and total liver
volume were calculated by volumetric assessment of CT imaging. Subsequently,
the dose of 90Y microspheres was administered with the catheter tip in the hepatic
artery or one of its branches, at the same position as used for the injection of 99mTc-
MAA.
the The
catheter tip total
in the liver weight
hepatic artery o(m
r one o
liver
) f was derivedat from
its branches, CTpvolumetric
the same osition as used measurements
for the injection of
assuming a density of 1 kg/L. liver

99mTc-‐MAA. The total liver weight (m
The net amount of administered radioactivity
) was derived from CT volumetric measurements (Anet)a
assuming
Andor F. van den
density of 1 kg/L. The net amount of administered radioactivity (Anet) (prepared activity minus residual
(prepared activity minus residual activity in administration system and catheter) Verwijderd: -‐
activity in administration system and catheter) was calculated. The whole liver absorbed dose (Dliver),
was calculated. The whole liver absorbed dose (Dliver), assuming a homogeneous Andor F. van den
assuming a homogeneous distribution and full absorption of activity in the liver, was then estimated using Verwijderd: l
distribution and full absorption of activity in the liver, was then estimated using the
the following Medical Internal Radiation Dose (MIRD) committee-‐based formula17:
following Medical Internal Radiation Dose (MIRD) committee-based formula17: Andor F. van den

Verwijderd: [17]
Anet [GBq ]
Dliver [Gy ] = 49.38
mliver [ kg ]

Patients received 90Y-radioembolization as a whole liver treatment in a single
Patients received 90Y-‐radioembolization as a whole liver treatment in a single angiographic procedure
angiographic procedure (i.e., whole liver delivery), whole liver treatment in
(i.e., whole liver delivery), whole liver treatment in two sessions (i.e., sequential delivery) or as treatment
two sessions (i.e., sequential delivery) or as treatment of a single lobe (i.e., lobar
of a single lobe (i.e., lobar treatment). In cases of sequential delivery, the aim was to perform both
treatment). In cases of sequential delivery, the aim was to perform both treatment
treatment sessions within a commonly accepted interval of 30 – 45 days.11 The distribution of 90Y
sessions within
microspheres was a assessed
commonly accepted
with either interval of 30 – SPECT
bremsstrahlung 45 days.or 11 The distribution
90Y-‐positron of
emission
Andor F. van den
Part IV Chapter 13
Verwijderd: [11]
90
Y microspheres was
tomography/computed assessed
tomography with either
(PET/CT). bremsstrahlung
Our institution’s SPECT
radiation safety or Y-positron
90
committee required all
emission
patients tomography/computed
to stay tomography
in the hospital for a minimum of 12 hours a(PET/CT). Our institution’s radiation
fter treatment.
safety committee required all patients to stay in the hospital for a minimum of 12
hours after
Toxicity treatment.
assessment
Posttreatment, patients reported to the outpatient clinics at intervals of approximately four weeks. At
Toxicity assessment
these visits, physical examination and laboratory tests were performed. The following laboratory
Posttreatment, patients reported to the outpatient clinics at intervals of approxi-
investigations were included in our analysis in order to assess laboratory toxicity: total bilirubin, alkaline
mately four weeks. At these visits, physical examination and laboratory tests were
phosphatase (ALP), gamma-‐glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine
performed. The following laboratory investigations were included in our analysis
aminotransferase (ALT), albumin, hemoglobin (Hb) and white blood cell count (leukocytes). Blood
in order
samples, to up
taken assess laboratory
to four toxicity:
weeks prior total bilirubin,
to 90Y-‐administration alkaline
and during phosphatase
a four (ALP),
months follow-‐up were
gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine
used for toxicity analysis. Laboratory toxicity was graded according to the Common Terminology Criteria
aminotransferase (ALT), 18
for Adverse Events (CTCAE) v4.0. albumin, hemoglobin (Hb) and white blood cell count
GGT, AST, ALT and Hb reference values were gender dependent. For
Andor F. van den
(leukocytes).
each Blood
patient, baseline samples,
CTCAE grades taken up to CTCAE
and maximal four weeks grades prior tofollow-‐up
during 90
Y-administration andIn
were determined.
Verwijderd: [18]
duringnaew four
addition, months
toxicity follow-up
or progression were used
of baseline for
toxicity to toxicity
a higher Canalysis.
TCAE grade Laboratory
was grouped toxicity
separately
and will be referred to as “new toxicity“. Patients, in whom data on baseline and/or follow-‐up laboratory
investigations were not available in our center, were excluded from the laboratory toxicity assessment.
The clinical toxicity assessment was based on the reporting of periprocedural complications, treatment-‐
- 243 -
related symptoms (CTCAE grade 1 – 2) and serious adverse events (CTCAE grade 3 – 4), in the patient’s
charts.

was graded according to the Common Terminology Criteria for Adverse Events
(CTCAE) v4.0.18 GGT, AST, ALT and Hb reference values were gender dependent.
For each patient, baseline CTCAE grades and maximal CTCAE grades during
follow-up were determined. In addition, new toxicity or progression of baseline
toxicity to a higher CTCAE grade was grouped separately and will be referred to
as “new toxicity”. Patients, in whom data on baseline and/or follow-up laboratory
investigations were not available in our center, were excluded from the laboratory
toxicity assessment. The clinical toxicity assessment was based on the reporting of
periprocedural complications, treatment-related symptoms (CTCAE grade 1 – 2)
and serious adverse events (CTCAE grade 3 – 4), in the patient’s charts.
Response assessment
Baseline imaging was performed with CT or magnetic resonance imaging (MRI) of
the liver. In addition, patients with (suspected) 18F-fluorodeoxyglucose (18F-FDG)-
avid tumors received 18F-FDG-PET to assess the presence of extrahepatic
metastases. Follow-up imaging was performed with CT or MRI of the liver
(depending on the modality used for baseline imaging) at approximately 1, 3 and
6 months posttreatment. Response assessment was performed in accordance with
the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) on the level of
target lesions (TL), whole liver (including non-target lesions) and overall response
(including non-target lesions and extrahepatic disease) at 3 months (range, 2.0 – 4.5
months) and 6 months (range, 4.5 – 7.5 months) after the first 90Y-radioembolization
procedure.19 Up to five target lesions per patient were identified by an observer
(either MS or CR) and the maximal cross-sectional diameter of each target lesion
was subsequently measured by the other observer. Observers were blinded for the
Chapter 13 Part IV
identity and characteristics of the patient; date of imaging and whether it was a
baseline or follow-up scan. Data on progression of non-target lesions, new liver
lesions and progression of extrahepatic disease were extracted from radiologic
reports. Patients who were lost to follow-up were regarded as having progressive
disease (PD) on the ‘overall response level’ at the time of death. Median time to
progression (TTP) was calculated for all response levels per Kaplan-Meier analysis.
Survival Analysis
Overall survival was defined as the interval between the date of (first)
90
Y-radioembolization treatment and the date of death or most recent contact
(alive). Median overall survival (including corresponding 95 % CI) was calculated
through Kaplan-Meier survival-analysis. Statistical analyses were performed with
SPSS Statistics 20.0 for windows (IBM SPSS, Chicago, IL). All percentages were
rounded to the nearest whole number.
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RESULTS
Patients
Between February 1st 2009 and March 31st 2012, a total of 73 consecutive patients
(excluding patients participating in a prospective clinical trial) with liver metastases
were considered eligible for 90Y-radioembolization treatment at our institute and
received a pretreatment angiographic procedure with 99mTc-MAA. A flowchart
of the study design and patient treatment is presented in Figure 1. Fourteen
patients (19 %) could not be treated with 90Y-radioembolization, due to persistent
extrahepatic deposition (PED) of 99mTc-MAA (n = 11), rapidly progressive disease
(n = 2) and a lung shunt fraction exceeding twenty percent (26 %, n = 1). Fifty-nine
patients received 90Y-radioembolization treatment.
Part IV Chapter 13
Figure 1: Flowchart. Flowchart displaying treatment selection and study design. *11
patients were non-evaluable for the laboratory toxicity assessment. Abbreviations: PED
= persistent extrahepatic deposition; PD = rapidly progressive disease.
Baseline characteristics of these patients are presented in Table 1. The majority

of the patients (30/59, 51 %) had colorectal cancer liver metastases, six patients
(10 %) had neuroendocrine tumor (NET) liver metastases, and 23 patients (39 %)
suffered from liver metastases from various other primary tumors.
- 245 -
Table 1: Baseline characteristics

Baseline Characteristics Value
Mean age (years) 60 ± 12
Gender
Male 32 (54 %)
Female 27 (46 %)
Primary tumor
Colorectal cancer 30 (51 %)
Neuroendocrine cancer 6 (10 %)
Uveal melanoma 6 (10 %)
Breast cancer 5 (9 %)
Esophageal cancer 2 (3 %)
Gallbladder cancer 2 (3 %)
Gastric cancer 1 (2 %)
Pancreatic cancer 1 (2 %)
Nasopharyngeal cancer 1 (2 %)
Extrahepatic cholangiocarcinoma 1 (2 %)
ACUP 2 (3 %)
UCC 1 (2 %)
GIST 1 (2 %)
WHO performance score
WHO = 0 31 (53 %)
WHO = 1 14 (24 %)
WHO ≥ 2 7 (12 %)
Unreported 7 (12 %)
Child-Pugh score
A5 - A6 53 (90 %)
B7 - B8 6 (10 %)
Tumor burden
Chapter 13 Part IV
< 25 % 43 (73 %)
≥ 25 % - < 50 % 11 (19 %)
≥ 50 % 5 (9 %)
Evidence of extrahepatic metastases
Yes 16 (27 %)
No 43 (73 %)
Prior treatment
Systemic treatment 51 (86 %)
Locoregional treatment 50 (85 %)
Salvage versus Non-salvage therapy
Salvage therapy 41 (70 %)
Non-salvage therapy 17 (29 %)
Unreported 1 (2 %)
Values are presented as n (percentage) or mean ± standard deviation. Percentages do not add up to 100
%, due to rounding to the nearest whole number. Salvage therapy = 90Y-radioembolization after all reg-
ular treatment options have been tried. Non-salvage therapy 90Y-radioembolization, when not all treat-
ment options have been tried yet. Abbreviations: ACUP = adenocarcinoma of unknown primary; UCC
= urothelial cell carcinoma; GIST = gastrointestinal stromal tumor; WHO = world health organization.
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Treatment details are presented in Table 2. The majority of the patients received a
whole liver treatment in one session (n = 38, 64 %), with a selective administration
of 90Y microspheres in the left and right hepatic artery (n = 28) or administration
in the proper (n = 9) or common hepatic artery (n = 1). In ten patients, whole
liver treatment was performed selectively in sequential sessions (n = 10, 17 %),
with a median interval of 14 days (range 12 – 77 days) between both treatment
sessions. Eleven patients received unilobar treatment (n = 11, 19 %). The
mean net administered activity was 1473 MBq (standard deviation 447) with
an estimated mean liver-absorbed dose of 42.0 Gy (standard deviation 14.3).
Posttreatment bremsstrahlung scintigraphy or 90Y-PET, revealed no extrahepatic
deposition of radioactivity in any of the patients. Four patients were retreated
with 90Y-radioembolization after disease progression had occurred, with a median
interval of 9 months (range, 5 – 25 months) between the first and second treatment.
Median time of hospital admission was 2 days (range, 1 – 4 days). Fifty-four
patients (92 %) were discharged the day after treatment. The other five patients
required longer hospitalization (one or two days extra), due to comorbidities such
as renal insufficiency, diabetes mellitus or heart failure.
Table 2: Treatment details

Treatment details Value
Initial extrahepatic deposition of 99mTc-MAA 12 (20 %)
Median 99mTc-MAA lung shunt fraction 6 % (0 – 20 %)
Dose reduction required in n patients 3 (5 %)
Part IV Chapter 13
Mean 90Y administered activity (MBq) 1473 ± 447
Mean 90Y liver absorbed dose (Gy) 42.0 ± 14.3
Whole liver treatment in one session 38 (64 %)*

Selective administration (LHA & RHA) 28 (48 %)
PHA 9 (15 %)
CHA 1 (2 %)
Whole liver treatment in sequential sessions (LHA & RHA) 10 (17 %)
Lobar treatment 11 (19 %)
Retreatment with 90Y-radioembolization after progression 4 (7 %)

Median time to retreatment (months) 9 (5 – 25)
Values are presented as n (percentage), median (range) or mean ± standard deviation. * This number
includes four patients with a history of previous hemihepatectomy. Abbreviations: MBq = mega-
becquerel; Gy = gray; LHA = left hepatic artery; RHA = right hepatic artery; PHA = proper hepatic
artery; CHA = common hepatic artery.
- 247 -
Toxicity
Eleven patients (19 %) were excluded from laboratory toxicity analysis, because
data on laboratory investigations at baseline or during follow-up, within our defined
intervals, were not available in our center. In the remaining 48 patients, there were
values missing for some laboratory parameters, therefore the denominator was
adjusted accordingly when calculating incidences. CTCAE grades at baseline,
maximum CTCAE grades during follow-up and corresponding new toxicity are
presented in Figure 2. Grade 3 – 4 toxicity at baseline was observed for GGT (16/47,
34 %) and ALP (1/47, 1 %). Grade 3 – 4 new toxicity was observed in 18 patients
(38 %), including following parameters: GGT (13/47, 27 %), ALP (10/27, 21 %),
bilirubin (1/41, 2 %), AST (1/47, 2 %), ALT (1/47, 2 %), and albumin (1/42, 2 %).
In addition, the incidence of grade 3 – 4 new toxicity was stratified according to
treatment strategy. Ten of 28 evaluable patients (36 %) who received whole liver
treatment in one session had grade 3 – 4 new toxicity, compared to five of ten
patients (50 %) who received whole liver treatment in sequential sessions, and
three of ten patients (30 %) who received unilobar treatment (Table 3).
Chapter 13 Part IV
Figure 2: Laboratory toxicity. Clustered bar chart displaying the incidence of laboratory toxicity at
baseline (BL), during follow-up (FU) and corresponding ‘new toxicity’ (NT) per laboratory value.
CTCAE grades: blue = grade 1; green = grade 2; orange = grade 3; red = grade 4. Abbreviations: ALT
= alanine amino-transferase; Hb = hemoglobin; AST = aspartate aminotransferase; AP = alkaline
phosphatase; GGT = gamma-glutamyl transferase.
- 248 -
Table 3: Grade 3/4 laboratory toxicity

Treatment strategy Incidence of new grade 3/4 laboratory toxicity
All evaluable patients 18/48 (38 %)
Whole liver treatment in one session 10/28* (36 %)
Whole liver treatment in sequential sessions 5/10 (50 %)
Single lobar treatment 3/10 (30 %)
Values are presented as n (percentage). * This number includes four patients with a history of previ-
ous hemihepatectomy.
The following periprocedural complications were reported: allergic reaction

to contrast agent (n = 6), arterial dissection (n = 2), nausea/vomitus during
angiography (n = 1), delayed hemostasis at the access site requiring prolonged
clamping (n = 1), inguinal hematoma at the access site (n = 1). Complications
did not prevent any patients from receiving therapy. Back pain or abdominal pain
during angiography was managed with fentanyl (37 % of patients, 50 – 200 mcg
i.v.) and/or diclofenac (35 % of patients, 50 – 125 mg i.v.).
Clinical symptoms associated with the postembolization syndrome (CTCAE
grade 1 – 2) were observed in the majority of the treated patients. This syndrome
comprised the following symptoms (in order of frequency): fatigue and loss
of appetite, pain/discomfort in the right upper abdominal quadrant requiring
analgesics (paracetamol and/or diclofenac and/or morphine), nausea and vomitus,
fever and general discomfort. In general, these symptoms started on the day of
treatment and lasted up to two weeks after treatment. No grade 3 – 4 clinical
Part IV Chapter 13
toxicity was observed after 90Y-radioembolization treatment and no serious
treatment-related complications such as duodenal or gastric ulceration, radiation
pneumonitis or RILD, were observed.
Response
Target lesion, whole liver and overall response rates and TTP (for all patients
and per tumor type) at 3- and 6-months are displayed in Table 4. Target lesion,
whole liver and overall disease control rates (complete response + partial response
+ stable disease) at 3-months posttreatment were 35, 21 and 19 % respectively.
Corresponding disease control rates at 6-months were 25, 13 and 12 %. Median
TTP for all patients was 6.2 months (95 % CI, 2.2 – 10.0) for target lesions, 3.3
months (95 % CI, 2.8 – 3.8) for the whole liver and 3.0 months (95 % CI, 2.4 – 3.5)
overall.
- 249 -
Table 4: Response rates and Time To Progression
Target Lesion Whole liver Overall

3 months 6 months 3 months 6 months 3 months 6 months
CR 2 (3 %) 0 2 (3 %) 0 1 (2 %) 0
PR 3 (5 %) 3 (5 %) 2 (3 %) 2 (3 %) 2 (3 %) 1 (2 %)
SD 16 (27 %) 12 (20 %) 9 (15 %) 6 (10 %) 8 (14 %) 6 (10 %)
PD 16 (27 %) 6 (10 %) 26 (44 %) 16 (27 %) 30 (51 %) 19 (32 %)
Deceased 9 (15 %) 24 (41 %) 9 (15 %) 24 (41 %) 9 (15 %) 24 (41 %)
NE 9 (15 %) 10 (17 %) 7 (12 %) 7 (12 %) 5 (9 %) 5 (9 %)

Loss FU 4 (7 %) 4 (7 %) 4 (7 %) 4 (7 %) 4 (7 %) 4 (7 %)
Disease control rate 35 % 25 % 21 % 13 % 19 % 12 %
TTP (all patients) 6.2 months (2.2 – 10.0) 3.3 months (2.8 – 3.8) 3.0 months (2.4 – 3.5)
TTP (CRLM) 6.2 months (2.5 – 9.8) 3.0 months (2.8 – 3.3) 2.8 months (2.2 – 3.3)
TTP (NET) 36.4 months (0 – 8.7) 19.0 months (0 – 62.0) 11.7 months (0 – 24.8)
TTP (Other) 4.4 months (0.8 – 8.0) 3.8 months (1.9 – 5.5) 3.3 months (2.2 – 4.4)
Values are presented as n (percentage) or median Kaplan-Meier estimate (95 % confidence interval).
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive
disease; NE = non-evaluable; Loss FU = loss to follow-up; TTP= time to progression.
Survival
At the time of analysis, 49 patients had died and 10 patients were still alive. Median
overall survival for the entire group of patients (n = 59) was 8.9 months (95 %
Chapter 13 Part IV
CI, 7.2 – 10.6). The Kaplan-Meier survival curve is displayed in Figure 3. Median
overall survival was 8.9 months (95 % CI, 6.9 – 10.9) for colorectal cancer liver
metastases (n = 30), 40.3 months (0 – 107.9) for NET metastases (n = 6) and 7.8
months (95 % CI, 5.0 – 10.6) for other metastases (n = 23) (Figure 4).
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Figure 3: Kaplan-Meier Survival curve for all 59 patients.
Part IV Chapter 13
Figure 4: Kaplan-Meier Survival curve per tumor type.

The blue line represents patients with colorectal liver
metastases (CRLM), the green line represents patients
with neuroendocrine tumor (NET) liver metastases,
and the red line represents patients with liver metastases
from other primary tumors.
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DISCUSSION
The primary objective of this study was to investigate treatment-related clinical
and laboratory toxicity in patients with unresectable liver metastases, treated with
90
Y-radioembolization. Secondary objectives were to assess tumor response and
overall survival. Clinical toxicity was confined to grade 1 – 2 symptoms of the
postembolization syndrome. No RILD or other grade 3 – 4 clinical toxicity was
observed, whereas laboratory toxicity grade 3 – 4 was observed in 38 % of patients.
In this cohort, a disease control rate of up to 35 % was obtained at 3-months
posttreatment, and median overall survival was 8.9 months.
Tumor response rates vary widely in the 90Y-radioembolization literature.4 This
may be explained in part by differences in methodology for response assessment.
Various studies do not specify whether RECIST criteria have been followed.
According to these criteria, tumor response should be differentiated in target lesion,
liver and overall response.19 In order to improve interpretability of overall response
rates, studies should indicate whether patients had evidence of extrahepatic disease
at baseline. Response rates are commonly divided into 3- and 6-months rates
posttreatment. However, it should be clearly stated which imaging intervals are
chosen to represent this 3- and 6-months measurements. In addition, it would be
preferable to score target lesion response blindly, to assure objective measurements.
In a comprehensive review of the 90Y-radioembolization literature, twelve studies
were identified that reported a 3-month disease control rate, ranging from 63 –
100 %.4 In most of these studies, the level on which response assessment had been
performed was not specified. Assuming these are whole-liver disease control rates,
our 3-month disease control rate was much lower: 21 %. This difference could be
Chapter 13 Part IV
attributable to differences in methodology of response assessment, as mentioned

above. However, less stringent patient selection criteria and the heterogeneity
of our cohort, including hyper- and hypovascular liver metastases from various
primary tumors, could also have attributed to lower response rates.
Toxicity due to radiation to the liver has first been described after external radiation
therapy.20-21 It was found that the liver is very sensitive to radiation and patients
may develop RILD, months after an overdose of radiation. Histopathologically,
RILD is characterized by veno-occlusive disease with congestion of the central
veins and sinusoids.21-24 The symptoms of RILD comprise fatigue, anicteric
ascites, hepatomegaly, and elevated liver function tests (especially alkaline
phosphatase).23 High dose corticosteroids can be given to mitigate the course
of this disease. It is, however, hard to recognize RILD since it has a long latency
time and many of its symptoms can also occur after non-complicated treatment
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with 90Y-radioembolization. A better understanding of the physiological variation

of treatment-related laboratory toxicity after 90Y-radioembolization would be
very helpful in discriminating early signs of RILD from transient laboratory
abnormalities after treatment. Mild toxicity (grade 1 – 2) of liver function tests is
common after 90Y-radioembolization, occurring in up to 70 % of the patients.25-27
Reported incidences of grade 3 – 4 toxicity are much lower and vary widely across
studies. Van Hazel et al.2 observed no grade 3 – 4 toxicity in their study, Piana et
al.25 found an overall incidence of 7 % and Kennedy et al.8 reported an incidence
of up to 20.5 % for ALP. In the study of Piana et al., one patient died of RILD.25 In
our study we found higher incidences of laboratory toxicity, with new laboratory
toxicity grade 3 – 4 occurring in up to 38 % of the patients. However, we did not
observe any serious treatment-related complications, nor did we observe any
RILD. This indicates that serious laboratory toxicity regarding transaminases and
liver function tests can occur as part of the physiological reaction of the liver to
90
Y-radioembolization treatment.
One of the factors complicating the interpretation of toxicity results is that
abnormalities in liver function tests and transaminases could be the result of tumor
progression instead of treatment-related toxicity. Moreover, results of toxicity are
often incompletely reported in the 90Y-radioembolization literature. Many studies
do not specify how CTCAE scores for laboratory toxicity have been determined.
This could inadvertently lead to an underestimation of treatment toxicity and it
limits the comparability of studies. Therefore, we aimed to report our methods and
results in an unambiguous and transparent fashion.
Part IV Chapter 13
The most important limitations of this study were its retrospective design and
the lack of standardization of laboratory investigations and reporting of clinical
symptoms during physical examination. Therefore, our results in terms of the
incidence of laboratory or clinical toxicity are likely to be underestimations of the
real incidence of toxicity. Another limitation was the heterogeneity of our study
population. However, this heterogenic group does reflect the typical population of
patients referred for 90Y-radioembolization treatment.
Fourteen of the 73 patients (19 %) who received workup angiography did not
receive 90Y-radioembolization. The majority of these patients (n = 11) were not
eligible because of persisting extrahepatic deposition (PED) of 99mTc-MAA. This
PED rate of 11/73 (15 %) is much higher than the rates reported in the literature
(range, 0 – 10 %).16,18-29 A likely cause of the high PED rate in this study is the
relative large number of proximal injection positions (i.e., proper or common
- 253 -
hepatic artery). Several studies have demonstrated that extrahepatic deposition

can be solved/prevented by more distal injection positions (left/middle/right
hepatic artery or even more selective).16,28,30 We have changed our current practice
accordingly and we rarely perform whole liver treatments from the proper hepatic
artery anymore. In addition, our center and many others increasingly use C-arm
cone beam computed tomography during the pretreatment angiography to help
prevent extrahepatic distribution and identify culprit vessels.31-32
The whole liver approach has also been associated with increased toxicity.
Seidensticker et al. have reported that a whole liver approach, in non-cirrhotic liver
metastases patients, resulted in a higher number of liver-related CTCAE grade 3
– 4 events as compared to a sequential lobar approach.14 We could not confirm
this finding in our patients. In fact, the number of patients with CTCAE grade
3 – 4 laboratory toxicity was even lower in the whole liver approach group (36 %)
than in the sequential lobar group (50 %). Selection bias, and confounding due to
differences in baseline characteristics, may play a significant role in this matter.
However, we do recognize the clinical importance, and we think that the question
whether treating the whole liver at once increases toxicity, should be determined
using a randomized controlled trial.
The majority of the patients (70 %) treated in our cohort, received
radioembolization as salvage therapy. This illustrates that 90Y-radioembolization
is still regarded as a treatment option of last resort, for patients who have
unresectable and chemorefractory liver tumors. The costs of radioembolization
treatment (approximately €11.000 for one dose of SIR-spheres plus the costs of
the procedure, the involved imaging, hospitalization and follow-up) need to be
Chapter 13 Part IV
weighed against the potential benefit to the patient.33 For this purpose, prospective
comparative studies evaluating survival, tumor response, and quality of life
after 90Y-radioembolization are strongly warranted. In addition, it will become
increasingly important to select those patients that will benefit most from this
therapy. Performing radioembolization at an earlier stage in patients with liver
metastases might for instance translate into improved tumor response rates and
overall survival. Two large randomized controlled trials are currently ongoing,
investigating the effect on overall survival (SIRFLOX study) and progression free
survival (FOXFIRE study) of the addition of 90Y-radioembolization to FOLFOX
(fluorouracil, leucovorin, oxaliplatin) with or without bevacizumab as first-line
treatment for patients with unresectable colorectal liver metastases.34
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CONCLUSION
The risk of severe complications or grade 3 – 4 clinical toxicity in patients with liver
metastases of various primary tumors undergoing 90Y-radioembolization is low. In
contrast, laboratory toxicity grade 3 – 4 was observed in more than one-third of the
patients without any signs of RILD. This physiological reaction of liver enzymes to
90
Y-radioembolization therapy may mask early signs of toxicity due to RILD.
Part IV Chapter 13
- 255 -
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Pregl 68: 341-348.
20. Reed GB, Jr., Cox AJ, Jr. (1966) The human
28. Dudeck O, Wilhelmsen S, Ulrich G, et al.
Part IV Chapter 13
liver after radiation injury. A form of veno-
(2012) Effectiveness of repeat angiographic
occlusive disease. Am J Pathol 48: 597-611.
assessment in patients designated for
21. Lawrence TS, Robertson JM, Anscher MS, radioembolization using yttrium-90
et al. (1995) Hepatic toxicity resulting from microspheres with initial extrahepatic
cancer treatment. Int J Radiat Oncol Biol accumulation of technitium-99m
Phys 31: 1237-1248. macroaggregated albumin: A single center's
experience. Cardiovasc Intervent Radiol 35:
22. da Silveira EB, Jeffers L, Schiff ER (2002)
1083-1093.
Diagnostic laparoscopy in radiation-
induced liver disease. Gastrointest Endosc 29. Smits ML, Nijsen JF, van den Bosch MA, et
55: 432-434. al. (2012) Holmium-166 radioembolisation
in patients with unresectable,
23. Guha C, Kavanagh BD (2011) Hepatic
chemorefractory liver metastases (HEPAR
radiation toxicity: Avoidance and
amelioration. Semin Radiat Oncol 21: 256-
Lancet Oncol 13: 1025-1034.
263.
- 257 -
30. Lam MG, Banerjee S, Louie JD, et 33. Garin E, Rolland Y, Boucher E, et al.
al. (2013) Root cause analysis of (2010) First experience of hepatic
gastroduodenal ulceration after yttrium-90 radioembolization using microspheres
radioembolization. Cardiovasc Intervent labelled with yttrium-90 (TheraSphere):
Radiol 36: 1536-1547. Practical aspects concerning its
implementation. Eur J Nucl Med Mol
31. Louie JD, Kothary N, Kuo WT, et al.
Imaging 37: 453-461.
(2009) Incorporating cone-beam CT into
the treatment planning for yttrium-90 34. Sharma RA, Wasan HS, Love SB, et al.
radioembolization. J Vasc Interv Radiol 20: (2008) FOXFIRE: A phase III clinical trial
606-613. of chemo-radio-embolisation as first-line
treatment of liver metastases in patients
32. Heusner TA, Hamami ME, Ertle J, et al.
with colorectal cancer. Clin Oncol (R Coll
(2010) Angiography-based C-arm CT for
Radiol) 20: 261-263.
the assessment of extrahepatic shunting
before radioembolization. Rofo 182: 603-
608.
Chapter 13 Part IV
- 258 -
C hap ter
PART IV 14
Radiation-induced cholecystitis
after hepatic radioembolization:
Do we need to take
precautionary measures?
J.F. Prince
A.F. van den Hoven
M.A.A.J. van den Bosch,
M. Elschot
H.W.A.M. de Jong
M.G.E.H. Lam
Journal of Vascular and Interventional Radiology 2014

Radiation-induced cholecystitis after hepatic radioembolization
ABSTRACT
Controversy exists over the need to take precautionary measures during hepatic ra-
dioembolization to minimize the risk of radiation-induced cholecystitis. Strategies
for a variety of clinical scenarios are discussed on the basis of a literature review.
Precautionary measures are unnecessary in the majority of patients and should be
taken only when single-photon emission computed tomography (CT; SPECT)/CT
shows a significant concentration of technetium-99m macroaggregated albumin
in the gallbladder wall. In this case report with quantitative SPECT analysis, it is
illustrated how an adjustment of the catheter position can effectively reduce the
absorbed dose of radiation delivered to the gallbladder wall by more than 90 %.
Chapter 14 Part IV
- 262 -
INTRODUCTION
Intra-arterial hepatic radioembolization has been established as a safe and effective
treatment modality for patients with unresectable liver tumors. Although treat-
ment complications are rare, serious clinical toxicity can follow unintentional ex-
trahepatic deposition of radioactive microspheres.1 Various safety precautions can
be taken to minimize this risk, including permanent or temporary occlusion of
non-target vessels, induction of vasospasm with the use of a microwire, choosing a
distal catheter position, and use of an anti-reflux infusion system.1-3 Unfortunately,
comparative studies on the efficacy of these precautionary measures are lacking.
Therefore, controversy exists as to which of these precautions are appropriate in a
variety of clinical scenarios; for example, the need for coil embolization is debated.4
Similarly, the need for gallbladder protection remains a matter of debate. It has
been reported that deposition of radioactive microspheres in the gallbladder wall
may cause radiation-induced cholecystitis, occasionally necessitating surgical in-
terference.5-11 Therefore, some authors advocate routine prophylactic embolization
of the cystic artery before radioembolization.10,12 A recent survey among Europe-
an interventional centers revealed that 41 % of these centers follow this strategy
and always embolize the cystic artery.13 However, others argue that prophylactic
embolization may not be desirable in all patients for the following reasons: (i) in
as many as one-third of patients the catheter can be positioned distal to the cystic
artery without compromising the intrahepatic microsphere distribution, (ii) only
a small fraction of patients in whom a proximal catheter position is chosen will
exhibit an increased uptake of technetium-99m (99mTc) macroaggregated albumin
(MAA) and radioactive microspheres in the gallbladder wall, (iii) the occurrence
Part IV Chapter 14
of symptomatic radiation-induced cholecystitis is rare, and (iv) embolization of the
cystic artery may incidentally cause ischemic cholecystitis by itself.14 Remarkably,
clinical guidelines for radioembolization do not provide further guidance in this
matter.15-19A case is presented here in which a highly perfused gallbladder wall, ex-
hibiting extraordinarily high 99mTc-MAA activity on single-photon emission com-
puted tomography (CT; SPECT)/CT, is protected by slightly adjusting the catheter
position. In addition, strategies that seem most appropriate for a variety of clinical
scenarios are discussed, based on the best available evidence.
CASE REPORT
A 64-year-old man diagnosed with unresectable colorectal cancer liver metastases,
refractory to standard systemic chemotherapy, was referred for radioembolization.
Routine pretreatment whole-body [18F] fluorodeoxyglucose positron emission to-
- 263 -
mography/CT and triphasic liver CT revealed multiple liver metastases, no extra-

hepatic disease and a variant configuration of the hepatic arterial vasculature: a
replaced left hepatic artery (LHA) originating from the left gastric artery vascu-
larizing segments 2-3, and a segment 4 artery (i.e., A4) originating from the right
hepatic artery (RHA). The patient was considered eligible for radioembolization
by multidisciplinary tumor board review. He provided written informed consent
to participate in an ongoing clinical phase II trial that is investigating the efficacy
of radioembolization performed with holmium-166 (166Ho) microspheres (Radio-
active Holmium Microspheres for the Treatment of Unresectable Liver Metastases;
clinicaltrials.gov ID, NCT01612325).
In short, 166Ho-poly-(L-lactic acid) microspheres have been developed at our in-
stitution to allow for visualization of the in vivo microsphere biodistribution after
radioembolization.20 Quantification of 166Ho microspheres is feasible on magnetic
resonance (MR) imaging and SPECT/CT, by using the paramagnetic properties of
holmium or the emission of γ-photon radiation respectively.21 Patients participat-
ing in the aforementioned ongoing phase II trial first receive a workup angiogra-
phy, during which 99mTc-MAA is administered. On the day of treatment, a scout
dose (60 mg, 250 MBq) and a therapeutic dose (540 mg, varying activities) of 166Ho
microspheres are administered sequentially to evaluate the accuracy of 166Ho scout
dose imaging. MR imaging and SPECT/CT are acquired after the scout dose and
therapeutic dose.
The gastroduodenal artery and right gastric artery were prophylactically coil em-
bolized to minimize the risk of non-target distribution. Subsequently, the replaced
LHA and the RHA, proximal to the origin of the A4 segment (Figure 1), were cho-
Chapter 14 Part IV
sen as planned injection positions. Next, 99mTc-MAA (52 MBq in the replaced LHA
and 95 MBq in the RHA) was administered. SPECT/CT did not reveal significant
99m
Tc-MAA activity in the gallbladder wall, but it did reveal a small extrahepatic
focus in the duodenum (Figure 2A).
Because of this extrahepatic uptake, the workup angiography was repeated and
three selective catheter positions were chosen: the replaced LHA, the A4, and the
RHA proximal to the origin of the cystic artery (Figure 1B). In these positions
99m
Tc-MAA (34 MBq in the replaced LHA, 23 MBq in the A4 segment and 93 MBq
in the RHA) was administered. This time, SPECT/CT did not reveal any extrahe-
patic deposition. However, the amount of 99mTc-MAA activity in the gallbladder
wall was now extraordinarily high.
- 264 -
Part IV Chapter 14
Figure 1: Injection positions in the RHA during the pretreatment and treatment procedures. The
injections in the replaced LHA (originating from the left gastric artery) are not shown. A) Catheter
position during the first workup angiography. The 99mTc-MAA was administered in the RHA, proximal
to the A4. B) Catheter position during repeat workup angiography. The 99mTc-MAA was administered
in the RHA selectively. Note that the cystic artery fills with contrast medium. C) Adjusted catheter
position (black arrow) during the administration of the scout dose of 166Ho microspheres. D) Identical
catheter position (black arrow) during the administration of the therapeutic dose of 166Ho microspheres.
Note that the cystic artery is not visible (white arrow). Corresponding SPECT/CT images of 99mTc-MAA
and 166Ho microsphere distribution are shown in Figure 2.
- 265 -
Chapter 14 Part IV
Figure 2: SPECT/CT images of 99m

Tc-MAA and 166Ho microsphere distribution. Note the marked
difference in gallbladder wall activity (arrows). A) The 99mTc-MAA was administered in the RHA,
proximal to the A4. B) During repeat workup angiography, 99mTc-MAA was administered in the RHA
selectively. A significant amount of 99mTc-MAA activity is observed in the gallbladder wall. C) More
proximal catheter position in the RHA during the administration of the scout dose 166Ho microspheres.
Little to no activity is seen in the gallbladder wall. D) Identical catheter position during administration
of the therapeutic dose of 166Ho microspheres.
With the use of a quantitative SPECT/CT reconstruction22, the relative amount of

activity in the gallbladder was determined, and the gallbladder absorbed dose that
would result from treatment was estimated (Table 1).
- 266 -
Table 1: Quantitative SPECT/CT analysis
Infused Activity ratio (Predicted) Treatment (Predicted) Absorbed

Procedure activity Gallbladder/Liver activity Gallbladder dose Gallbladder
(MBq) (%) (MBq) (Gy)
99m
Tc-MAA 132 3.3 225 187
Ho Scout
166
278 0.7 46 14
Ho Therapy
166
6,866 0.5 36 11
MAA = macroaggregated albumin, SPECT = single-photon emission computed tomography
To this purpose, the whole gallbladder and liver were manually delineated by
consensus of two authors (J.F.P. and A.F.v.d.H.) by using the low-dose CT of the
SPECT/CT examination. A 2 cm margin was added to the segmentation of the
liver to account for suboptimal co-registration of SPECT and CT, patient breath-
ing and partial volume effects. The ratio of the 99mTc-MAA activity in the gall-
bladder volume of interest (VOI) to the extended liver VOI was multiplied by the
administered therapeutic activity (6,866 MBq 166Ho) to provide an estimate of the
treatment activity that would have been distributed to the gallbladder. Calculations
were performed under the assumptions of complete local energy deposition (15.87
J/GBq of 166Ho microspheres) and a gallbladder density of 1 kg/L for the volume
determined by the gallbladder VOI.
The concentration of radioactivity in the gallbladder was six times as high as the
mean uptake in the liver, and would have resulted in an estimated treatment ab-
Part IV Chapter 14
sorbed dose of 187 Gy (Table 1, Figure 2B). After considering various prophylactic
options, including coil embolization of the cystic artery, it was decided to attempt
to avoid targeting of the gallbladder by placing the catheter more in a proximal
position in the RHA during the 166Ho-scout procedure. Digital subtraction an-
giographic images obtained from this position showed a lack of contrast medium
filling in the cystic artery (Figure 1C). Subsequently, a scout dose of 166Ho micro-
spheres was administered in three branches (85 MBq in the replaced LHA, 40 MBq
in the A4 and 175 MBq in the RHA). SPECT/CT showed a lack of activity in the
gallbladder, and an adequate intrahepatic biodistribution of 166Ho microspheres
(Figure 2C). Retrospective quantitative analysis with the same VOI approach de-
scribed earlier estimated an absorbed dose to the gallbladder of 14 Gy (Table 1).
The required 166Ho microsphere treatment activity, calculated for a desired whole
liver absorbed dose of 60 Gy, was 8,509 MBq. Stasis of blood flow prohibited a
complete administration, resulting in net infused activity of 1,265 MBq in the re-
- 267 -
placed LHA, 1,262 MBq in the A4 segment and 4,212 MBq in the RHA. Posttreat-
ment SPECT/CT showed a lack of activity in the gallbladder wall, and an adequate
intrahepatic 166Ho microsphere biodistribution, comparable to the scout dose dis-
tribution (Figure 2D). Quantitative analysis showed that the gallbladder absorbed
dose was successfully reduced to 11 Gy, a reduction of more than 90 % versus that
estimated on the 99mTc-MAA procedure.
The patient experienced abdominal pain, nausea and vomiting (National Cancer
Institute Common Terminology Criteria for Adverse Events [CTCAE] grade 3)
during treatment, as part of the postembolization syndrome. Symptoms were treat-
ed with analgesic and antiemetic drugs, and resolved 1 day after therapy. Clinical
follow-up at 2 weeks and 2 months after treatment showed that the patient was in
good clinical condition (World Health Organization performance score of 0) and
had no clinical toxicity. Triphasic liver CT at 3 months after treatment showed no
abnormalities of the gallbladder.
DISCUSSION
Uniform criteria for the diagnosis of radiation-induced cholecystitis are currently
lacking. Classical symptoms include persistent fever, right upper quadrant pain,
nausea and vomiting, occurring shortly after radioembolization treatment.6 How-
ever, these symptoms can also occur as part of the common postembolization syn-
drome or as a first sign of progressive disease.23 Unfortunately, physicians cannot
rely upon imaging findings, as it has been demonstrated that gallbladder wall ab-
normalities on ultrasound, CT and MRI are frequently found after radioemboli-
zation in asymptomatic patients, and do not correlate with clinical severity or the
Chapter 14 Part IV
need for surgical intervention.5,24

In addition, it remains unclear whether the occurrence of symptomatic radia-
tion-induced cholecystitis is correlated with 99mTc-MAA (reported in 7 – 20 % of
cases2,14,25) or yttrium-90 (90Y) activity (reported in 20 % of cases25) in the gall-
bladder wall on nuclear imaging (i.e., SPECT/CT or positron emission tomogra-
phy/CT). Therefore, radiation-induced cholecystitis will be diagnosed only when
symptoms are refractory to medical therapy and other diagnoses are ruled out. The
reported incidence of radiation cholecystitis varies with grade of severity (grading
per CTCAE26). The overall incidence, reported by 14 different studies published
between 2007 and 20132,5,7-8,10,14,24-25,27-32, ranges from 0 to 7 %. Symptomatic cho-
lecystitis manageable with medical therapy such as adequate hydration and nu-
trition, pain medication and antibiotic therapy (CTCAE grade 2) is reported in as
many as 4.8 % of patients, and severe (CTCAE grade 3) or life-threatening (CT-
CAE grade 4) cholecystitis requiring surgery is reported in as many as 2.4 % of
- 268 -
patients. Surgical morbidity rates may be higher for patients with underlying liver
disease and recent radioembolization treatment, compared with otherwise healthy
patients who undergo cholecystectomy for biliary cholecystitis.6
To date, few studies have reported whether any form of gallbladder protection was
used during radioembolization. Recently, Theyson et al.14 compared the incidence
of symptomatic cholecystitis after the application of different strategies of gallblad-
der protection in 295 patients with primary or metastatic liver cancer, undergoing
90
Y-radioembolization. The authors reported that they were able to place the cath-
eter distal to the cystic artery in 91 of 295 patients (30.8 %) without compromising
tumor targeting. In 184 patients (62.4 %), a proximal catheter position did not lead
to 99mTc-labeled human serum albumin activity in the gallbladder wall on SPECT/
CT, and no further measures were taken to protect the gallbladder. However, in 20
patients (6.8 %) a significant accumulation of 99mTc human serum albumin in the
gallbladder wall (higher activity than in the healthy liver tissue) was observed. In
these patients, gallbladder protection was performed by temporary occlusion of
the cystic artery with Gelfoam (Pharmacia and Upjohn, Kalamazoo, Michigan; n
= 5), permanent occlusion with coils (n = 1), induction of vasospasm in the cystic
artery with a microwire (n = 4), or alteration the catheter position to change the
direction of blood flow (n = 10). In only one of these patients, in whom the cystic
artery was embolized with Gelfoam, did cholecystitis develop after radioemboliza-
tion.14 In another study, McWilliams et al.10 studied the safety and efficacy of two
different methods of cystic artery embolization in 46 patients undergoing 90Y-ra-
dioembolization. The cystic artery was temporarily occluded with Gelfoam in 35
patients, and permanently embolized with coils in 10 patients. SPECT/CT did not
Part IV Chapter 14
reveal any 99mTc-MAA activity in the gallbladder wall, but cholecystitis developed
in three patients (6.7 %) nevertheless. In each group, CTCAE grade 2 cholecystitis
developed in one patient, and grade 3 cholecystitis requiring surgical intervention
developed in the coil embolization group.10 Ahmadzadehfar et al.2 performed a
retrospective cohort study in 76 patients who received preparatory angiography
with administration of 99mTc-MAA. Seven patients showed 99mTc-MAA activity in
the gallbladder wall on SPECT or SPECT/CT, and gallbladder protection was per-
formed before treatment. In six of these patients, the catheter was positioned distal
to the origin of the cystic artery, and the cystic artery was coil embolized in one pa-
tient. None of these patients exhibited the development of cholecystitis during fol-
low-up.2 In a cohort study of 15 patients treated with 90Y-radioembolization, Garin
et al.25 reported that they did not perform any gallbladder protection and observed
99m
Tc-MAA activity in the gallbladder wall on SPECT/CT in three patients (20 %),
without the occurrence of cholecystitis during follow-up (Table 2).25
- 269 -
Chapter 14 Part IV
Table 2: Literature overview on radiation-induced cholecystitis

Overall incidence of Cholecystitis
Precautionary Gallbladder wall Symptomatic Cholecystitis
Author Year (Reference) Nr. patients symptomatic chole- Requiring Surgery
measures taken? activity on SPECT (CTCAE grade 2)
cystitis (CTCAE grade 3 or 4)
Peterson et al. 201327 112 NR NR 6 % (7/112) 4.5 % (5/112) 1.8 % (2/112)
Bester et al. 201328 427 NR NR NR 0.5 % (2/427) 0
0.6 % (2/339) at 1 mo
Bester et al. 2 201329 339 NR NR 1.8 % (6/339) 0
1.8 % (6/339) at 3 mo
Theyson et al. 201314 295 Yes 6.8 % (20/295) 0.03 % (1/295) 0.03 % (1/295) 0
McWilliwams et al. 201110 46 NR 0 6.5 % (3/46) 4.3 % (2/46) 2.2 % (1/46)
Ahmadzadehfar et al. 20102 76 Yes 13.1 % (10/76) 0 0 0
- 270 -
Cianni et al. 201032 110 NR NR 2.7 % (3/110) 2.7 % (3/110) at 1 mo 0
25
Garin et al. 2010 15 No 20.0 % (3/15) NR NR NR
Cianni et al. 200930 41 NR NR 2.4 % (1/41) 2.4 % (1/41) at 1 mo 0

7
Jakobs et al. 2008 41 NR NR 2.4 % (1/41) 0 2.4 % (1/41)
5
Atassi et al. 2008 327 NR NR 0.6 % (2/327) 0 0.6 % (2/327)
Atassi et al. 2 200824 130 NR NR 1.5 % (2/130) 0 1.5 % (2/130)
31
Jiao et al. 2007 21 NR NR 4.8 % (1/21) 4.8 % (1/21) NR
Miller et al. 20078 42 NR NR 2.3 % (1/42) 0 2.3 % (1/42)
Articles were identified by performing a search in PubMed and EMBASE databases on November 8, 2013. Synonyms for radioembolization were combined
with cystic artery, gallbladder or cholecystitis. CTCAE = common terminology criteria for adverse events, NR = not reported, SPECT = single-photon emission
computed tomography
The use of antibiotic prophylaxis in patients with 99mTc-MAA activity in the gall-
bladder wall has previously been described, but its efficacy is yet unknown.25,27
In the present report, a case is presented in which repositioning of the catheter
reduced the potential gallbladder wall absorbed dose by more than 90 %. Partial
volume effects and errors in registration, caused by breathing and/or movement,
influence these numbers. The absorbed dose is averaged over the gallbladder, a
composite of gallbladder wall and the contained bile, whereas only the dose to the
gallbladder wall is relevant for complications. As such, these numbers must be seen
as an illustration of the relative reduction of the absorbed dose that is possible by
adjusting the injection position.
Repositioning of the catheter can change the position of the tip inside the vessel
lumen, not only along the longitudinal axis, but also in the cross-sectional plane of
the vessel. This results in different outflow trajectories. Simulations studies show
that the particle trajectories are influenced by release position, downstream resis-
tance, type of particle, and timing of release.33-34 Digital subtraction angiography
can be used to confirm lack of flow directed toward the cystic artery. Although
catheter manipulation will not have a predetermined effect, marked differences
can often be seen between two catheter positions, as shown in the present report.
Subsequently, injection of 99mTc-MAA is used to simulate the distribution of radio-
active microspheres.
Based on the summarized evidence, we postulate a scenario-based approach for
gallbladder protection during radioembolization (Table 3). The microcatheter can
be positioned distal to the cystic artery whenever possible. If, however, a significant
concentration of 99mTc-MAA is observed in the gallbladder wall, the catheter posi-
Part IV Chapter 14
tion can be adjusted to alter the direction of blood flow33, as shown in the present
case report and previously described by Theyson et al..14 The risk of inducing isch-
emic cholecystitis by taking other measures such as Gelfoam or coil embolization
of the cystic artery, should be carefully weighed against the expected risk of symp-
tomatic radiation-induced cholecystitis. We present a case in which we were able
Table 3: Summary of gallbladder protection integrated in radioembolization procedure
Identify cystic artery

If possible, position microcatheter distal to cystic artery origin
Inject 99mTc-MAA and qualitatively assess gallbladder activity on SPECT/CT, if needed:
Adjust microcatheter position, check reduction of cystic artery flow during angiography
Embolize cystic artery using Gelfoam pledgets or coils
- 271 -
to protect a highly perfused gallbladder by slightly adjusting the catheter position.

Scientific evidence is scarce for diagnostic features of radiation-induced cholecys-
titis, its correlation with 99mTc-MAA and 90Y activity in the gallbladder wall, the
efficacy of various precautionary measures, and the efficacy of medical treatment.
Researchers are encouraged to report the occurrence and CTCAE grade of radi-
ation-induced cholecystitis as well as (quantitative) findings on nuclear imaging
and protective measures taken in these patients, when publishing future radioem-
bolization studies. This way, we can come to a better understanding of this rare but
severe treatment complication.
Chapter 14 Part IV
- 272 -
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Brachytherapy 12:573–579.
20. Smits MLJ, Nijsen JFW, van den Bosch
28. Bester L, Feitelson S, Milner B, et al. (2014)
MAAJ, et al. (2012) Holmium-166 radio-
Impact of prior hepatectomy on the safety
embolisation in patients with unresectable,
and efficacy of radioembolization with yt-
chemorefractory liver metastases (HEPAR
trium-90 microspheres for patients with
unresectable liver tumors. Am J Clin Oncol
Lancet Oncol 13:1025–1034.
37: 454-60.
21. Smits MLJ, Elschot M, van den Bosch
29. Bester L, Meteling B, Pocock N, et al. (2012)
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tive cohort study of survival outcomes and
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30. Cianni R, Urigo C, Notarianni E, et al. 33. A. Basciano C, Kleinstreuer C, S. Kennedy

(2009) Selective internal radiation therapy A (2011) Computational fluid dynamics
with SIR-spheres for the treatment of un- modeling of 90Y microspheres in human he-
resectable colorectal hepatic metastases. patic tumors. J Nucl Med Radiat Ther 2:112.
Cardiovasc Intervent Radiol 32:1179–1186.
34. Kennedy AS, Kleinstreuer C, Basciano CA,
31. Jiao LR, Szyszko T, Al-Nahhas A, et al. Dezarn WA (2010) Computer modeling of
(2007) Clinical and imaging experience yttrium-90-microsphere transport in the
with yttrium-90 microspheres in the man- hepatic arterial tree to improve clinical out-
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32. Cianni R, Urigo C, Notarianni E, et al.

(2010) Radioembolisation using yttrium 90
(Y-90) in patients affected by unresectable
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633.
Part IV Chapter 14
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C hap ter
PART IV 15
Insights into the dose-response
relationship of radioembolization
with resin yttrium-90 microspheres:
A prospective cohort study in
patients with colorectal cancer
liver metastases
A.F. van den Hoven

C.E.N.M. Rosenbaum
S.G. Elias
H.W.A.M. de Jong
M. Koopman
H.M. Verkooijen
A. Alavi
M.G.E.H. Lam
Journal of Nuclear Medicine 2016

Insight into the dose-response relationship of radioembolization
ABSTRACT
Randomized controlled trials are investigating the benefit of hepatic radioembolization
added to systemic therapy in the first/second-line treatment of patients with
colorectal liver metastases (CRLM). Remarkably, administered activity may still be
suboptimal, because a dose-response relationship has not been defined. The purpose
of this study was to characterize the relationship between tumor absorbed dose and
response after 90Y-radioembolization treatment for CRLM.
Methods
30 patients with unresectable chemorefractory CRLM were treated with resin 90Y
microspheres in a prospective phase II clinical trial. Tumor absorbed dose was
quantified on 90Y-PET. Metabolic tumor activity, defined as tumor lesion glycolysis
(TLG*) on 18F-FDG-PET, was measured at baseline and 1 month posttreatment.
The relationship between tumor absorbed dose and posttreatment metabolic
activity was assessed per metastasis, with a linear mixed effects regression model.
Results
133 treated metastases were identified. Mean tumor absorbed dose was 51 ± 28 Gy
(range 7 – 174 Gy). A 50 % reduction in TLG* was achieved in 46 % of metastases,
and in 11/30 (37 %) patients for the sum of metastases. The latter was associated
with prolonged median overall survival (11.6 vs. 6.6 months, p = 0.02). A strong,
and statistically significant dose-response relationship was found (p < 0.001). The
dose-effect depended on baseline TLG* (p < 0.01). Effective tumor absorbed dose
was conservatively estimated at a minimum of 40 – 60 Gy.
Conclusion
A strong dose-response relationship exists for the treatment of CRLM with resin
microspheres 90Y-radioembolization. Treatment efficacy is however still limited,
Chapter 15 Part IV
because the currently used pretreatment activity calculation methods curb

potentially achievable tumor absorbed dose values. A more personalized approach
to radioembolization is required before concluding on its clinical potential.
- 278 -
INTRODUCTION
Radioembolization has become an established treatment for patients with unresectable
chemorefractory colorectal cancer liver metastases (CRLM). During this treatment,
the hepatic arterial vasculature is catheterized and radioactive microspheres are
injected into the bloodstream. The preferential arterial vascularization of liver tumors
induces selective clustering of yttrium-90 (90Y) microspheres around tumors, where
they emit tumoricidal β-irradiation, while relatively sparing healthy liver tissue.1
A beneficial effect on liver disease control has already been shown in the salvage
setting, and large randomized controlled trials (RCTs) are investigating the role
of radioembolization with concomitant systemic therapy as first or second line
treatment.2-3
Prescribed activity calculations are currently not personalized. For resin 90Y
microspheres, activity planning is based on the body surface area (BSA) method.
This simple method was developed to calculate safe treatment activities, but it does
not incorporate a target tumor absorbed dose, nor does it account for interindividual
differences in microspheres distribution. Achievable tumor absorbed doses may
consequently be suboptimal and impair treatment efficacy.
Moreover, tumor absorbed dose quantification is scarce, and a clear dose-response
relationship is lacking. Thus, effective tumor absorbed dose values remain uncertain
(reported range 66 – 495 Gy).4 Better definition of required absorbed tumor doses
is crucial to assess whether the results of large comparative trials are the best that
radioembolization has to offer, before concluding its definitive role in the treatment
of CRLM. Furthermore, establishing the dose-response relationship could stimulate
the development of personalized methods for optimal prescribed activity calculation.
The purpose of this study was to assess the relationship between tumor absorbed dose
and response after resin microspheres 90Y-radioembolization in a prospective phase II
Part IV Chapter 15
clinical trial in patients with CRLM. Absorbed dose was quantified on posttreatment
90
Y-positron emission tomography (PET), while response was measured by metabolic
tumor response on 2-deoxy-2-[fluorine-18]fluoro-D-glucose PET (18F-FDG-PET).

Study design and patient selection
Between November 2011 and August 2014, a prospective, single institution,
phase II clinical trial (RADAR trial) was conducted. In this trial, 42 patients with
unresectable, chemorefractory CRLM underwent resin 90Y microspheres (SIR-
Spheres®, SIRTeX, Lane Cove, Australia) radioembolization. All patients were
in good clinical condition (WHO performance score < 2), had adequate liver,
- 279 -
renal and bone marrow functions, a liver tumor burden < 70 %, and no other
contraindications for radioembolization. Workup and treatment protocol were
in accordance with current standards of practice5-6, and were described in detail
elsewhere.7 In brief, multimodality imaging (18F-FDG-PET, multiphasic liver CT,
and liver MRI), laboratory and clinical examinations were performed during
workup. A week before treatment, patients underwent a standard preparatory
angiography with the administration of technetium-99m-labeled macroalbumin
aggregates (99mTc-MAA). During treatment, radioactive 90Y microspheres
microspheres were administered in the same catheter position. Pretreatment
dosimetry was performed with the BSA-method, as per manufacturer’s
recommendation. With this method prescribed activity is calculated in GBq by
the following equation: BSA – 0.2 + fractional tumor burden. A bremsstrahlung
SPECT/CT (in the first 10 patients) or 90Y-PET/CT (n = 32) was obtained after
treatment. At 1 month follow-up (1m FU) the 18F-FDG-PET scan and MRI of the
liver were repeated for tumor response assessment. The Medical Ethics Committee
of the University Medical Center Utrecht approved this trial. Written informed
consent was obtained from all patients before study entry.
For the current dose-response evaluation, only patients who were enrolled in
the RADAR trial, and who underwent an 18F-FDG-PET scan at our institution
at baseline and 1m FU, as well as a post-radioembolization 90Y-PET/CT, were
included.
This study is reported according to the Strengthening the Reporting of Observational
Studies in Epidemiology (STROBE) recommendations.8
Dose-response evaluation
Tumor absorbed dose and metabolic tumor response were assessed on 90Y-PET
and 18F-FDG-PET respectively, on a per-lesion basis and on a per-liver basis for
Chapter 15 Part IV
the sum of all metastases.

All PET analyses were performed with ROVER software (ABX GmBH, Radeberg,
Germany), which was developed for analysis of 18F-FDG-PET scans. Phantom
experiments and clinical patient data were used to validate quantitative 90Y-PET
analyses with this software (see the supplemental data for a detailed description).
The relationship between radiation absorbed dose and metabolic tumor response
was evaluated with a regression model (see statistical analysis). For this purpose,
individual metastases were automatically defined on the baseline 18F-FDG-PET
scan in ROVER. An absolute threshold for activity concentration, based on the
aortic blood pool activity as recommended by the PERCIST criteria9 (threshold
= 2 x mean standardized uptake value normalized for lean body mass [SULmean],
- 280 -
measured in the aortic blood pool), and a volume restriction of ≥ 5 cm3 were used
to delineate solitary metastases with a metabolic activity exceeding the background
activity of the healthy liver. Only regions with metabolic activity were delineated,
thereby excluding non PET-avid necrotic tumor cores. The resulting regions of
criteria
criteria99 (ROIs)
interest (threshold
(threshold =
= 2
were x
x mean
2 saved. standardized
mean For each tumor,
standardized value normalized
metabolic
uptake value activity
normalized for lean
for lean
was body mass
recorded
body mass
[SUL
[SULmean
as a partial
mean], measured in the aortic blood pool), and a volume restriction of ≥ 5 cm
], measured in the aortic blood pool), and a volume restriction of ≥ 5 cm
volume corrected total lesion glycolysis (TLG*) value, which was were used to
33 were used to
delineate solitary metastases with a metabolic activity exceeding the background activity of the
delineate solitary metastases with a metabolic activity exceeding the background activity of the
determined by multiplying the metabolic tumor volume with its partial volume
healthy liver. Only regions with metabolic activity were delineated, thereby excluding non PET‐
healthy liver. Only regions with metabolic activity were delineated, thereby excluding non PET‐
corrected SULmean value.
avid necrotic tumor cores. The resulting regions of interest (ROIs) were saved. For each tumor,
avid necrotic tumor cores. The resulting regions of interest (ROIs) were saved. For each tumor,
This process was repeated for the 1m FU scan to assess the metabolic tumor
metabolic activity was recorded as a partial volume corrected total lesion glycolysis (TLG*) value,
metabolic activity was recorded as a partial volume corrected total lesion glycolysis (TLG*) value,
response (change in TLG*) on a per-lesion basis. Care was taken to record baseline
which was
which was determined
determined by by multiplying
multiplying the
the metabolic
metabolic tumor
tumor volume
volume with
with its
its partial
partial volume
volume
and FU valuesmeanfor
corrected SULmean
the exact same lesions by reviewing the baseline and 1m FU
value.
corrected SUL value.
images side-by-side. A TLG* value of 0 was appointed to lesions that were no
This process was repeated for the 1m FU scan to assess the metabolic tumor response (change in
This process was repeated for the 1m FU scan to assess the metabolic tumor response (change in
longer identified at 1 month FU, because the SULmean had fallen below the detection
TLG*) on a per‐lesion basis. Care was taken to record baseline and FU values for the exact same
TLG*) on a per‐lesion basis. Care was taken to record baseline and FU values for the exact same
threshold.
lesions by
lesions by ROVER
reviewing classified
reviewing the baseline
the multiple
baseline 1m lesions
and 1m
and FU images
FU as side‐by‐side.
images one in theA A case
side‐by‐side. TLG*
TLG* ofvalue
oneof
value hot
of voxel
0 0 was
was
connection. Therefore, in cases in which separate baseline metastasesmean
appointed to lesions that were no longer identified at 1 month FU, because the SUL
appointed to lesions that were no longer identified at 1 month FU, because the SUL appeared
mean
had fallen
had fallen as
‘fused’
below at 1m
the FU,
detection separate
threshold. volumes
ROVER were determined
classified multiple for
lesions the
as metastases
one in the case
below the detection threshold. ROVER classified multiple lesions as one in the case of one hot on magnetic
of one hot
resonance imaging (MRI) of the liver at 1m FU, and multiplied by the mean overall
voxel connection. Therefore, in cases in which separate baseline metastases appeared as ‘fused’
voxel connection. Therefore, in cases in which separate baseline metastases appeared as ‘fused’
at 1m FU, separate volumes were determined for the metastases on magnetic resonance imaging
activity value of the ‘fused’ metastasis to obtain separate TLG* values.
at 1m FU, separate volumes were determined for the metastases on magnetic resonance imaging
(MRI) of
of the
the liver
liver at 1m
1m FU,
FU, and
and multiplied
multiplied by the mean
mean overall activity value of
of the ‘fused’
Next,
(MRI) baseline F-FDG-PET
18 at
and 90Y-PET by the volumes were
overall loaded
activity value into the ROVER
‘fused’
metastasis to obtain separate TLG* values.
and co-registered on the basis of their low-dose CTs, using a built-in rigid
metastasis to obtain separate TLG* values.
Next, baseline 18F‐FDG‐PET and 90 90Y‐PET volumes were loaded into ROVER and co‐registered on
transformation algorithm. TheY‐PET volumes were loaded into ROVER and co‐registered on
Next, baseline 18F‐FDG‐PET and saved tumor ROIs were automatically transferred to
the basis of their low‐dose CTs, using a built‐in rigid transformation algorithm. The saved tumor
thethe basis of their low‐dose CTs, using a built‐in rigid transformation algorithm. The saved tumor
90
Y-PET volumes after overlaying90 on the co-registered 18F-FDG-PET volume,
ROIs were automatically transferred to the 90 Y‐PET volumes after overlaying on the co‐registered
ROIs were automatically transferred to the
enabling recovered activity calculations Y‐PET volumes after overlaying on the co‐registered
in Bq/ml for each metastasis (see Figure 1
18F‐FDG‐PET volume, enabling recovered activity calculations in Bq/ml for each metastasis (see
18F‐FDG‐PET volume, enabling recovered activity calculations in Bq/ml for each metastasis (see
forFigure 1 for an example).
an example).
Figure 1 for an example).
A correction factor (branching
A correction factor (branching ratio
ratio10
10
) wasapplied
) was then then to applied to thisactivity
this recovered recovered activity
to adjust for
A correction factor (branching ratio10) was then applied to this recovered activity to adjust for
to the difference in specific positron branching fraction between the isotope selected in the scanner
adjust for the difference in specific positron branching fraction between the
the difference in specific positron branching fraction between the isotope selected in the scanner
Part IV Chapter 15
isotope selected
settings (β in the scanner settings (βx, in90
x, in our case zirconium‐89 = 0.2275) and our90Ycase
Y (β zirconium-89
= 31.86 x 10 ‐6): = 0.2275) and
settings (βx, in our case zirconium‐89 = 0.2275) and 90Y (β
90Y = 31.86 x 10 ):
‐6
90
Y (β90Y = 31.86 x 10-6):

��
�� β�
�� β�� β�
β��

TheThe corrected activity at time of
corrected activity at time 90Y‐PET acquisition was recalculated to the corrected activity at
of 90Y-PET acquisition was recalculated to the
The corrected activity at time of 90Y‐PET acquisition was recalculated to the corrected activity at
time of treatment by adjustment for the radioactive decay. Consequently, tumor absorbed doses
corrected activity at time of treatment by adjustment for the radioactive decay.
time of treatment by adjustment for the radioactive decay. Consequently, tumor absorbed doses
were calculated as follows:
Consequently, tumor absorbed doses were calculated as follows:
were calculated as follows:

�50 �� ⁄��
�� 50 �� ⁄��
�� 1.06 �/��⁄1000
�� 1.06 �/��⁄1000

Liver tumor dose (i.e., tumor absorbed dose averaged over all liver metastases) was determined
Liver tumor dose (i.e., tumor absorbed dose averaged over all liver metastases) was determined
in a similar fashion, using the summed corrected activity and ROI volume for all liver metastases
in a similar fashion, using the summed corrected activity and ROI volume for all liver metastases
within a patient’s liver to fill in the former equation. Total liver dose (i.e., total absorbed dose in
- 281 -
within a patient’s liver to fill in the former equation. Total liver dose (i.e., total absorbed dose in
5
Figure 1: Example of the quantitative PET analyses in ROVER. A) The baseline 18F-FDG-PET scan was
used to delineate multiple metastases, and determine the TLG* per metastasis (for example #1 1042, #2
496). B) The 90Y-PET scan was used to determine the tumor absorbed dose on a per-lesion basis (#1 76
Gy, #2 14 Gy). Metastasis #1 in the right hemi-liver showed a complete metabolic response at 1 month
posttreatment, whereas residual metabolic activity was present in the exophytic growing metastasis #2
in segment 2. C-D) The low-dose CTs of the PET scans were used for image registration.
Chapter 15 Part IV
Liver tumor dose (i.e., tumor absorbed dose averaged over all liver metastases)
was determined in a similar fashion, using the summed corrected activity and ROI
volume for all liver metastases within a patient’s liver to fill in the former equation.
Total liver dose (i.e., total absorbed dose in the entire treated liver) was determined
using the net administered activity – calculated by dose calibrator measurements
of the activity not injected – and the treated liver volume. The (first) treated liver
lobe was included in the analysis in patients who received treatment of only a
single lobe, or sequential treatment of both lobes.
- 282 -
Scanner equipment, acquisition and image reconstructions

All PET/CT images were acquired on a Siemens Biograph™ mCT Time-of-Flight
PET/CT scanner with TrueV (Siemens Healthcare, Erlangen, Germany). Our
acquisition protocol for 18F-FDG-PET scans has been published elsewhere, and
includes daily quality controls.11 The PET/CT scans for 90Y-PET quantification
were obtained on the day of treatment or the day after. This acquisition protocol
consisted of two 20-minutes bed positions. Image reconstructions were performed
with an iterative reconstruction algorithm, containing point spread function model
and time of flight information, using 4 iterations with 21 subsets and a 5 mm full-
width at half maximum Gaussian post-reconstruction filter. A model-based scatter
correction method was used. Reconstructed voxel size was 2x2x2 cm3. A low dose
CT was acquired for attenuation correction, using an effective tube current time-
product of 40 mAs per rotation, an effective tube potential of 120 kV, and a slice
thickness of 3 mm.
Descriptive analyses were performed to summarize patient demographics,
treatment characteristics, as well as TLG* and radiation absorbed dose values.
A linear mixed effects regression (LMER) model was fitted to evaluate the
relationship between tumor absorbed dose and posttreatment TLG* at 1m FU,
adjusted for baseline TLG*, on a per-lesion basis. A more detailed explanation of
this method can be found in the supplemental data.
Metabolic tumor and liver response were defined as ≥ 50 % decrease in TLG* at
1m FU for a metastasis or the sum of all liver metastases in a patient respectively.
Univariable survival analysis was used to compare estimates in median overall
survival (OS) between patients with and without metabolic liver response, as well
as average liver tumor dose > 60 Gy and < 60 Gy. OS was defined as the interval
Part IV Chapter 15
between treatment and death or last contact (date of censoring).
All analyses were performed with R version 3.1.2. A two-sided p value < 0.05 was
considered statistically significant.
RESULTS
Patient demographics and treatment characteristics
Twelve of 42 patients were excluded for the following reasons: no post-
radioembolization 90Y-PET/CT (n = 10), baseline 18F-FDG-PET/CT not obtained
at our institute (n = 1), and no 18F-FDG-PET/CT at 1m FU (n = 1).
Baseline characteristics of the 30 included patients are summarized in Table 1.
- 283 -
Table 1: Baseline characteristics (30 patients)

Gender
Male 19 (63 %)
Female 11 (37 %)
Age (years) 63 ± 12
Liver metastases
Synchronous 24 (80 %)
Metachronous 6 (20 %)
WHO performance status
0 16 (53 %)
1 13 (43 %)
2 1 (3 %)
Previous systemic therapy lines
0 0 (0 %)
1 12 (40 %)
2 11 (37 %)
>2 7 (23 %)
Received bevacizumab
Yes 17 (57 %)
No 13 (43 %)
Extrahepatic disease before treatment
Yes 10 (33 %)
Lymph node 5
Lung 2
Bone 3
Recurrence (colon/rectum) 3
Other 4
No 20 (67 %)
Tumor burden (% of whole liver)
< 25 % 27 (90 %)
25 – 50 % 3 (10 %)
> 50 0
Chapter 15 Part IV
Metabolic tumor volume (ml) 301 ± 248

Baseline characteristics of the included 30 patients are displayed in this table. Values are given as
number of patients (% of total) or mean ± standard deviation. Metabolic tumor volume is the total
volume of metastases as delineated on 18F-FDG-PET at baseline.
Mean prescribed 90Y activity was 1827 ± 294 MBq. In two patients (7 %), reduction
in prescribed activity was necessary due to a liver-to-lung shunt fraction > 10 %.
Whole liver treatment was performed in 25 patients (83 %). Only a single lobe was
treated in 3 patients (10 %), and 2 patients (7 %) were treated with a sequential
lobar approach. The mean net administered 90Y activity was 1751 ± 331 MBq,
corresponding to a mean total liver dose of 50 ± 20 Gy (range, 18 – 109 Gy).
- 284 -
Tumor dose and metabolic tumor response

A total of 113 metastases were delineated with a median number of 3 metastases
per patient (range 1 – 9). Mean tumor absorbed dose was 51 ± 28 Gy (range 7 – 174
Gy [Table 2]). In 28 patients (93 %), tumor absorbed dose exceeded 10 Gy in all
metastases; this was 21 (70 %) for > 20 Gy, 14 (47 %) for > 30 Gy, 6 (20 %) for > 40
Gy, 3 (10 %) for > 50 Gy, and 1 (3 %) for > 60 Gy. Fifty-two of 113 metastases (46
%) had a metabolic tumor response.
Mean liver tumor dose (averaged over all metastases per patient) was 57 ± 26 Gy
(range, 18 – 109 Gy), corresponding to a mean tumor-to-total-liver dose ratio of
1.3 ± 0.6 (range, 0.5 – 3.2). Eleven of 30 patients (37 %) had a metabolic liver
response.
Table 2: Results – Tumor absorbed dose and metabolic tumor response

Individual metastases Sum of all metastases within the liver
Tumor absorbed dose 51 ± 28 Gy (7 – 174) 57 ± 26 Gy (18 – 109)
Baseline TLG* 177 (28 – 5891, 459) 1350 (181 – 5891, 2212)
Posttreatment TLG* at 1m FU 115 (0 – 7111, 478) 1016 (0 – 7341, 2786)
Metabolic response rate 52/113 (46 %) 11/30 (37 %)
Tumor absorbed dose and metabolic tumor response results on the level of individual metastases
(n = 113) and for the sum of all metastases per liver (n = 30). Data are presented as mean ± standard
deviation (range), median (range, interquartile range), or n (%).
Dose-response relationship
The relation between tumor absorbed dose, baseline TLG* and posttreatment TLG*
was best explained by a LMER model using a linear function of dose, a quadratic Part IV Chapter 15
function of baseline TLG*, and a logarithmic transformation of posttreatment
TLG* (log [1m FU TLG* + 8]).
A strong, and statistically significant dose-response relationship was found, with
the dose-effect depending on baseline TLG* (Table 3, Figures 2A and 2B). Increasing
tumor absorbed dose values were associated with better metabolic tumor response
(decreased posttreatment TLG*, Figure 2A), and metastases with high baseline
TLG* required higher tumor absorbed doses to show a reduction in metabolic
activity than metastases with lower baseline TLG* (Figure 2B). By conservative
estimation, at least 40 – 60 Gy is required to induce a 50 % reduction in TLG* for a
metastasis with an average baseline TLG* value.
- 285 -
B
Chapter 15 Part IV
Figure 2: Dose-response curves estimated by the LMER model. A) Illustration of the relationship
between tumor absorbed dose (x-axis) and metabolic tumor response (y-axis, 1m FU TLG* : baseline
TLG*) for a metastases with a mean baseline TLG* value (black line). The blue lines indicate associated
95 % confidence interval bands. By conservative estimation, at least 40 – 60 Gy is required for a 50 %
TLG* reduction (intersection of black line and upper 95 % CI line with dotted reference line). B) The
added color grading in this illustration indicates how the dose-response curve differs for other levels
of baseline TLG* (increasing from green to orange and red). With increasing absorbed dose, metabolic
tumor response is more likely, but with increasing baseline TLG* (i.e. color grading) tumor response is
less likely. Metastases with a high baseline TLG* value need to absorb a higher radiation dose to achieve
the same metabolic tumor response as metastases with a lower baseline TLG*.
- 286 -
Table 3: Results – Summary of the LMER model for TLG* at 1 month posttreatment as a function of
tumor absorbed dose and baseline TLG*
Fixed effects Direction of association P value
Tumor absorbed dose Negative 1.9 x 10-7
Baseline TLG* Positive 2.2 x 10-16
Interaction (Dose:Baseline TLG*) Negative 1.4 x 10-3
This table summarizes the most important findings of the LMER model. The direction of association
is shown in this table, instead of the regression coefficients, to simplify the interpretation of this
complex model. The negative direction of association for tumor absorbed dose for example indicates
a negative regression coefficient, meaning that increased tumor absorbed dose is associated with
decreased posttreatment TLG*. Exact p values are given for the fixed effects.
The model with and without the random patient-level intercept explained 78 and
56 % of the variation in 1m FU TLG* respectively.
Rerunning the analysis without the fused lesions or without truncation of baseline
TLG* values did not diminish the dose-response relationship.
Exploratory survival analysis
Median OS was 9.4 months (95 % CI 5.4 – 11.8 months). Exploratory survival
analysis suggested a significant association between metabolic liver response and
OS (log-rank test, p = 0.02). Estimated median OS time was 11.6 months (95 % CI
11.51 – ∞, n = 11) and 6.6 months (95 % CI 4.8 – 11.7, n = 19) in patients with and
without metabolic liver response respectively (Figure 3A). Median TLG* was 987
(range, 256 – 3374) at baseline and 240 (range, 0 – 1185) at 1m posttreatment for
responders. In the non-responders, median TLG* was 2266 (range, 181 – 5891)
Part IV Chapter 15
Figure 3: Survival curves stratified on metabolic liver response and average liver tumor dose. A) Patients
with (blue line) metabolic liver response (50 % decrease in TLG* at 1 month posttreatment) showed a
significantly longer median OS than non-responders (red line). B) Patients with an average liver tumor
dose exceeding 60 Gy (blue line) showed a trend of longer median OS than those with a lower liver
tumor dose (red line).
- 287 -
at baseline and 2892 (range, 104 – 7341) at 1m posttreatment. Patients with an

average liver tumor dose > 60 Gy showed a trend (p = 0.05) of longer median
overall survival (Figure 3B): 5.3 months (95 % CI 4.4 – 14.3, n = 18) versus 11.5
months (95 % CI 10.6 – ∞, n = 12).
DISCUSSION
This study is the first prospective study to report a dose-response relationship in
patients with CRLM treated with 90Y-radioembolization. With the currently used
methods for activity prescription, tumor absorbed doses were unexpectedly low
and showed a strong intra-patient heterogeneity. Our results show that metastases
with a higher tumor absorbed dose have better metabolic tumor response at
one month posttreatment, a relation that was more pronounced in metastases
with a high baseline metabolic activity. Furthermore, metabolic liver response
was associated with prolonged OS, which further supports the idea that tumor
absorbed dose optimization improves patient outcome.
The success of radioembolization as a salvage treatment for patients with CRLM
and other tumor types has brought investigations to a critical point. Now, several
large, multicenter RCTs are investigating the benefit of adding radioembolization
treatment to systemic therapy in the first and second-line treatment of CRLM.12
These trials have the potential to define the role of radioembolization in the
treatment paradigm for CRLM.
The results of our study are critical for a well-informed interpretation of these trials.
For one, prescribed activity calculation methods are not yet optimized. The BSA-
method, used for radioembolization with resin 90Y microspheres, does not account
for liver mass or expected intrahepatic microsphere distribution. The mono-
compartmental medical internal radiation dosimetry method, recommended
Chapter 15 Part IV
for the use of glass 90Y microspheres, is only slightly more patient specific; it
incorporates a target dose for the entire liver and adjusts for the liver mass. Yet,
inter-patient variability is neglected with both methods, as if radioembolization
were a ‘one-size-fits all’ treatment.
The results of our study prove this assumption to be false. A true heterogeneity
in absorbed dose distribution exists, between and within patients. Furthermore,
tumor absorbed doses observed in our study were relatively low; only 20 % of
patients had a tumor absorbed dose > 40 Gy in all metastases, whereas the dose-
response curve indicated 40 – 60 Gy as effective values for average metastases.
Current pretreatment 90Y activity calculations curb the maximum tolerable healthy
liver tissue dose. As a consequence, a metabolic tumor response was achieved in
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less than half of metastases, and metabolic liver response in only one-third of
patients. Although the patients in our trial were heavily pretreated salvage patients,
this seems insufficient.
Thus, a more personalized approach to radioembolization is needed to optimize
tumor dose delivery in patients with CRLM. This requires several changes to
the current treatment paradigm. Using a scout dose of radioactive microspheres
during the preparatory angiography may prove better suited to predict the
therapeutic microsphere distribution than 99mTc-MAA.13 Once the therapeutic
microsphere distribution can be predicted, pretreatment activity calculation can
be tailored to the individual patient with the previously described artery-specific
partition model, yielding a distribution-specific maximum tolerable treatment
activity.14 Furthermore, different strategies may improve tumor targeting during
the treatment procedure itself, including the use of a vasoconstrictor or another
catheter type to affect hemodynamics.15-16 A better understanding of the dose-
response relationship also creates a framework for the measurement of technical
success after treatment, both in clinical practice and in research. If, for example,
posttreatment 90Y-PET demonstrates a subtherapeutic tumor absorbed dose in
a metastasis in clinical practice, additional treatment with another therapeutic
modality or selective retreatment with radioembolization may be considered. In
a research setting, investigators should implement in vivo dose quantification into
their study protocol and report tumor absorbed dose data. This may help readers
to distinguish between suboptimal tumor response rates due to technical failure or
refractory disease.
Interestingly, we found that the dose-effect is dependent on the baseline TLG*. To
the best of our knowledge, this has not been reported before. With increasing tumor
volume, a homogeneous 90Y microsphere distribution in the tumor compartment
Part IV Chapter 15
becomes less likely, so a high tumor absorbed dose may be required in metastases
with a high baseline TLG* to ensure a minimum dose throughout the entire tumor.
In addition, the aggressive nature of metastases with a high baseline TLG* may
render these tumors less likely to respond to therapy. The dependency of the dose-
effect on baseline metabolic activity suggests that one threshold for an effective
tumor absorbed dose following radioembolization may be too simplistic. Further
research has to show whether our range of effective tumor absorbed dose values as
a function of baseline metabolic activity can be further refined.
Distinctive strengths of our investigation include the prospective study design that
ensures standardization of study procedures, the per-lesion basis analyses, the use
of a LMER model that accounts for data clustering, actual quantitative absorbed
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dose measurements on 90Y-PET, and the use of objective metabolic tumor response
parameters based on 18F-FDG-PET.
Previous studies have reported retrospective data to support a dose-response
association for radioembolization treatment, but failed to uncover the nature of
this relationship in patients with CRLM.17-20 The majority of other dose-response
evaluations in radioembolization studies either focused on hepatocellular
carcinoma or used glass 90Y microspheres. The dose-response associations derived
from these studies are, however, not directly comparable to our findings. For one,
radiosensitivity may be dependent on tumor type, similar to findings in external
beam radiotherapy.21 Furthermore, tumor absorbed dose values are generally higher
with glass microspheres, but this does not necessarily imply greater treatment
efficacy. This may be attributed to the fact that glass microspheres are injected in
lower numbers, but with much higher specific activity per sphere. Furthermore,
treatment with resin microspheres likely results in a combined embolic and
radiation effect, while glass microspheres rely much heavier on radiation alone.
Our study also had several limitations. First, the number of study patients was
limited, and substantial inter-patient heterogeneity existed despite similar tumor
types and disease stages. Therefore, the variation explained by the LMER model
heavily depended on the random intercept. Consequently, our model’s ability to
predict metabolic tumor response on the basis of tumor absorbed dose may be
limited in an external dataset. Furthermore, it seems reasonable to assume that the
observed tumor response is a consequence of absorbed radiation doses, because
all patients had confirmed progressive disease at time of inclusion in our study, no
competing therapies were given, and we adjusted for baseline TLG*, which contains
information about the volume and metabolic activity of individual metastases.
Nonetheless, we cannot rule out potential confounding by tumor biology. Second,
Chapter 15 Part IV
we only measured tumor response at 1m FU. Third, since the found dose-response
relationship is specific for resin 90Y microspheres radioembolization in salvage
patients with CRLM, validation in other disease stages, tumor types and type of
microspheres is required. Fourth, the generalizability of TLG* values is limited.
They are not a biological constant, but depend on the use of specific hardware,
image acquisition and reconstruction protocol, and image analysis software
for 18F-FDG-PET scans. Fifth, the co-registration of the baseline 18F-FDG-PET
and 90Y-PET images is challenging, and small registration errors are currently
unavoidable.
With the increasing application of radioembolization as a treatment for CRLM,
and a gradual shift towards earlier disease stages, it is of paramount importance
to critically reflect on the current status of this technique and acknowledge
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aspects that are in need for optimization. These aspects need to be improved to
enable a personalized approach to radioembolization that aims for maximum
treatment efficacy while respecting safety concerns. The limitations of current
radioembolization practice should also be considered when interpreting the results
of large RCTs.
CONCLUSION
A strong dose-response relationship exists for the treatment of CRLM with resin
microspheres 90Y-radioembolization. Treatment efficacy is however still limited,
because the currently used pretreatment activity calculation methods curb
potentially achievable tumor absorbed dose values. A more personalized approach
to radioembolization is required before concluding on its clinical potential.
Part IV Chapter 15
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REFERENCES
1. Kennedy A (2014) Radioembolization (STROBE) statement: Guidelines for
of hepatic tumors. J Gastrointest Oncol reporting observational studies. J Clin
5:178–189. Epidemiol 61:344-349.
2. Rosenbaum CENM, Verkooijen HM, Lam 9. Wahl RL, Jacene H, Kasamon Y, Lodge MA
MGEH, et al. (2013) Radioembolization for (2009) From RECIST to PERCIST: Evolving
treatment of salvage patients with colorectal considerations for PET response criteria in
cancer liver metastases: A systematic solid tumors. J Nucl Med 50 (supplement
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3. Dutton SJ, Kenealy N, Love SB, et al. 10. Pasciak AS, Bourgeois AC, Bradley YC
(2014) FOXFIRE protocol: An open- (2014) A comparison of techniques for
label, randomised, phase III trial of (90)Y PET/CT image-based dosimetry
5-fluorouracil, oxaliplatin and folinic acid following radioembolization with resin
(OxMdG) with or without interventional microspheres. Front Oncol 4:121.
selective internal radiation therapy (SIRT)
as first-line treatment for patients with
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unresectable liver-on. BMC Cancer 14:497.
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4. Cremonesi M, Chiesa C, Strigari L, et workup for yttrium-90 radioembolisation
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lesions from a radiobiology and dosimetric metastases. Eur Radiol 23:931–937.
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12. Braat AJAT, Smits MLJ, Braat MNGJA, et
5. Mahnken AH, Spreafico C, Maleux G, et al. al. (2015) 90Y hepatic radioembolization:
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Radiol 36:613–622.
13. Prince JF, van Rooij R, Bol GH, et al.
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(2011) EANM procedure guideline for hepatic radioembolization with 166Ho
the treatment of liver cancer and liver microspheres. J Nucl Med 56:817–823.
Chapter 15 Part IV

14. Kao YH, Hock Tan AE, Burgmans MC,
et al. (2012) Image-guided personalized
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predictive dosimetry by artery-specific
7. van den Hoven AF, Smits MLJ, de Keizer SPECT/CT partition modeling for safe and
B, et al. (2014) Identifying Aberrant effective 90Y radioembolization. J Nucl Med
Hepatic Arteries Prior to Intra-arterial 53:559–566.
Radioembolization. Cardiovasc Intervent
Radiol 37:1482-1493.
CENM, et al. (2014) The effect of intra-
8. von Elm E, Altman DG, Egger M, Pocock arterial angiotensin II on the hepatic
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(2008) The strengthening the reporting radioembolization: A systematic review.
of observational studies in epidemiology PLoS One 9:e86394.
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16. Pasciak AS, McElmurray JH, Bourgeois 19. Lam MGEH, Banerjee A, Goris ML, et al.
AC, et al. (2015) The impact of an (2015) Fusion dual-tracer SPECT-based
antireflux catheter on target volume hepatic dosimetry predicts outcome after
particulate distribution in liver-directed radioembolization for a wide range of
embolotherapy: A pilot study. J Vasc Interv tumour cell types. Eur J Nucl Med Mol
Radiol 26:660-669. Imaging. 42:1192-1201.
17. Flamen P, Vanderlinden B, Delatte 20. Demirelli S, Erkilic M, Oner AO, et al.
P, et al. Multimodality imaging can (2015) Evaluation of factors affecting tumor
predict the metabolic response of response and survival in patients with
unresectable colorectal liver metastases to primary and metastatic liver cancer treated
radioembolization therapy with yttrium-90 with microspheres. Eur J Gastroenterol
labeled resin microspheres. Phys Med Biol. Hepatol 36:340-349.
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21. Lausch A, Sinclair K, Lock M, et
18. Lam MGEH, Goris ML, Iagaru AH (2013) al. Determination and comparison
Prognostic utility of 90Y radioembolization of radiotherapy dose responses for
dosimetry based on fusion 99mTc- hepatocellular carcinoma and metastatic
macroaggregated albumin-99mTc-sulfur colorectal liver tumours. Br J Radiol
colloid SPECT. J Nucl Med 54:2055-2061. 86:20130147.
Part IV Chapter 15
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SUPPLEMENTAL DATA
This supplemental data document provide information about the validation
process of the method for quantitative 90Y-PET analyses and the linear mixed
effects regression model used in our study.
Background
Quantitative analyses of the posttreatment 90Y activity distribution after
radioembolization have been challenging due to the lack of positron and γ-ray
emission. The first method to become available was the detection of secondary
γ-rays, a product of bremsstrahlung, on SPECT. Unfortunately, bremsstrahlung
SPECT proved to be of little clinical value for dose quantification in small tumors
(< 2 – 3 cm), due to its limited spatial resolution and high scatter. Nowadays, the
quantitative accuracy of bremsstrahlung SPECT can be improved by specialized
reconstruction algorithms, as demonstrated in previous phantom studies1-2, but
this is computationally intensive and not widely available in clinical practice.
The acknowledgement that the 90Y activity distribution can also be quantified on
PET, utilizing the naturally occurring phenomenon of internal-pair production3-5,
sparked a renewed interest in 90Y imaging.6-7 Since then, an abundance of
scientific evidence has shown that quantification of 90Y absorbed doses on PET is
valid6,8-9, superior to bremsstrahlung SPECT10-12, and accurate enough for clinical
practice13-16.
So far, no commercial software package has been specifically developed and
validated for quantitative analyses of 90Y-PET images. We used ROVER software
(ABX GmBH, Radeberg, Germany) for this purpose. This software was originally
developed and validated for quantitative analysis of 18F-FDG-PET scans, allowing
for threshold-based automatic tumor delineation and partial volume correction.17-20
It also enables co-registration of different scans and ROI transfers between them,
Chapter 15 Part IV
so that tumors can be identified on 18F-FDG-PET and absorbed doses can be

determined in the same locations on 90Y-PET. Slight differences between 18F and 90Y
quantification are to be expected, mainly due to extremely low positron abundance
of 90Y (32 x 10-6 versus 0.98 for 18F). In a recent phantom study, it was demonstrated
that quantification of 90Y activity in spheres with a diameter of 10 – 30 mm on PET
was similar when using ROVER or three other software packages.21
Validation of 90Y-PET analyses: Phantom experiments
To validate our 90Y-PET measurements, phantom experiments were performed
and analyzed with ROVER. First, a cylindrical phantom with a capacity of 6266 g
was filled with a hydrochloric acid solution (concentration 1M), and 3.09 GBq of
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90
Y citrate. The total 90Y activity in the phantom was measured with the same dose
calibrator as used in clinical radioembolization procedures to confirm the activity
at starting point. Subsequently, PET images of this phantom were acquired directly
after filling the phantom and at four different time points. Finally, the 90Y-PET
images were analyzed in ROVER to determine the recovered activity by drawing a
total phantom ROI. These measurements were then compared to the real activity at
the different time points, as calculated by the decay curve of 90Y (T½ = 64 hours).
An excellent correlation (R2 = 0.999) was found between the PET measurements
and actual activity from dose calibration (Supplemental Table 1, Supplemental
Figure 1). Compared with the actual activity, recovered activity measures showed
a maximum error of -4.7 % down to an activity of 500 kBq/ml, which supports the
validity of the 90Y-PET acquisitions and analyses in ROVER.
Supplemental Table 1: Difference between the actual Y activity in the phantom and the activity
90
recovered on Y-PET
90
Time Actual Recovered Recovered -

activity (MBq) activity (MBq) Actual activity (% error)
T0 3089 3038 - 51 (-1.7 %)
0.01*T½ 3069 2924 -145 (-4.7 %)
1.89*T½ 835 807 -29 (-3.4 %)
2.26*T½ 645 628 -18 (-2.8 %)
2.62*T½ 500 515 +15 (+ 3 %)
For five different time points, the actual and recovered 90Y activity is given in MBq. The percentage of
error is calculated as follows: (recovered – actual activity)/actual activity * 100. T½ = half-life.
Part IV Chapter 15
Supplemental Figure 1: Scatterplot showing a linear relationship between 90Y-PET recovered activity
measures and the actual activity in a 6266 g cylindrical phantom filled with a hydrochloric acid
90
Y-citrate solution, at five different time points. This relationship can be described by: Actual activity
(MBq) = -13.38 MBq + 1.04 x Recovered activity. The correlation was excellent (R2 = 0.999). Compared
with the actual activity, recovered activity measures showed a maximum error of -4.7 % down to an
activity of 500 kBq/ml.
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Validation of 90Y-PET analyses: Clinical patients

As an extra validation step, net administered 90Y activity at time of scanning was
compared with the recovered 90Y-PET activity in the liver. The net administered 90Y
activity at the time of scanning was calculated by subtracting the residual activity
in the administration vial (measured by the dose calibrator) from the prepared
activity corrected for the radioactive decay between administration and the scan.
To determine the recovered 90Y-PET activity, a mask was placed over the entire
liver (slightly extending across all edges), and the total activity within this mask
was determined in Bq.
Supplemental Figure 2: Scatterplot showing a linear relationship between recovered whole liver activity
on 90Y-PET and the net administered activity at time of the scan in all 30 patients. This relationship can
be described by: Activity at scan time (MBq) = 199 MBq + 0.78 x Recovered liver activity.
Chapter 15 Part IV
Supplemental Figure 3: Bland-Altman plot showing a fair agreement between recovered whole liver
activity on 90Y-PET and the net administered activity at time of the scan (95 % limits of agreement:
-140 – 482 MBq). The recovered 90Y activity measurements overestimate the net administered activity,
with increasing overestimation for higher activities. This may be explained by scatter detection at the
liver-lung surface.
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A strong correlation and fair agreement was found between the mean 90Y-PET
recovered liver activity and the mean administered activity at scan time
(Supplemental Figures 2 and 3). A small overestimation of the administered activity
may be attributable to scatter detection at the liver-lung surface, which was avoided
in tumor absorbed dose quantification. Thus, quantitative 90Y-PET analyses were
considered accurate.
Linear mixed effects regression model
A linear mixed effects regression (LMER) model was fitted to evaluate the
relationship between tumor absorbed dose and posttreatment TLG* at 1m FU,
adjusted for baseline TLG*, on a per-lesion basis.
The mixed model accounted for within patient clustering by random intercept.22
We anticipated that the effect of tumor absorbed dose on 1m TLG* may depend
on the baseline TLG*, and therefore included an interaction term (Dose:Baseline
TLG*). An analysis of variance method with a Chi-square test was used to compare
nested models and generate p values for the fixed effects.
To fulfill model assumptions, posttreatment TLG* was logarithmically transformed.
To take potential non-linear relations between dose and baseline TLG* with
posttreatment log(TLG*+8) into account, we first evaluated transformations of
these variables and selected the transformations providing the lowest Aikaike’s
Information Criteria value for a model containing these variables and their
interaction. The top 10 % of baseline TLG* values were truncated before these
analyses to prevent inappropriate influential points.
The model explained variance, with and without random intercept, was assessed
with R2 for mixed effects models.23
The model-derived relation between dose and metabolic response and its
dependency on baseline TLG* was graphically displayed (including 95 %
Part IV Chapter 15
confidence interval lines) after back transformation of all involved variables to
their original scale.
The package ‘lme4’ (version 1.1-7) was used for LMER modeling in R version 3.1.2.
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1. Minarik D, Sjögreen Gleisner K, Ljungberg assessment and accurate quantification of
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10. Padia SA, Alessio A, Kwan SW, et al.
2. Rong X, Du Y, Ljungberg M, Rault (2013) Comparison of positron emission
E, Vandenberghe S, Frey EC (2012) tomography and bremsstrahlung imaging
Development and evaluation of an improved to detect particle distribution in patients
quantitative (90)Y bremsstrahlung SPECT undergoing yttrium-90 radioembolization
method. Med Phys 39:2346-2358. for large hepatocellular carcinomas or
associated portal vein thrombosis. J Vasc
3. Gates VL, Esmail AAH, Marshall K, Spies
Interv Radiol 24:1147-1153.
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of 90Y permits hepatic localization of 11. Lam MGEH, Wondergem M, Elschot
microspheres using routine PET: Proof of M, Smits MLJ. (2013) Reply: A clinical
concept. J Nucl Med 52:72-76. dosimetric perspective uncovers new
evidence and offers new insight in favor
4. D’Arienzo M (2013) Emission of β+
of 99m
Tc-macroaggregated albumin
particles via internal pair production in
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the 0+ – 0+ transition of 90Zr: historical
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background and current applications in
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following radioembolization with resin
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(2013) Assessment of acquisition protocols
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for routine imaging of Y-90 using PET/CT.
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EJNMMI Res 3:11.
tumor predictive dosimetry for resin
8. Attarwala AA, Molina-Duran F, Büsing KA, microspheres. EJNMMI Res 3:57.
et al. (2014) Quantitative and qualitative
15. Lea WB, Tapp KN, Tann M (2014)
assessment of yttrium-90 PET/CT imaging.
Microsphere localization and dose
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quantification using positron emission
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intraarterial radioembolization with 19. Hofheinz F, Langner J, Petr J (2012) A
yttrium-90 in patients with advanced method for model-free partial volume
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(2013) Absorbed dose to lesion and clinical An automatic method for accurate volume
outcome after liver radioembolization with delineation of heterogeneous tumors in
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of quantitative 90Y PET/CT for dosimetric
17. Torigian DA, Lopez RF, Alapati S, et al. purposes after radioembolization with
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software to quantify metabolically active 1222.
volumes and 3D partial volume corrected
22. Casals M, Girabent-Farrés M, Carrasco
SUV and metabolic volumetric products
JL (2014) Methodological quality and
of spinal bone marrow metastases on
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18F-FDG-PET/CT. Hell J Nucl Med 14:8-14.
models in clinical medicine (2000–2012): A
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software tool and comparison with
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C hap ter
PART IV 16
Anatomical versus metabolic
tumor response assessment after
radioembolization treatment
A.F. van den Hoven

C.E.N.M. Rosenbaum
M.N.G.J.A. Braat
M.S. van Leeuwen
D.Y. Sze
M.G.E.H. Lam
Submitted
Anatomical versus metabolic tumor response assessment after radioembolization treatment
ABSTRACT
Purpose
Size-based criteria for tumor response frequently underrepresent the effects of
locoregional therapy for colorectal cancer liver metastases (CRLM), and contrast
enhancement-based viability criteria are not applicable in hypovascular tumors.
We compared metabolic response assessment by 18F-FDG-PET/CT to size-based
assessment (RECIST) by their correlations to overall survival (OS) after treatment
by hepatic radioembolization.
Methods
A prospective cohort study was performed on patients with CRLM undergoing
radioembolization. MRI and 18F-FDG-PET/CT imaging were performed at
baseline, 1 and 3 months follow-up. Longest tumor diameter (LTD) reduction on
MRI at 1 and 3 months was compared to reduction in total lesion glycolysis (TLG*)
on 18F-FDG-PET/CT, by linear regression and Bland-Altman analysis. Hepatic
response was compared between RECIST and total liver TLG* (TL-TLG*). Tumor
response assessment by both methods was correlated with overall survival (OS).
Results
Important differences in liver response classification by RECIST and TL-TLG* were
found, with TL-TLG* generally indicating a more favorable treatment response
than RECIST. A significant association with prolonged OS was found for reduction
in TL-TLG* at 1 month (hazard ratio [HR] 0.64, p < 0.01) and 3 months (HR
0.43, p < 0.01) by univariable analysis. For reduction in sum of LTD, a significant
association with OS was only found at 3 months posttreatment (HR 0.10, p < 0.01).
Conclusion
TLG* response assessment on 18F-FDG-PET/CT is more sensitive and accurate,
especially at early follow-up, than size-based response assessment on MRI in
patients with CRLM treated by radioembolization. Automated liver response
Chapter 16 Part IV
assessment with TL-TLG* is rapid, reproducible, and prognostic.
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INTRODUCTION
Adequate posttreatment tumor response assessment is essential to enable timely
intervention in cancer patients who show progression of disease, and withhold
unnecessary treatment in patients with disease control. The Response Evaluation
Criteria in Solid Tumors (RECIST) system has been widely adopted, and currently
serves as standard method in oncological care and research. This anatomical
response assessment method relies on the association between change in one-
dimensional tumor diameter on cross-sectional imaging and patient prognosis,
as demonstrated in cytotoxic drug studies.1-3 For other sorts of therapies, it is,
however, questionable whether RECIST is applicable, since treatment response
may not primarily be characterized by tumor shrinkage.
Therefore, other response criteria systems have been developed for specific
purposes: the European Association for the Study of the Liver (EASL) criteria and
modified RECIST (mRECIST) for intra-arterial therapy in primary liver tumors4,5,
the Choi criteria for the treatment of Gastrointestinal Stromal Tumors (GIST)6,
and the Immune-Related Response Criteria (ir-RC) for immunotherapy7.
Now radioembolization (RE) is increasingly applied as a treatment for unresectable
chemorefractory colorectal cancer liver metastases (CRLM), it is important to
critically reflect on the applicability of RECIST in this setting as well. An argument
against the use of RECIST is that tumor shrinkage may also not be the primary
indicator of response.8 Besides, choosing two metastases as target lesions in severely
diseased livers is highly subjective, and their response may not accurately represent
the response of other metastases (non-target lesions). Furthermore, RECIST may
attribute too much significance to the appearance of small new liver lesions with
an unknown prognostic value. Even more so, their appearance may actually
sometimes represent necrosis of previously undetected lesions. Unfortunately,
using alternative response criteria systems based on tumor vascularization is not
an option due to the relatively hypovascular nature of CRLM.
Another approach could be to determine metabolic tumor response on
F-fluordeoxyglucose positron emission tomography/computed tomography
Part IV Chapter 16
18
(18F-FDG-PET/CT). Total lesion glycolysis (TLG) – the product of the mean

standardized uptake value (SUV) and metabolic volume of a tumor – is a parameter
of metabolic activity that especially holds prognostic promise.9-10 Quantification of
total liver TLG can be automated, allowing for an unbiased comparison between
baseline and follow-up scans.
Hence, the purpose of this study is to assess the applicability of metabolic tumor
response assessment on 18F-FDG-PET/CT after radioembolization in patients
with CRLM, by comparison with size-based response assessment on MRI. We
performed the largest prospective cohort study so far.
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METHODS
Patient selection and study design
Between November 2011 and August 2014, 42 patients with CRLM underwent
radioembolization treatment with resin yttrium-90 (90Y) microspheres in a
prospective cohort study (RADAR trial) at the University Medical Center Utrecht.
Patients with unresectable, chemorefractory, liver-dominant metastases had
to meet eligibility criteria for radioembolization to participate in the trial.
Radioembolization workup and treatment were performed in accordance with
current standards of practice.11 All patients received a magnetic resonance imaging
(MRI) scan of the liver and an 18F-FDG-PET/CT at baseline and during follow-
up to assess treatment response. Posttreatment imaging was acquired at 1 month
follow-up, and at 3 months (unless progressive disease per RECIST at the target
lesion, liver or overall level, was noted at the first follow-up). Patients with disease
control at 3 months continued to receive an MRI at 3 months intervals, but no
18
F-FDG-PET/CT. Only the patients with an in-house liver MRI and 18F-FDG-
PET/CT, obtained per protocol, at baseline and follow-up, were included for the
present comparison of tumor response assessment methods.
The medical ethics committee of the University Medical Center Utrecht approved
this study, and informed consent was obtained from all patients before study
inclusion. All study procedures were performed in accordance with the Declaration
of Helsinki.
Image acquisition
MRI scans of the liver were acquired on a 1.5 T scanner (Philips, Best, The
Netherlands), using a SENSE body coil. Our acquisition protocol contained a pre-
contrast T1 weighted (T1W) Turbo Field Echo (TFE) in breath-hold, a respiratory
triggered T2W TFE, in-phase and opposed-phase T1W TFE in breath-hold, and
respiratory triggered diffusion weighted imaging (DWI) with b-values of 10,
150 and 1000 s/m2. An intravenous single-dose injection of gadobutrol (Gd-BT-
Chapter 16 Part IV
DO3A; 0.1 ml/Kg Gadovist of 1.0 mmol/ml at 1 ml/s) was followed by 25 ml of

saline solution at 1 ml/s. Dynamic contrast enhanced (DCE) images were acquired
with a four-dimensional T1W volume-excited imaging method with fat saturation
(4D-Thrive), containing one pre-contrast three-dimensional (3D) dataset and 15
post-contrast 3D datasets (up to 5 min.).12
A Time-of-Flight PET/CT scanner with TrueV capacity (Biograph™ 40 mCT,
Siemens Healthcare, Erlangen, Germany) was used for PET imaging. All patients
had to fast for at least 6 hours before the image acquisition. Subsequently, 2.0 MBq/
Kg of FDG was injected intravenously. After a post-injection delay of 60 minutes,
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images were acquired using a 3D acquisition technique, 216 mm FOV, and 3

minutes per bed position. Low dose attenuation CT images were obtained with a
pitch of 0.8, slice thickness of 10 mm, tube voltage of 120 kV and current exposure
time current of 180 mAs. PET/CT images were reconstructed using ordered subset
expectation maximization iterative reconstruction, including a Gaussian filter, 4
iterations and 21 subsets.13
Response assessments
Anatomical and metabolic tumor response assessments were performed
independently, and by two different raters (MB and AvdH respectively).
Anatomical tumor response was assessed per RECIST 1.1 on liver MRI.3 The
rater was allowed to use any MRI sequence, according to individual preference,
as in clinical practice. The only requirements were that no diffusion-weighted
images were used and that the same sequence at baseline and follow-up was
used. The longest unidirectional tumor diameter (LTD) of all metastases > 1
cm was recorded at baseline and follow-up. The two largest and/or the two best
measurable metastases on the baseline scan were identified as target lesions, and
the other metastases were defined as non-target lesions. The appearance of new
liver metastases during follow-up was recorded.
Metabolic tumor response on 18F-FDG-PET was assessed quantitatively with
ROVER software (ABX GMBH, Radeberg, Germany).14 A scan-specific activity
threshold and a volume restriction were used to let the software automatically
delineate the solitary liver metastases with a metabolic activity exceeding the
background activity of the healthy liver. The activity threshold was based on the
mean aortic blood pool activity (2*SULmean [= SUVmean corrected for lean body
mass]) in the same PET scan, as per PERCIST recommendations for patients with
diseased livers.15 Additionally, a volume restriction of > 5 mm3 was used. After
tumor delineation, a partial volume corrected SULmean value and metabolic
volume was recorded for each metastasis. TLG* (partial volume corrected total
Part IV Chapter 16
lesion glycolysis) was calculated by taking the product of SULmean and metabolic
volume. Total liver TLG* (TL-TLG*) was determined by taking the sum of the
TLG* values for all the individual liver metastases. This entire process was repeated
for the follow-up scans and care was taken that TLG* values were recorded for
the same lesions at follow-up as during baseline, by visual comparison on a side-
to-side view. The TLG* of newly developed metastases was included in follow-up
TL-TLG* values.
First, a comparison of anatomical and metabolic tumor response was done at the
level of the individual metastases, for 1 and 3 months posttreatment separately.
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Given the differences in spatial resolution and method of tumor delineation

between 18F-FDG-PET and MRI, it was expected that differences in tumor
identification could occur. Therefore, it was chosen to use the tumor identification
on 18F-FDG-PET as reference. Only the response of metastases that were identified
on both 18F-FDG-PET and MRI was compared. If a cluster of tumors (as identified
on MRI) appeared fused on 18F-FDG-PET, the sum of the LTDs on MRI was taken
to compare with the metabolic activity on 18F-FDG-PET. Response at the level of
individual metastases was defined as the percentage decline in LTD and TLG* at 1
or 3 months respective to baseline.
Second, the response of the two TLs and the two largest NTLs on MRI (% decline
LTD) was compared, to evaluate whether TL response is representative for response
in other liver lesions.
Third, the classification of liver response as defined by RECIST and TLG* criteria
were compared for 1 and 3 months separately. For RECIST, complete response
(CR) / partial response (PR) / stable disease (SD) / progressive disease (PD) were
defined as a 100 % / ≥ 30 % – < 100 % / > -20 % – < 30 % / ≤ -20 % reduction in
the sum of TL LTD. Appearance of a new liver metastasis indicated PD, regardless
of the reduction in the sum of TL LTD. The TLG* response classification was self-
defined based on reasonable assumption, with CR / PR / SD / PD being a 100 % / ≥
50 % – < 100 % / > -30 % – < 50 % / ≤ -30 % reduction in TL-TLG*. The appearance
of a new liver metastasis was not taken into consideration as a factor, but the TLG*
values of these metastases were included in the TL-TLG*.
Fourth, the association of liver response for RECIST and TLG* criteria with overall
survival (OS) was explored.
Statistical Analysis
Standard descriptive statistics were used to display patient demographics and
summarize response measures. All response measures were converted from
absolute differences (in LTD or TLG*) between baseline and follow-up to
Chapter 16 Part IV
percentages decline, to simplify comparisons.

For all response comparisons, linear relationships were explored by simple linear
regression with calculation of a Pearson’s correlation coefficient (ρ) and R2, and
agreement was determined by Bland-Altman analysis with assessment of the
average difference between two measures, standard deviation of this difference,
and 95 % limits of agreement.
Univariable survival analysis by the Kaplan-Meier method was used to estimate
median OS, including 95 % confidence intervals (CI). A univariable Cox Regression
analysis was used to explore associations between percentage decrease in sum of
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LTD and TL-TLG* at 1 and 3 months and OS. A log-rank test was used to test for
differences between median OS estimates between the different response classes, as
defined per RECIST and TLG-TLG*. Multivariable modeling was not feasible due
to the limited sample size.
All analyses were performed with R version 3.1.2. A two-sided p value < 0.05 was
considered statistically significant.
RESULTS
Patient demographics
A total of 42 patients with unresectable chemorefractory CRLM were treated in
the RADAR trial with resin 90Y microspheres between November 2011 and August
2014. Four patients were excluded from this analysis due to: inability to administer
18
F-FDG intravenously (n=1), baseline 18F-FDG-PET/CT performed at a different
center, and no MRI (n = 1) or 18F-FDG-PET/CT at 1 month follow-up.
The baseline and treatment characteristics for the remaining 38 patients are
summarized in Tables 1 and 2 respectively.
Comparison of lesion response: LTD vs. TLG*
The response of 106 metastases (in 38 patients) was compared at 1 month
posttreatment. Of these, 44 (41 %) appeared ‘fused’ on PET, while being identified
as individual metastases on MRI. Mean ± standard deviation (range) percentage
decrease relative to baseline was 13 ± 25 % (-141 – 65 %) for LTD, and 35 ± 84 %
(-434 – 100 %) for TLG* (Figures 1A-B). There was a positive correlation between
percentage decrease in LTD and TLG* at 1 month posttreatment, but the reduction
in LTD observed generally underestimated the reduction in TLG* (Figures 2B-C).
Much between-tumor heterogeneity was observed.
The 3 months posttreatment response of 58 metastases (in 22 patients) was
compared. Of these, 28 (48 %) appeared ‘fused’ on PET. Mean ± standard deviation
(range) percentage decrease relative to baseline was 16 ± 29 % (-94 – 62 %) for
Part IV Chapter 16
LTD, and 17 ± 106 % (-290 - 100 %) for TLG* (Figures 1C-D). A positive correlation
was also found for percentage decrease in LTD and TLG* 3 months posttreatment
(Figure 2C). The average difference between both measures was smaller at 3 months
(Figure 2D) than at 1 month posttreatment. Yet, again a different outcome for
both response measures was commonly observed. Even more so, the discrepancy
between both measurements increased, as response/progression got more extreme
(Figures 2B and 2D).
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Table 1: Baseline Characteristics (38 patients)

Gender
Female 11 (29 %)
Male 27 (71 %)
Age (years)
Mean (range) 62 (34 - 83)
Liver metastases
Synchronous 29 (76 %)
Metachronous 9 (24 %)
ECOG performance status
0 22 (58 %)
1 14 (37 %)
2 2 (5 %)
Previous chemotherapy lines
0 0
1 14 (37 %)
2 15 (40 %)
>2 9 (23 %)
Previous bevacizumab
Yes 22 (58 %)
No 16 (42 %)
Extrahepatic disease
None 25 (66 %)
Lymph node 7
Lung 2
Bone 3
Recurrence (colon) 3
Other 4
Liver tumor burden
Mean % (range) 15 (1 - 50)
<25 % 33 (87 %)
26-50 % 5 (13 %)
>50 0
This table shows the baseline characteristics for the 38 included patients. The numbers represent
Chapter 16 Part IV
number of patients ( % of total) or mean (range). No percentage of total is given for the extrahepatic
disease site categories, since patients can have multiple sites of extrahepatic disease.
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Table 2: Treatment Characteristics (38 patients)
Reduction of prescribed activity*

Yes 4 (11 %)
No 34 (89 %)
Net administered activity (MBq)
Median (range) 1533 (670 – 2241)
Whole liver dose (Gy)

Median (range) 44 (24 – 78)
Treatment strategy
Whole liver treatment in one session 29 (76 %)
Sequential whole liver treatment 7 (18 %)
Lobar treatment 2 (5 %)
Retreatment after initial progression
Yes 2 (5 %)
No 36 (95 %)
This table shows the most important treatment characteristics for the 38 included patients. The
numbers represent number of patients (% of total) or median (range). * Reduction of prescribed
activity is in accordance with the manufacturers recommendation if the liver-to-lung shunt exceeds
10 %.
A B
C D
Part IV Chapter 16
Figure 1: Waterfall plots demonstrating TLG* (A, C) and LTD (B, D) reduction on a per-lesion basis, at
1 (A, B) and 3 (C, D) months. Notice that the waterfall plots for TLG* and LTD response resemble each
other in shape, but the response/progression signal appears amplified for TLG*.
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A B
C D
Figure 2: Comparison of diameter and TLG* reduction, on a per-lesion basis. A-B) Linear regression
and Bland-Altman plot for 1 month posttreatment. There was a positive correlation between percentage
decrease in LTD and TLG* with ρ = 0.44 and R2 = 0.19 (A). The average difference between both
measures ± standard deviation was 22 ± 76 %, and 95 % limits of agreement were -128 – 171 % (B). This
indicates that response in LTD generally underestimated the TLG* response. C-D) Plots for 3 months
posttreatment. A positive correlation was also found for percentage decrease in LTD and TLG* 3
month posttreatment, with ρ = 0.66 and R2 = 0.43 (C). The average difference between both measures ±
standard deviation at 3 months was 2 ± 90 %, and 95 % limits of agreement were -174 – 177 % (D). Thus,
the difference between both response measures was on average smaller than at 1 month posttreatment.
Note the positive trend in the Bland-Altman plots for 1 and 3 months posttreatment, indicating that
the difference between LTD and TLG* response increases, as response/progression gets more extreme.
Comparison of TL and NTL response: sum of LTD

In 6 patients no NTLs were identified on the baseline MRI. In the remaining 32 patients,
Chapter 16 Part IV
mean ± (range) percentage decrease in sum of LTD at 1 month was 13 ± 16 % (-13 –

61 %) for TLs (Figure 3A), and 11 ± 24 % (-76 – 39 %) for NTLs. There was a negative
correlation (Figure 4A) and fair agreement (Figure 4B) between percentage decrease in
sum of TL and NTL LTD at 1 month posttreatment.
At 3 months posttreatment, mean ± (range) percentage decrease in sum of LTD in 17
patients was 12 ± 38 % (-95 – 66 %) for TLs (3B), and 22 ± 33 % (-66 – 59 %) for NTLs.
Again, a strong negative correlation (Figure 4C) and fair agreement (Figure 4D) was
found between percentage decrease in sum of TL and NTL LTD.
Thus, TL response only reasonably reflected response in other liver lesions.
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A B C D
Figure 3: Waterfall plots demonstrating total liver TLG* (A, C) and sum of target lesion LTD (B, D)
reduction, at 1(A, B) and 3 months (C, D) posttreatment.
A B
C D
Part IV Chapter 16
Figure 4: Comparison of TL and NTL reduction, on a per-lesion basis. A-B) Linear regression and
Bland-Altman plots for 1 month posttreatment. There was a negative correlation between percentage
decrease in sum of TL and NTL LTD at 1 month, with ρ = 0.57 and R2 = 0.33 (A). The average
difference of both measures was -2 ± 20 %, and 95 % limits of agreement were -41 – 37 % (B). A strong
negative correlation was also found for percentage decrease in sum of TL and NTL LTD at 3 months
posttreatment, with ρ = 0.84 and R2 = 0.78 (C). The average difference was 10 ± 20 %, and 95 % limits
of agreement -31 – 50 % (D). Thus, the percentage reduction in sum of LTD was strongly correlated
between TLs and NTLs, but agreement was fair at best, indicating that TL response only reasonably
reflected response in the other liver lesions.
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Comparison of liver response classification: RECIST vs. TL-TLG*

Important differences in liver response classification were noted between RECIST
and TL-TLG* (Table 3 and 4), with TL-TLG* generally indicating a more favorable
treatment response than RECIST.
At 1 month posttreatment, 6 patients (16 %) had newly appeared liver metastases
on MRI. Local disease control rate at 1 month was 82 % for both RECIST and TL-
TLG*. Objective response rates were 11 % for RECIST and 40 % for TL-TLG*. The
specific proportion of agreement between RECIST and TL-TLG* liver response
classification at 1 month posttreatment was 40 %. A total of 17 patients (45 %) were
found to have progressive disease per RECIST (on either the TL, liver or overall
level) at 1 month. These patients did not have a 3 months follow-up.
At 3 months, new liver metastases were found on MRI in 9 patients (43 %). Local
disease control rates at 3 months were 52 % for RECIST and 67 % for TL-TLG*.
Objective response rates were 24 % for RECIST and 33 % for TL-TLG*. The
specific proportion of agreement between RECIST and TL-TLG* liver response
classification at 3 months posttreatment was 48 %.
Table 3: Liver response classification at 1 month posttreatment

CMR PMR SMD PMD Total
CR 0 0 0 0 0
PR 1 1 2 0 4 (11 %)
SD 1 11 11 4 27 (71 %)
PD 0 1 3 3 7 (18 %)
Total 2 (5 %) 13 (34 %) 16 (42 %) 7 (18 %) 38
This table shows a comparison of the liver response classification per RECIST and TL-TLG* at 1
month posttreatment. Numbers represent number of patients (% of total).
Chapter 16 Part IV
Table 4: Liver response classification at 3 months posttreatment

CMR PMR SMD PMD Total
CR 0 0 0 0 0
PR 3 2 0 0 5 (24 %)
SD 0 1 3 2 6 (29 %)
PD 0 1 4 5 10 (48 %)
Total 3 (14 %) 4 (19 %) 7 (33 %) 7 (33 %) 21
This table shows a comparison of the liver response classification per RECIST and TL-TLG* at 3
months posttreatment. Numbers represent number of patients (% of total).
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Prognostic value of disease control: RECIST and TL-TLG*

Of the 38 patients, 34 were deceased at the time of analysis. Median OS for the
entire cohort was 9.3 months (95 % CI 6.6 – 11.8 months).
A reduction in TL-TLG* at 1 month posttreatment was associated with significantly
prolonged OS as determined by univariable Cox Regression (Hazard Ratio [HR]
0.64, 95 % CI 0.47 – 0.85, p < 0.01), but no such association was found for the
sum of LTD reduction (HR 0.14; 95 % CI 0.01 – 1.43; p = 0.10). At 3 months
posttreatment, both reduction in sum of LTD (HR 0.10; 95 % CI 0.02 – 0.50; p <
0.01) and TL-TLG* (HR 0.43; 95 % CI 0.24 – 0.76; p < 0.01) were associated with
significantly prolonged OS (Table 5).
Survival curves stratified on the separate liver response classes are displayed
in Figure 5. Only TL-TLG* liver response at 1 month posttreatment showed a
significant difference in median overall survival estimates between the different
response classes (log-rank test, p = 0.02).
Table 5: OS estimates per liver response classification

Follow-up Response N patients / Median OS 95 % CI Log-rank test
moment events in months
RECIST
CR 0/0 - -
PR 4/3 15.5 8.2 – ∞
SD 27 / 24 9.9 6.4 – 13.8 p = 0.05
1 month PD 7/7 6.6 4.4 – ∞
posttreatment TL-TLG*
CMR 2/1 19.3 19.3 – ∞
PMR 13 / 11 11.6 8.4 – ∞
p = 0.02*
SMD 16 / 15 8.4 5.3 – 11.8
PMD 7/7 4.4 2.9 – ∞
RECIST
CR 0/0 - -
Part IV Chapter 16
PR 5/2 § 12.3 – ∞
SD 6/5 11.7 11.2 – ∞ p = 0.05
3 months PD 10 / 10 8.7 5.4 – ∞
posttreatment TL-TLG*
CMR 3/2 12.3 11.7 – ∞
PMR 4/2 11.8 10.6 – ∞
p = 0.21
SMD 7/6 13.4 8.2 – ∞
PMD 7/7 9.3 4.8 – ∞
The median OS estimates and corresponding 95 % CI are shown per liver response classes as
defined by RECIST and TL-TLG* at 1 and 3 months posttreatment. § = Cannot be estimated, since
survival probability = 0.5 has not been reached (see Figure 5B, green line). ∞ = infinite.
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A B
C D
Figure 5: Kaplan-Meier survival curves, stratified per liver response classification. See Table 5 for
corresponding survival estimates.
DISCUSSION
In the present study, we have compared changes in TLG* on 18F-FDG-PET with
changes in LTD on MRI after 90Y-radioembolization treatment in 38 patients
with CRLM. This investigation was motivated by the hypothesis that RECIST is
not ideal for tumor response assessment after radioembolization in patients with
CRLM due to the lack of a primary therapeutic effect on tumor diameter, and the
inapplicability of other vascularity based response classifications in hypovascular
CRLM.
On a per-lesion basis, we have found that although changes in LTD and LTG* were
Chapter 16 Part IV
correlated at 1 and 3 months posttreatment, TLG* was more sensitive to change

after radioembolization. This may be explained by the fact that TLG* combines
metabolic activity and three-dimensional volume, thereby not only reflecting the
tumor burden more accurately than a one-dimensional LTD, but also providing
information on the aggressiveness of the tumor. Moreover, only a fair agreement
was found between LTD reduction for TLs and NTLs, indicating that response
classification by RECIST is too dependable on the choice of the target lesions
at baseline. With the aim to develop a more objective and automated response
assessment method, the TLG* value for all liver metastases was included in a
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TL-TLG* value, including that of new liver metastases. With this approach,
liver response was generally classified as more favorable than with RECIST.
Furthermore, it was demonstrated that liver response classification with TL-TLG*
holds prognostic value. Both percentage decrease in TL-TLG* at 1 and 3 months,
and a favorable liver response category at 1 month were significantly associated
with prolonged OS in our cohort. Three previous studies have also shown that
both a decrease in TLG at early (4 – 6 weeks)10-16 and late follow-up (3 months)9 is
associated with favorable OS.
Thus, 18F-FDG-PET derived TL-TLG* analyses could potentially replace RECIST
in patients with CRLM that undergo radioembolization treatment. This could
have several benefits. First, the fact that this assessment can be automated
solves the problem that RECIST assessments are time-intensive, and can be
challenging, especially in patients with extensive hypovascular liver metastases
such as CRLM that are not always visualized optimally on CT or MRI. Second,
the quantitative character of TL-TLG* calculations limits operator dependency,
whereas the subjectivity of choosing target lesions in RECIST evaluations may lead
to differences in final response classification between observers. Third, the early
detection of changes in tumor status with TLG* may allow for more accurate and
timely decisions to either manage patients expectantly or give additional treatment.
Whether the latter actually improves patient outcome remains, however, uncertain
and should be investigated.
Response assessment with 18F-FDG-PET after radioembolization has been
studied before, using different methods. The majority of these studies were small
and retrospective in nature. Nevertheless, they support our findings. Wong et al.
compared visual tumor response on 18F-FDG-PET at 3 months posttreatment with
tumor shrinkage on CT or MRI in 8 patients (19 tumors) with CRLM, treated
with glass 90Y-microspheres. They found a significantly higher tumor response rate
on 18F-FDG-PET than on CT or MRI (in 75 vs. 13 % of liver lobes respectively).
Furthermore, only the 18F-FDG-PET response correlated with decrease in
Part IV Chapter 16
CEA serum levels posttreatment.17 Bienert et al., subsequently compared post-

radioembolization response on 18F-FDG-PET with CT response in a case series
of 5 patients (30 tumors) with unresectable liver metastases. They demonstrated
that changes in tumor size did not correlate with changes in 18F-FDG uptake.
SUVpeak values on 18F-FDG-PET showed a significant decrease relative to baseline
at 1 and 3 months follow-up. The product of perpendicular LTDs (cross-product)
on CT, on the contrary, showed a slight average increase at 1 and 3 months,
and a remarkably wide range of change (from 83 % decrease to 340 % increase)
was observed.18 Lewandowski et al. compared visual 18F-FDG-PET response to
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decrease in the sum of cross products on CT at 1 and 3 months in 27 patients with

CRLM treated with glass 90Y-microspheres. Bilobar treatment was staged in two
sessions, and a response to therapy was noted on PET in 88 and 73 % of the first
and second treated lobes respectively, whereas this was only 35 and 36 % for CT
response.19 Similarly, Szyszko et al. demonstrated that up to 85 % of the 21 studied
patients with primary or metastatic liver tumors had a decrease in SUV value
after radioembolization, whereas CT scans remained largely unchanged. More
recently, Zerizer et al. assessed changes in SUVmax on 18F-FDG-PET 6 – 8 weeks
after radioembolization in 25 patients (121 tumors) with CRLM, and compared
it to changes in LTD and tumor density on contrast-enhanced CT. They found
that the 18F-FDG-PET response assessment was superior to the CT assessments
in predicting 2-year progression free survival. Furthermore, only decreases in
SUVmax correlated with changes in serum tumor markers after treatment such
as carcinoembryonic antigen (CEA), cancer-antigen 19-9 (CA 19-9) and lactate
dehydrogenase (LDH).8
There are also disadvantages to the use of 18F-FDG-PET. For one, clinicians need
to be convinced to perform quantitative PET analyses, instead of using visual
assessments, to achieve robust results. Second, the result of quantitative 18F-FDG-
PET analyses is very much dependent on hardware, and methods for image
acquisition, reconstruction and analyses. Besides, 18F-FDG-PET analyses are
not standardized. Although ‘PET Evaluation Response Criteria In Solid Tumors’
(PERCIST) have been described, investigations often deviate from these guidelines,
which may be explained by PERCIST’s complexity and poor substantiation with
sound scientific evidence. Third, current software packages for 18F-FDG-PET
analyses still need further refinement and simplification to enable a widespread use
of TL-TLG* assessments. Fourth, 18F-FDG-PET scans are more expensive than a
CT or MRI, especially in the United States. Yet, the potential clinical benefit clearly
outweighs the aforementioned disadvantages.
Our study has several limitations. Although we present the largest prospective
Chapter 16 Part IV
cohort published on this subject, the limited sample size prohibits extensive
multivariable modeling to prove superiority of survival prediction by TL-TLG*
over RECIST. Furthermore, liver response information (18F-FDG-PET + MRI) was
not available after 3 months posttreatment in the majority of the patients. This was
inherent to our study design, since liver response was not monitored any longer
once disease progression outside the liver was confirmed so that patients could
still receive experimental systemic therapy. Third, the cut-off values for TL-TLG*
response classification were chosen arbitrarily, a 50 % decrease and 30 % increase
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in TL-TLG* posttreatment seemed reasonable to define a clinically meaningful

treatment response and disease progression respectively. Fourth, we had to cluster
LTD response of individual metastases that appeared fused on 18F-FDG-PET/CT.
This difference can be explained by the lower spatial resolution of 18F-FDG-PET/
CT, whereby adjacent tumors may appear connected.
In summary, TLG* assessment on 18F-FDG-PET/CT is a promising method for
tumor response assessment in patients undergoing radioembolization treatment.
Further research is needed for external validation of our method, and to assess
whether increased response assessment sensitivity will enable adjustments in
treatment strategy that improve patient outcome. Finally, TL-TLG* response
assessment should be compared to other functional response assessment methods
such as diffusion weighted MRI and pharmokinetic analysis of dynamic contrast
enhanced MRI.20,21
CONCLUSION
TLG* response assessment by 18F-FDG-PET/CT is more sensitive and accurate,
especially at early follow-up, than size-based response assessment on MRI in
patients with CRLM treated by radioembolization. Automated liver response
assessment with TL-TLG* is rapid, reproducible, and prognostic.
Part IV Chapter 16
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C hap ter
PART IV 17
Yttrium-90 radioembolization for
colorectal cancer liver metastases:
A prospective cohort study on
circulating angiogenic factors and
treatment response
C.E.N.M. Rosenbaum
A.F. van den Hoven
M.N.G.J.A. Braat
M. Koopman
M.G.E.H. Lam
B.A. Zonnenberg
H.M. Verkooijen
Submitted
Circulating angiogenic factors and treatment response after radioembolization
ABSTRACT
Objective
Yttrium-90 radioembolization (90Y-RE) is an intra-arterial treatment option for
patients with unresectable, chemorefractory liver-only or liver dominant liver tu-
mors. 90Y-RE induces radiation damage and hypoxia in liver tissue, which is a pow-
erful trigger for the systemic release of angiogenic factors, potentially stimulating
tumor growth. Our aim was to examine changes in serum levels of angiogenic
factors following 90Y-RE, and to investigate the association between treatment re-
sponse and angiogenic factors.
Methods
In this prospective cohort study 42 patients with unresectable, chemorefracto-
ry metastatic colorectal cancer (CRLM) were treated with 90Y-RE (resin micro-
spheres). Blood samples for analyses of circulating angiogenic factors were collect-
ed pretreatment, directly after treatment, and 1, 3, 7 and 30 days after treatment.
Treatment response was measured according to RECIST criteria with MRI and
18
F-FDG-PET imaging, at baseline, one month after treatment and subsequently
at 3 months intervals until progressive disease occurred. Linear mixed model re-
gression analysis was used to investigate the association between plasma levels of
angiogenic factors and treatment response during follow-up.
Results
At 1 month after 90Y-RE 10 patients had progressive disease (PD) in the liver and
32 patients showed either partial response (PR) or stable disease (SD) of liver le-
sions. Progressive liver disease was mainly due to the appearance of new lesions
(n = 8/10). Following 90Y-RE, three angiogenic factors demonstrated an overall in-
crease in plasma levels, i.e. vascular endothelial growth factor (VEGF), hepatocyte
growth factor (HGF) and angiopoietin-2 (Ang-2). Non-responders (= progressive
disease at 1 month follow-up) had a statistically significant increase of angiopoie-
tin-2 (Ang-2) and hepatocyte growth factor (HGF) at 3 and 7 days posttreatment
compared to responders (= disease control, i.e. SD or better), who showed little to
no changes in plasma levels (respectively p = 0.01 and p = 0.007). Median overall
survival was 9.2 months (95 % confidence interval [CI] 6.1 – 12.4). Median time to
Chapter 17 Part IV
liver progression was 3.0 months (95 % CI 2.8 – 3.3).

Conclusion
Statistically significant increases in plasma levels of Ang-2 and HGF in the first
week after treatment were associated with rapid progressive disease of liver lesions,
i.e. at 1 month follow-up after 90Y-RE. Combination of 90Y-RE with anti-angiogenic
therapy may reduce these effects and result in better tumor response.
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INTRODUCTION
Yttrium-90 radioembolization (90Y-RE) is an intra-arterial treatment option for pa-
tients with liver dominant, unresectable and chemorefractory hepatic malignan-
cies. Microspheres with a diameter of 30 – 40 µm are embedded with radioisotope
yttrium-90 (90Y) and delivered to the liver via a catheter in the hepatic artery. These
microspheres will travel distally with the blood stream and lodge at the arteriolar
level inside the tumors, and cause tumor necrosis through radiation and embolic
effects.1-5
A possible consequence of locoregional treatment with 90Y-RE is the systemic re-
lease of angiogenic growth factors due to the embolic effect of this treatment, which
can induce growth of untreated lesions or extrahepatic (micro)metastases and po-
tentially affect patient survival. A systemic release of growth factors after resection
of the primary colon tumor has already been suggested based on an increased met-
abolic activity in liver metastases.6-7 Furthermore, in patients with hepatocellular
carcinoma (HCC), a rise in circulating levels of vascular endothelial growth factor
(VEGF) has been described following transarterial chemoembolization (TACE) as
well as after transarterial bland embolization.8-9 Also, serum levels of VEGF were
significantly different between responders and non-responders.8,10
Although 90Y-RE is a promising palliative treatment option for patients with col-
orectal cancer liver metastases, not all patients experience good response and some
patients show rapid progression of liver lesions or of extrahepatic lesions. However,
few large studies have been conducted in this specific patient group and by ex-
tension little prospectively collected evidence on predictive factors for outcome is
available.11 The variable response rates may be related to an increase in circulating
growth factors, or even to a higher baseline level of these factors prior to treat-
ment.12-14 To evaluate this, we conducted a prospective cohort study in patients
with colorectal cancer liver metastases treated with 90Y-RE (resin microspheres)
and measured circulating angiogenic factors at baseline and at several intervals af-
ter treatment. Aims of the study were 1) to examine changes in serum levels of sev-
eral angiogenic factors following 90Y-RE, and 2) to investigate the relation between
plasma levels of these factors and treatment response of liver lesions after 90Y-RE.
Part IV Chapter 17
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Patients
Patients with unresectable and chemorefractory colorectal cancer liver metastases
(CRLM) were enrolled in this prospective cohort study, the RADAR study (Radi-
oembolization: Angiogenic factors and Response). This study was approved by the
institutional review board (medical ethical committee). All patients gave written
informed consent.
Treatment and follow-up
An overview of all pretreatment and follow-up procedures is given in Figure 1.
All patients referred to our center for 90Y-RE were screened for eligibility with full
medical history, standard laboratory evaluation (including but not limited to liv-
er function tests) and 18F-FDG-PET/CT imaging (including diagnostic multipha-
sic contrast enhanced abdominal and thoracic CT). Consensus on treatment was
reached by a tumor board consisting of physicians from the department of medical
oncology, department of interventional radiology and department of nuclear med-
icine.
Figure 1: Outline of clinical evaluations and study procedures of the RADAR study.
Yttrium-90 radioembolization was performed by experienced interventional ra-

diologists in concordance with international guidelines.15-18 Vascular anatomy was
mapped during pretreatment angiography. Subsequently, 99mTc-MAA particles
were infused and the distribution was evaluated with SPECT/CT imaging. In a sec-
ond angiographic procedure, the 90Y microspheres (SIR-Spheres, SIRTeX Medical
Limited, Sydney, Australia) were infused with the catheter in a similar position as
Chapter 17 Part IV
during pretreatment angiography. Distribution of 90Y microspheres after treatment

was evaluated with 90Y-PET imaging.
Baseline blood sample measurements were performed prior to treatment. Fol-
low-up blood sampling for angiogenic factors was performed at days 0 (imme-
diately after injection of the microspheres), 1, 3, 7 and 30 after 90Y-RE treatment.
Blood samples consisted of EDTA and citrate samples. Platelet free plasma was
- 324 -
obtained from the EDTA sample prior to rapid storage at -80 °C (within one hour
from sample collection).
Treatment response of liver lesions was evaluated with RECIST 1.1 on magnet-
ic resonance imaging of the liver, including post-gadolinium series and diffu-
sion-weighted imaging. MRI was scored by an independent radiologist specialized
in abdominal imaging. In addition, whole body FDG-PET/CT was performed and
read by an independent experienced nuclear medicine physician.
Analyses of angiogenic factors
The following angiogenic factors were analyzed: vascular endothelial growth factor
(VEGF), hepatocyte growth factor (HGF), angiopoietin-2, basic fibroblast growth
factor (FGF-b), platelet-derived growth factor (PDGF-BB), stromal cell-derived
factor 1 (SDF-1a) and thrombospondin-1. Measurements were performed using
an in-house developed and validated multiplex immunoassay based on Luminex
technology (xMAP, Luminex Austin TX USA). Samples were incubated with anti-
body-conjugated MagPlex microspheres (Biorad) for one hour at room tempera-
ture with continuous shaking, followed by one hour incubation with biotinylated
antibodies, and 10 min incubation with phycoerythrin-conjugated streptavidin
diluted in high performance ELISA buffer (HPE, Sanquin the Netherlands19-20).
Acquisition was performed with the Biorad FlexMAP3D (Biorad laboratories,
Hercules USA) in combination with xPONENT software version 4.2 (Luminex).
Data was analyzed by 5-parametric curve fitting using Bio-Plex Manager software,
version 6.1.1 (Biorad).
Descriptive statistics were used to explore baseline characteristics and data on
response and angiogenic factors. When boxplots suggested a possible difference
between strata, independent samples t-tests were used to evaluate this. Data were
evaluated for normal distribution and transformed when necessary.
Overall survival was computed as the number of days from 90Y-RE treatment until
date of death. Seven patients were still alive at study closure and survival was cen-
sored for these patients at a common date (April 8, 2015). Progression free survival
of the liver was calculated as the number of days from 90Y-RE until documented
Part IV Chapter 17
disease progression on imaging. Kaplan-Meier estimates for survival intervals were

calculated using SPSS. Comparisons of survival distributions between strata were
done using a log-rank test.
To estimate the association between the plasma levels of angiogenic factors, tumor
response and days after treatment (longitudinal data or repeated measures) a linear
mixed regression model was used on the logarithmic transformed values. Time
- 325 -
nsored for these patients at a common date
lculated as the number of days from 90Y-‐RE
Meier estimates for survival intervals were
Circulating angiogenic
Andor F. van den Hoven 26-1-2016 10:59
factors and treatment response after radioembolization
between strata were done using a log-‐rank
Verwijderd:
ngiogenic factors, tumor response and days

points
ear mixed regression ofwblood
model sampling
as used on the were entered into the model as a factor, liver response
to treatment at 1 month follow-up was entered as a fixed effect (dichotomous as
ng were entered into the model as a factor,
response: complete response (CR), partial response (PR) or stable disease (SD);
d as a fixed effect (dichotomous as response:
no response: progressive disease (PD)), and random intercepts were used for the
Andor F. van den Hoven 26-1-2016 10:06
ease (SD); no response: progressive
individual patients disease
(independentVerwijderd:
data). An additional analysis was performed to
-‐month
patients (independent analyze theAn
data). influence of the received liver dose on the levels of angiogenic factors
additional
eived liver dose on the by adding
levels this as a factor in the models. Liver dose was calculated as:
of angiogenic
!"#$%$&'(!')" !"#$%$#&
was calculated as: ∗ 50.
!"#$!#% !"#$% !"#$%&
rmation criterion (AIC

Model values).
performanceSignificant
was evaluated with the Akaike’s information criterion (AIC
values). Significant contribution of separate factors was tested with ANOVA (χ2).
RESULTS
Patients
A total of 49 patients were included in our study. Seven patients were not suitable
for 90Y-RE due to uncorrectable extrahepatic deposition of 99mTc-MAA on SPECT/
CT (n = 4), unsuitable hepatic arterial configuration (n = 1), rapid progression of
disease (n = 1), and inadequate hemoglobin level (n = 1). A total of 42 patients
were treated with 90Y-RE and completed study follow-up.
Mean age was 62 years (female n = 13, male n = 29; Table 1). Most patients (30 of
42) had liver-only disease, while 12 patients had one or more tumor localizations
outside the liver, mainly local lymphadenopathy (mainly in the hepatoduodenal
ligament). Any measurable disease according to RECIST 1.1 outside the liver was
termed extrahepatic disease. In 3 patients, the primary colorectal tumor had not
been surgically resected, but treated with chemotherapy and/or radiation and was
no longer metabolically active on 18F-FDG-PET imaging. All patients had received
at least one regime of systemic treatment. Systemic treatment was stopped upon
progressive disease in 25 patients and due to toxicity in 5 patients. Twelve of 42
patients had declined further systemic treatment after having received at least one
regime. A limited number of patients had previously undergone treatment of liver
lesions, mainly surgical resection. At the time of 90Y-RE, tumor load in the liver was
< 25 % in 36 patients.
Chapter 17 Part IV
Tumor response
Proportions of responders were calculated for target lesions, whole liver and whole
body (Table 2). Even though target lesions showed disease control in all patients at
1 month follow-up (either partial response (PR) or stable disease (SD)), 10/42 (24
%) of these patients had progressive disease of the liver. This was due to the appear-
ance of new lesions in 8 patients and due to unequivocal progression of non-target
- 326 -
Table 1: Baseline characteristics (total nr of patients n = 42)

Gender (no. of pts)
Female 13
Male 29
Age (years)
Mean (range) 62 (34 – 83)
ECOG performance status (no. of pts)
0 23
1 17
2 2
Extrahepatic disease (no. of pts)a
None 30
Lymph node 7
Lung 3
Bone 3
Recurrence (colon) 3
Other c 4
Baseline serum level (mean and range)
Alkaline phosphatase
Elevated 34
Normal 8
Leucocytes
Elevated 0
Normal 42
Primary tumor surgically resected (no. of pts)
Yes 39
No 3
Previous local treatment for liver metastases (no. of pts)
Segmentectomy 5
Radiofrequency / microwave ablation 4
Hemihepatectomy 3
Other b 3
Liver metastases (no. of pts)
Synchronous 32
Metachronous 10
kRAS status (no. of pts)
Wild type 17
Mutation 9
Unknown 16
Previous systemic therapy lines (no. of pts)
0 0
1 15
2 16
>2 11
Received bevacizumab
Yes 25
No 17
Part IV Chapter 17
Tumor load as percentage of liver volume (no. of pts)

< 25 % 36
26 – 50 % 6
> 50 % 0
Mean % (range) 15 (1 – 50)

Liver dose (Gy)d 44.3 (24.1 – 87.5)
Baseline characteristic of 42 patients. aNumbers add to more than 42 because some patients had ex-
trahepatic disease at more than one site. bTransarterial chemoembolization n = 1, radiotherapy n = 1,
open/close procedure for intended RFA n = 1. cBrain n = 1, adrenal gland n = 2, peritoneal lesion n =
1. dAssuming homogeneous distribution of administered activity. Abbreviations: ULN = upper limit
of normal, NA = not available.
- 327 -
Chapter 17 Part IV
Table 2: Response after 90Y-RE treatment

Target lesions Whole liver Including extrahepatic lesions
1 month† 3 months 6 months 1 month† 3 months 6 months 1 month† 3 months 6 months
PR 5 6 3 4 6 3 4 5 1
SD 36 11 2 27 5 1 21 4 0
PD 0 5 1 10 11 2 16 13 5
Deceased 0 4 12 0 4 12 0 4 12
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Lost to follow-up 0 2 5 0 2 5 0 2 5
No follow-up due to - 14 19 - 14 19 - 14 19
earlier PD
Disease control rate 41/41 (100 %) 17/42 (40 %) 5/42 (12 %) 31/41 (76 %) 11/42 (26 %) 4/42 (10 %) 25/41 (61 %) 9/42 (21 %) 1/42 (2 %)
(PR+SD)
†
1 month follow-up was not performed in 1 patient, while this patient was imaged at three months after treatment.
lesions in 2 patients, while all target lesions showed stable disease. A total of 5 of 42
patients (12 %) were lost to imaging follow-up, mainly due to clinical progressive
disease, hampering hospital visits for study purposes. Disease control rates of liver
lesions were slightly higher for patients with liver-only disease compared to those
with extrahepatic disease at baseline, i.e. 79, 33 and 13 % versus 76, 26 and 10 % for
liver response at 1, 3 and 6 months follow-up respectively. Partial response of the
liver at 6 months after treatment was seen in 3 patients. At the level of extrahepatic
lesions, disease control rates were clearly lower, i.e. 61, 21 and 2 % at 1, 3 and 6
months follow-up respectively.
Survival
Median overall survival was 9.2 months (95 % confidence interval (CI) 6.1 – 12.4).
Median time to liver progression was 3.0 months (95 % CI 2.8 – 3.3). A significant
difference in time to liver progression was observed between patients with (n = 12)
versus without EHD (n = 30) at baseline (1.4 versus 3.5 months; log-rank test p =
0.001; Table 3).
Circulating angiogenic factors
A total of 214 blood samples were analyzed in 42 patients over 6 time points. In two
patients, the blood sample directly after injection of the microspheres (+ 0 days)
was not collected, due to symptoms of postembolization syndrome directly follow-
ing 90Y-RE treatment. Most missing values occurred at three and seven days after
treatment (respectively 16 and 12 missing), as patients were at that moment often
not able to visit the hospital due to complaints of fever and fatigue, as part of the
postembolization syndrome. At 30 days follow-up blood samples were not collect-
ed in 4 patients, 2 due to severe illness from probable radioembolization-induced
liver disease (REILD) and 2 were lost to follow-up.
A range of normal values for these factors is not available. We observed large vari-
ations between patients in plasma levels of the angiogenic factors at baseline. Base-
line levels of angiopoietin-2 were higher in patients with median overall survival
(OS) < 6 months compared with those with median OS > 6 months. Patients with
extrahepatic disease at baseline had significantly higher baseline values of FGF-b
than those with liver-only disease.
Part IV Chapter 17
Following 90Y-RE, three of the investigated angiogenic factors demonstrated an

overall increase in plasma levels, i.e. VEGF, HGF and Ang-2. Figure 2 shows the
plasma values for these three angiogenic factors, stratified for patients with re-
sponse (CR, PR or SD, n = 32) and those with progressive disease (n = 10) of the
liver at 1 month follow-up. The linear mixed model analysis showed that time as a
factor did not contribute to the model performance for FGF-b and SDF-1a, there-
fore excluding a significant change over time.
- 329 -
Table 3: Time to progression of liver lesions and overall survival.

No. of pts Median overall survival Median PFS liver
in days (95 % CI) in days (95 % CI)
EHD at baseline
Yes 12 200 (164 – 236) 83 (0 – 179)
No 30 302 (216 – 388) 108 (79 – 137)†
Metastases
Synchronous 32 255 (151 – 359) 92 (82 – 102)
Metachronous 10 286 (60 – 512) 92 (88 – 96)
Bevacizumab treatment
Yes 25 322 (247 – 397) 108 (75 – 141)
No 17 215 (180 – 250)† 92 (87 – 97)
kRAS status
Wild type 17 302 (244 – 360) 108 (51 – 165)
Mutation 9 166 (75 – 257) 87 (0 – 187)
Unknown 16 282 (93 – 470) 92 (91 – 93)
Previous liver treatment
Yes 12 286 (142 – 430) 86 (59 – 113)
No 30 255 (148 – 362) 92 (91 – 94)
Baseline serum level
Alkaline phosphatase
Elevated 34 249 (159 – 339) 274 (SE 0)
Normal 8 355 (345 – 365)† 92 (90 – 94)†
Albumin
Decreased 11 166 (94 – 238) 90 (72 – 108)
Normal 31 351 (263 – 439)† 92 (91 – 93)
Treatment setting
Salvage setting 25 215 (137 – 293) 92 (86 – 98)
Non-salvage setting 17 358 (347 – 369)† 120 (43 – 197)
Liver response at 1 month
CR, PR or SD 31 341 (224 – 458) -
PD 10a 160 (122 – 198)† -
Non-salvage setting: patient declines (further) systemic treatment or systemic treatment must be
stopped due to toxicity. † Significant difference, log-rank test p < 0.05. a One patient was not evaluated
at 1 month follow-up, but first at 3 months follow-up. Abbreviations: PFS = progression free survival,
EHD = extrahepatic disease, PR = partial response, SD = stable disease, PD = progressive disease.
Chapter 17 Part IV
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PR or SD at 1 month
PD at 1 month
400
Plasma level of VEGF (pg/ml)
300
200
100
0
Baseline +0 +1 +3 +7 +30
Days after treatment

10000
PR or SD at 1 month
PD at 1 month
8000
Plasma level of HGF (pg/ml)
6000
4000
2000
0
Baseline +0 +1 +3 +7 +30

7000
PR or SD at 1 month
PD at 1 month
Plasma level of Ang.2 (pg/ml)
5000
3000
1000
Part IV Chapter 17
0
Baseline +0 +1 +3 +7 +30

Figure 2: VEGF (top), HGF (middle) and Angiotensine-2 (bottom) levels per time point (Baseline, +0,
+1, +3, +7 and +30 days posttreatment respectively), for patients with and without response at 1 month
posttreatment, i.e. partial response and stable disease (n = 32) versus progressive disease (n = 10) of
the liver.
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For VEGF, a slight overall rise in plasma level was observed at 7 days posttreat-
ment, though more pronounced in patients with progressive disease at 1 month
after 90Y-RE. This time effect did contribute to the model performance, however,
there was no statistically significant difference between the model with and with-
out response as a fixed effect (p = 0.28). Liver dose did not contribute to the model
performance either.
Plasma levels of HGF demonstrated a rise promptly after injection of the micro-
spheres (blood drawn from the still indwelling sheath in the femoral artery). This
holds true for both responders and non-responders. Yet, plasma levels of non-re-
sponders showed another peak, i.e. at 3 and 7 days after treatment, which was sig-
nificantly different from responders (p = 0.007). Angiopoeitin-2 levels were also
statistically significantly higher at 3 and 7 days after treatment for patients with
rapid progressive disease, i.e. liver progression at 1 month follow-up, compared to
those with disease control (p = 0.01). Model performances for HGF and Angiopoe-
itin-2 did not improve on adding received liver dose as a factor.
Furthermore, a statistically significant difference in median overall survival was
demonstrated between early responders and non-responders, of 341 (224 – 458)
days versus 160 (122 – 198) days respectively (Table 3). There was no difference in
baseline value of HGF and Ang-2 between early responders and non-responders.
No statistical significant differences were seen between the 10 patients with rapid
progressive disease at 1 month follow-up and the 32 patients with CR, PR or SD at
1 month follow-up with respect to a number of characteristics that can be assumed
Table 4: Responders (PR or SD) and non-responders (PD) at 1 month after treatment
PR or SD (n=32) PD (n=10)
WHO performance score (n)
0 19 4
1 12 5
2 1 1
Extrahepatic disease at baseline (n)
Yes 7 5
Chapter 17 Part IV
No 25 5
Tumor load (% of the liver) 12 % 22 %
Liver dosea (Gy) 45 43
Several patient characteristics of the patients defined as responders (PR or SD) and those defined as
non-responders (PD). No statistically significant differences were observed. a Liver dose was calcu-
lated as: (administered activity)/(treated liver volume) * 50. Abbreviations: PR = partial response, SD
= stable disease, PD = progressive disease, Gy = gray.
- 332 -
to be important influences on prognosis and response, i.e. liver tumor involve-

ment, performance score, presence of extrahepatic disease and received liver dose
(Table 4). The difference in Ang-2 levels at 3 and 7 days after treatment between
responders and non-responders is still statistically significant when comparing pa-
tients based on response at three months posttreatment.
DISCUSSION
Yttrium-90 radioembolization is an increasingly utilized treatment in clinical prac-
tice for unresectable and chemorefractory liver tumors. A large group of patients
who can potentially benefit from this therapy are those with liver metastases from
colorectal cancer.1-3,5,11 Although the group of patients with CRLM seems relatively
homogeneous, response to treatment varies considerably. Probably, more hetero-
geneity between patients exists on an internal level rather than on a macroscopic
level, resulting in a difference in treatment response. At present, however, no defi-
nite evidence for predictive factors for treatment response of 90Y-RE (or systemic
treatment for that matter) has been identified, although for example presence of
extrahepatic disease and performance status have been associated with surviv-
al.21-22 In clinical practice, we have observed that patients with EHD appear to
have poorer response rates to 90Y-RE than those with liver-only disease. Possibly, a
systemic trigger of the angiogenic cascade underlies this phenomenon. With this
hypothesis, we started a prospective study to investigate the angiogenic cascade
following treatment with 90Y-RE.
The median overall survival in our group was 9.2 months. This is in accordance
with recently published data on similar patient groups with heavily pretreated ad-
vanced colorectal cancer, reporting median overall survival ranging from 8.3 to
11.9 months.21,23-25 Additionally, we focused first on the baseline levels of several
classic angiogenic factors. Relatively large variations were found in baseline plasma
levels of these angiogenic factors between patients. However, there was no appar-
ent threshold that separated patients with early response from those with rapid
progressive disease (at 1 month follow-up).
Secondly, we evaluated the changes in plasma levels after treatment in relation to
Part IV Chapter 17
treatment response at 1 month follow-up (Figure 2). Statistically significant differ-

ences were found between patients with early disease control (CR, PR or SD) and
those with rapid progression (PD) at 1 month follow-up. Both HGF and angio-
poietin-2 plasma levels showed a rise at three and seven days after treatment in
non-responders, while hardly any changes were seen in responders. In principal,
one would argue that the embolic effect of 90Y-RE, if any, would be the same in
- 333 -
all patients, yet not all of our patients seem to have been equally susceptible to
an upregulation of angiogenic factors. And at the same time, this upregulation of
angiogenic factors is connected to early progressive disease, and thus perhaps an
early predictor of unfavorable response to treatment.
Furthermore, a statistically significant difference in median overall survival was
observed between responders and non-responders at 1 month follow-up, 341 (224
– 458) versus 160 (122 – 198) days respectively. No statistically significant differ-
ences in baseline patient characteristics were observed between these responders
and non-responders. Our findings suggest that 90Y-RE can cause an increase in cir-
culating angiogenic factors, which may be predictive of rapid progressive disease.
Over the past decades, several studies have been conducted on systemic release
of angiogenic factors after transarterial treatment of liver tumors. An overview of
these papers is presented in Table 5. The first studies included patients with HCC
treated with either chemoembolization (TACE) or bland embolization (TAE) and
the focus of angiogenic analysis was on VEGF.8-10,26 Suzuki et al. measured serum
levels of HGF and VEGF at 1, 3 and 7 days after bland embolization of HCC. They
observed a rise in VEGF at day 7, but did not demonstrate the subsequent fall in
VEGF nor did they evaluate tumor response.9 Korse et al. included 12 patients with
neuroendocrine tumors into their study and followed VEGF and endothelin levels
during the first 8 days after bland embolization.27 Unfortunately, they too did not
include tumor response into their study. Sergio et al. analyzed VEGF and b-FGF
and the association with response at one month after TACE. Response was not
scored according to (modified) RECIST, but expressed as the percentage of resid-
ual activity at CT imaging, and responders were defined as those with an ablation
rate between 70 – 100 % and non-responders as those with residual activity higher
than 30 %. Even though all 71 patients demonstrated an increase in VEGF level at
30-days follow-up, non-responders showed the highest increment.10
Recently, Carpizo et al.28 have conducted a pilot study on angiogenic factors and
90
Y-RE. They included 15 patients with CRLM and 7 patients with HCC and mea-
sured several angiogenic factors, including non-classical factors such as interleu-
kin-8, at baseline and during follow-up until 120 days after treatment. As in our
Chapter 17 Part IV
present study, they too demonstrated rises in VEGF and Ang-2 after treatment,
even though their sample size was rather limited. Unfortunately, they did not re-
port tumor response in relation to the levels of angiogenic factors, but only survival
data. Median overall survival for the entire patient group was 8 months, but no
separate values for CRLM and HCC patients were reported.
- 334 -
Table 5: Overview of previous studies on angiogenic factors and transarterial treatment of liver tumors
Author Year Patients Treatment Factors Samples collected Results

VEGF, Ang-2,
Baseline * Transient increases in many angiogenic
28
n = 15 CRLM 90
b-FGF, PDGF-BB,
Carpizo et al. 2014 Y-RE 6 hours, and 3, 14, 30, 60, 90 cytokines
n = 7 HCC TSP-1, follistatin,
and 120 days follow-up * Some changes associated with worse OS
leptin, IL-8
Baseline
VEGF, ET-1, * VEGF and proET-1 showed temporarily
Korse et al.27 2011 n = 12 NET HAE 1, 2, 3, 4, 5, 6, 7 and 8 days
proET-1 increase after treatment
follow-up
* VEGF levels were higher in non-responders
VEGF, b-FGF, Baseline at one month follow-up
Sergio et al.10 2008 n = 71 HCC TACE
uPA 3 and 30 days follow-up * Below-median VEGF levels predicted a
longer survival
* High increment in serum VEGF level 1 – 2
- 335 -
Baseline
Shim et al.26 2008 n = 147 HCC TACE VEGF days posttreatment was associated with dis-
1-2 and 30 days follow-up
tant metastasis and unfavorable outcomes
n = 45 HCC * A high pretreatment VEGF level was asso-
Baseline
n = 20 benign disease ciated with poor response
Li et al.8 2004 TACE VEGF 1, 3, 7 and 30 days
n = 17 healthy * VEGF levels increased significantly on the
follow-up
controls first day posttreatment
* No significant alterations in HGF levels
Baseline
Suzuki et al.9 1999 n = 38 HCC TAE VEGF, HGF * VEGF levels increased significantly at 7
1, 3 and 7 days follow-up
days posttreatment
Abbreviations: CRLM = colorectal cancer liver metastases, HCC = hepatocellular carcinoma, 90Y-RE = yttrium-90 radioembolization, VEGF = vascular endo-
thelial growth factor, Ang-2 = angiopoietin-2, b-FGF = basic fibroblast growth factor, PDGF-BB = platelet-derived growth factor subunit BB, TSP-1 = thrombo-
spondin-1, IL-8 = interleukin-8, NET = neuroendocrine tumors, HAE = hepatic artery embolization, ET-1 = endothelin-1, proET-1 = proendothelin-1, TACE =
transarterial chemoembolization, uPA = urokinase-type plasminogen activator, TAE = transarterial embolization, HGF = hepatocyte growth factor.
Part IV Chapter 17
Meanwhile, the early progression of liver lesions in 10 patients largely consists of

the appearance of new liver lesions (n = 8/10), and not of the growth of (non)target
lesions. Target lesions, in fact, were stable in all 10 of 10 patients. This supports our
hypothesis that an increase in circulating angiogenic factors may induce growth
of previously invisible hepatic micrometastases. Even though these new appearing
lesions are located in the treated organ, the largest arterial flow at the time of treat-
ment will have been to the macroscopic metastases, leaving the micrometastases
(and of course the normal liver parenchyma) relatively untreated and susceptible
to growth stimulating factors. Perhaps the concomitant use of an anti-angiogenic
agent could counteract this phenomenon. Gorski et al. have described the relation
between VEGF and the antitumor effects of ionizing radiation.29 They report that
VEGF expression is induced in Lewis lung carcinomas both in vitro and in vivo af-
ter exposure to ionizing radiation. Furthermore, they demonstrated that treatment
of tumor-bearing mice with a neutralizing antibody to VEGF prior to irradiation
was associated with a greater than additive anti-tumor effect. With this, they em-
phasize the potential importance of combining radiation therapy with systemic
anti-angiogenic treatment to increase anti-tumor effects.
In addition to the above-described increase in HGF at days 3 and 7 after treatment
in non-responders, a large rise in HGF directly after microsphere injection (ap-
proximately 5 min after end of injection) was observed for all patients. This may be
related to the angiographic procedure itself, with catheter manipulation in the he-
patic arteries, giving rise to this release of hepatocyte growth factor. One day after
treatment, HGF levels have returned approximately to baseline. During follow-up,
patients with PR or SD at 1 month after treatment do not experience any other
rises in HGF plasma levels during the first 30 days, contrary to patients with early
PD. Suzuki et al. also investigated HGF levels but did not find this large increase,
because their first follow-up sample was collected one day after treatment instead
of directly after microsphere injection.9
Survival analysis showed a remarkable difference in time to liver progression be-
tween patients with and without extrahepatic disease at baseline. Obviously, 90Y-RE
is a liver treatment and any extrahepatic lesions will not be treated when no sys-
Chapter 17 Part IV
temic therapy is added. However, in our cohort, patients with extrahepatic lesions
had earlier progression of liver lesions than those with liver-only disease at base-
line. Perhaps this reflects a more aggressive tumor type that is less susceptible to
radiation damage as well as more prone to disseminate throughout the body. This
may be an additional reason to primarily select patients with liver-only disease for
90
Y-RE as stand-alone treatment, as they may benefit more with respect to their
- 336 -
liver lesions, on top of the fact that extrahepatic lesions would be left untreated. For
patients with extrahepatic lesions, a combination of 90Y-RE and systemic treatment
is perhaps more suitable.2,30 One of the next steps for this would be a safety study
on the concomitant use of bevacizumab with 90Y-RE.
An important limitation of our study was the relatively small sample size that did
not allow development of a clinical prediction model given the limited number of
predictors that can be included into a model with this sample size. Advantages of
our study were its prospective design that ensured standardization of study pro-
cedures and the homogeneity of our study population, consisting of only patients
with unresectable and chemorefractory colorectal cancer liver metastases. Fur-
thermore, we have created a special protocol for blood collection and processing to
ensure that platelet free plasma was produced and all plasma samples were stored
at -80 °C within 60 min, to avoid breakdown of the angiogenic proteins, to which
mainly VEGF is prone at room temperature. In addition, our study was the first
and largest cohort study to investigate circulating angiogenic factors after 90Y-RE
for CRLM in relation to treatment response according to RECIST.
CONCLUSION
We showed for the first time that a significant rise in plasma levels of HGF and
Ang-2 at 3 and 7 days post 90Y-RE treatment was associated with progressive liver
disease at 1 month follow-up. Moreover, these early non-responders have signifi-
cantly worse overall survival compared to responders, i.e. 5.2 versus 11.1 months.
In addition, our data showed that the presence of extrahepatic disease at baseline is
a predictor for early disease progression of the tumors in the liver.
Our results may open the discussion for more stringent patient selection for 90Y-
RE, with respect to for example extrahepatic disease, and combining 90Y-RE with
systemic anti-angiogenetic treatment for better treatment response in CRLM sal-
vage patients. Part IV Chapter 17
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28. Carpizo DR, Gensure RH, Yu X, et al. 30. Heinemann V, Sharma NK, Findlay MPN,
(2014) Pilot study of angiogenic response et al. (2015) SIRFLOX : Randomized phase
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Chapter 17 Part IV
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C hap t er
PART IV 18
The effect of intra-arterial angiotensin II
on the hepatic tumor to non-tumor blood
flow ratio for radioembolization:
A systematic review
A.F. van den Hoven

M.L.J. Smits
C.E.N.M. Rosenbaum
H.M. Verkooijen
M.G.E.H. Lam
PLoS ONE 2014

The effect of intra-arterial AT-II on the hepatic T/N blood flow ratio for radioembolization
ABSTRACT
Purpose
Treatment efficacy of intra-arterial radioembolization for liver tumors depends on
the selective targeting of tumorous tissue. Recent investigations have demonstrated
that tumors may receive inadequate doses of radioactivity after radioembolization,
due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive
microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-
II) is reported to increase the T/N blood flow ratio. The purpose of this systematic
review was to provide a comprehensive overview of the effect of hepatic arterial AT-
II on T/N blood flow ratio in patients with hepatic malignancies, and determine its
clinical value for radioembolization.
Methods
This review was conducted in accordance with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured
search was performed in the PubMed, EMBASE and Cochrane databases. Only
studies that presented data on T/N ratios before and after infusion of AT-II into
the hepatic artery, in human patients with hepatic malignancies, were selected.
Median T/N ratios before, during and after AT-II infusion, and the median T/N
ratio improvement factor were extracted from the selected articles. All data on
systemic blood pressure measurements and clinical symptoms were also extracted.
Results
The search identified 524 titles of which 5 studies, including a total of 71 patients
were considered relevant. Median T/N ratios before infusion of AT-II ranged
from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio
after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A
transitory increase of systemic blood pressure was observed during AT-II infusion.
Conclusions
Infusion of AT-II into the hepatic artery leads to an increase of the tumor to
non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are
warranted to assess safety aspects, optimal administration strategy and impact on
treatment efficacy during radioembolization.
Chapter 18 Part IV
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INTRODUCTION
Intra-arterial radioembolization with yttrium-90 (90Y) microspheres has proven
to be an effective treatment option for patients with unresectable primary or
metastatic liver tumors, refractory to chemotherapy.1-5 During this minimally
invasive therapy, a percutaneous approach is used to place a catheter in the hepatic
artery and administer high-energy β-radiation emitting 90Y microspheres that will
irradiate liver tumors from within. This therapy thrives on the fact that liver tumors
are primarily vascularized by the hepatic artery, while normal liver parenchyma
receives the majority of its blood supply from the portal vein.6 In theory, this
should translate into a higher concentration of microspheres within the tumorous
liver tissue than in healthy liver tissue, i.e. a favorable (> 1) tumor to non-tumor
(T/N) uptake ratio of radioactive microspheres.
Single-photon emission tomography - computed tomography (SPECT-CT)
imaging, routinely performed after the arterial administration of 99mTc-labelled
macroalbumin aggregates (99mTc-MAA) to estimate the fraction of liver-to-lung
shunt and exclude potential extrahepatic shunting prior to radioembolization,
has been used to predict individual T/N microsphere uptake ratios based on the
intrahepatic distribution of 99mTc-MAA. Several studies reported that favorable
T/N uptake ratios of 99mTc-MAA are associated with improved posttreatment
tumor response7-9, whereas other studies contradict these findings and emphasize
that assuming an equal intrahepatic distribution of 99mTc-MAA and 90Y
microspheres may not be justified.10-13 Still, a consistent finding of these studies
is a strong interindividual heterogeneity in T/N uptake ratios, with a reported
range of 0.6 – 25.9.7-9,1-12,14-17 Furthermore, a recent study assessing the radioactive
microsphere biodistribution on posttreatment quantitative imaging following
radioembolization, demonstrated that the T/N uptake ratio per tumor may also
show marked variability within the same liver. Up to 60 % of the patients had at
least one tumor that received a concentration of radioactivity equal to or lower than
the normal liver tissue (T/N ≤ 1). Thus, some tumors receive below therapeutic
doses of radioactivity, whereas healthy liver tissue may receive toxic doses of
radioactivity, resulting in suboptimal treatment.18 The heterogeneity in T/N uptake
ratios is a result of various factors including differences in tumor angiogenesis,
microsphere characteristics and flow-bound distribution physics.9
A common feature among liver tumors is that the vasculature of liver tumors
Part IV Chapter 18
is immature, lacking normal neurovascular innervation and a well-developed

smooth muscle coating.19-21 This allows for manipulation of the fraction of
blood flowing to tumorous liver tissue (T/N blood flow ratio) by infusion of a
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vasoconstrictive agent. As opposed to the vasculature of the healthy liver tissue,

tumor vessels will not respond to infusion of vasoconstrictive drugs, leading
to an increase in preferential blood flow to the tumorous liver tissue. Various
vasoconstrictors, including epinephrine, noradrenaline and angiotensin-II have
shown the potential to increase the hepatic T/N blood flow ratio, in both preclinical
and clinical studies.19,22-25 Angiotensin II (AT-II) is an octapeptide hormone that
acts as a vasoactive agonist and induces arterial vasoconstriction26, with the most
pronounced effect in the splanchnic vasculature.24 Therefore, hepatic arterial AT-II
infusion during radioembolization seems a promising method to increase the T/N
uptake ratio of radioactive microspheres.27
Previously, various clinical studies have reported the routine use of AT-II infusion
during 90Y-radioembolization.2,4,12,28-30 However, the efficacy of using AT-II for this
purpose is not clear. Therefore, we performed a systematic review of the available
evidence on the effect of intra-arterial AT-II infusion on the hepatic arterial T/N
blood flow ratio in human patients with hepatic malignancies, weighing potential
benefits for radioembolization against expected side effects.
METHODS
This systematic review was conducted according to the guidelines of the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.31
A structured search was performed in PubMed, EMBASE and Cochrane databases
on February 28th 2013. Various synonyms for vasoconstrictors were combined
with synonyms for blood flow and liver (Table 1). The search results were screened
for potentially relevant articles on title/abstract and full-text using predefined
inclusion and selection criteria. To improve comparability between different
studies, only articles that presented data on T/N ratios before and after infusion
of AT-II into the hepatic artery in human patients with liver malignancies, were
included. Cross check of reference lists from identified articles was performed to
identify additional articles (Figure 1).
Subsequently, a quality assessment of the selected articles was performed with the
use of the Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) statement.32 All articles were assessed according to the following criteria:
clearly described inclusion criteria, presence of a control group, standardization
of the AT-II administration, standardization of the T/N ratio measurement and
Chapter 18 Part IV
blinding for the outcome measurement.

Two reviewers (AH, CR) independently extracted the following data from included
studies: the size of study population, tumor type, AT-II dose, method for estimating
- 346 -
Table 1: Search Syntax

PubMed (442 results)
(angiotensin OR noradrenaline OR vasopressin OR vasoconstrictor) AND ("blood-flow” OR
“blood flow") AND (liver OR hepatic)
Limit: title/abstract
EMBASE (500 results)
(angiotensin:ab,ti OR noradrenaline:ab,ti OR vasopressin:ab,ti OR vasoconstrictor:ab,ti) AND
(‘blood-flow’:ab,ti OR ‘blood flow’:ab,ti) AND (liver:ab,ti OR hepatic:ab,ti)
Cochrane (35 results)
(angiotensin OR noradrenaline OR vasopressin OR vasoconstrictor) AND ("blood-flow” OR
“blood flow") AND (liver OR hepatic)
In Cochrane Central Register of Controlled Trials (Clinical Trials)
In this table, the search syntax used in PubMed, EMBASE and Cochrane databases is displayed.
The search was performed on 28-02-2013. The number of results includes double titles. In total, 524
original titles were identified.
Figure 1: Flowchart illustrating the article selection process.

Part IV Chapter 18
the T/N blood flow ratio, median T/N ratios before and after administration of AT-
II, and median improvement factor. Reported mean T/N ratios were converted
to median values to account for non-normality and improve the comparability of
the results. Reported median improvement factors indicated the median factor of
- 347 -
improvement in T/N ratio induced by the infusion of AT-II, as calculated according

to the following formula:
T/N ratio after AT-II infusion

T/N improvement factor=
T/N ratio before AT-II infusion
Hypertension is a well-known side effect of intra-arterial AT-II infusion. Therefore,

we also extracted all data on systemic blood pressure measurements and clinical
symptoms due to AT-II infusion. Discrepancies in extracted data were resolved by
consensus, after revision of the reported data.
RESULTS
Search results
The search identified 524 original titles (Figure 1). After screening the articles on
title/abstract, and subsequently reading 32 articles in full-text, five relevant articles
were included. Two selected articles were published by Goldberg et al. in the same
year and journal, and are referred to as Goldberg et al. 1 and Goldberg et al. 2 to
avoid confusion.
Quality assessment and study characteristics
The quality assessment scores of the selected studies are listed in Table 2. All
selected studies were before-and-after studies. The inclusion criteria were not
clearly described in 4/5 (80 %) studies. None of the studies used a control group,
and the measurement of the outcome was not performed in a blinded fashion. All
studies standardized the AT-II administration and T/N ratio measurement.
Table 2: Quality assessment of selected studies

Author (year) Inclusion Control Standardization Standardization Blinding for
criteria clearly group of AT-II of T/N ratio outcome
described administration measurement measurement
Sasaki et al. 25 N N Y Y N
(1985)
Goldberg et al. 133 N N Y Y N
(1991)
Goldberg et al. 234 N N Y Y N
(1991)
Chapter 18 Part IV
Burke et al. 19 Y N Y Y N
(2001)
Ishikawa et al. 36 N N Y Y N
(2007)
Abbreviations: Y = Yes, N = No.
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Study methods and patients

The characteristics of the selected studies are summarized in Table 3.
Sasaki et al.25 investigated AT-II induced changes in the distribution of the hepatic
blood flow in a total of nine patients (14 tumors), including seven patients with
hepatocellular carcinoma (HCC, nine tumors) and two patients with colorectal liver
metastases (CRLM, five tumors). Radioactivity was measured with a scintillation
camera placed over the liver during a continuous infusion of a short-lived 81mKr-
solution (half-life 13 s). The planar images of the liver were then played back on a
color display according to the intensity of radioactivity. 81mKr-images and images of
a colloid hepatic scintigram were superimposed on the color display. Subsequently,
regions of interest (ROIs) were drawn both on tumor region, indicated by defects
in a baseline 99mTc-stannum colloid hepatic scintigram, and non-tumor region. The
radioactivity per frame was calculated for the ROI sets, and the effect of AT-II
on the T/N ratio was evaluated by comparing the radioactivity in the tumor and
non-tumor region before, and after a hepatic arterial infusion of 10 μg/min AT-II
for 3 – 4 minutes. In one patient, different AT-II administrations were compared
to determine the optimum administration strategy: hepatic arterial infusion of 5
μg/min, hepatic arterial infusion of 10 μg/min and intravenous infusion of 5 μg/
min. It was found that hepatic arterial infusion at a rate of 10 μg/min resulted in
higher T/N ratios when compared to using a rate of 5 μg/min, and did not increase
systemic blood pressure as much as an intravenous infusion.
Goldberg et al. 133 used a double isotope method to assess the effect of AT-II on the
distribution of radiolabeled microspheres in nine patients with liver metastases,
including eight patients with CRLM and one patient with an unknown primary.
The patients underwent a laparotomy under general anesthesia for the placement
of a hepatic arterial catheter for regional chemotherapy. First, a tracer dose of 131I
microspheres was injected. Subsequently, AT-II was infused into the catheter at
a rate of 10 μg/min for 100 s. Immediately after infusion of AT-II, a tracer dose
of 99mTc-microspheres was given. Biopsies of tumor and adjacent normal liver
tissue were obtained and weighed, and the uptake of 131I and 99mTc microspheres
in tumor and non-tumor tissue was determined by measuring radioactivity with a
gamma scintillation counter. T/N ratios were calculated by comparing the relative
microsphere content of the tissue samples.
In another study, Goldberg et al. 234 used scintigraphic planar and tomographic
Part IV Chapter 18
imaging to determine the effect of AT-II on the distribution of radiolabeled

albumin microspheres in nine patients with CRLM (48 tumors). Patients received
a SPECT scan at three different moments: 1) after intravenous injection of albumin
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Chapter 18 Part IV
Table 3: Characteristics of studies on the effect of AT-II on the T/N ratio in patients with hepatic malignancies
Author (year) Study size Tumor type AT-II dose Radioactive tracer T/N measurement
N patients (N patients)
(tumors)
81m
Sasaki et al. 25 9 (14) HCC (7) 10 μg/min for 3 – 4 min Kr solution RA measurement with scintillation camera during infusion
(1985) CRLM (2)
131
Goldberg et al. 133 9 CRLM (8) 10 μg/min for 100 s I before and Biopsies of tumor and non-tumor. RA measured with
99m
(1991) UP (1) Tc after AT-II scintillation camera
99m
Goldberg et al. 234 9 (48) CRLM (9) 10 μg/min for 100 s Tc MSA SPECT after albumin colloid injection and HAPS
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(1991)
62
Burke et al. 19 9 (11) CRLM (9) 5 μg/min for 45 min Cu-PTSM PET
(2001)
Ishikawa et al. 36 35 PCLM (35) 5 μg/min for 10 s None CT contrast enhancement measurement
(2007)
Abbreviations: HCC = hepatocellular carcinoma. CRLM = colorectal liver metastases. UP = metastases of an unknown primary. PCLM = pancreatic cancer liver
metastases. NA = not available. RA = radioactivity. SPECT = single-photon emission computed tomography. HAPS = hepatic arterial perfusion scintigraphy. PET =
positron emission tomography. 81mKr = krypton-81m. 131I = iodine-131. 99mTc MSA = radiolabeled albumin microspheres. 62Cu-PTSM = copper-pyruvaldehyde-bis
(N4-methylthiosemicarbazone).
colloid (99mTc-albumin colloid) to localize the metastatic tumors, 2) after injection

of radiolabeled albumin microspheres (99mTc-MSA) prior to the infusion of AT-II,
and 3) after injection of 99mTc-MSA, immediately after the hepatic arterial infusion
of AT-II at a rate of 10 μg/min for 100 s. All studies were performed in random order,
but at least three days apart and were completed within two weeks. A tomographic
gamma camera was used, and the planar anterior tomographic acquisitions were
reconstructed to transverse slices. After superimposing the albumin colloid study
and both microsphere studies, ROIs were drawn to define tumor (regions of low
uptake on the albumin colloid scan) and normal liver areas (a sampled area of
uniform high uptake on the albumin colloid scan). T/N ratios were calculated
before and after the infusion of AT-II, by comparing the activity within both
areas. Two patients with markedly hypervascular lesions (T/N ratios > 30 before
AT-II administration) were non-assessable, because it was not possible to obtain
sufficient counts in the normal liver, irrespective of the AT-II administration.
Burke et al.19 used Positron Emission Tomography (PET) after administration
of the short-half-life positron emitter copper-pyruvaldehyde-bis (N4-
methylthiosemicarbazone) (62Cu-PTSM) to study the effect of AT-II on the T/N
ratio in nine patients with CRLM (11 tumors). A baseline PET scan with 62Cu-
PTSM was compared to two additional PET scans with 62Cu-PTSM: one during
(10 minutes after the start of AT-II infusion) and one immediately after completion
of a continuous hepatic arterial infusion of AT-II at a rate of 5 μg/min for 45
minutes. In one patient with CRLM, AT-II had been substituted for physiological
saline to confirm the reproducibility of hepatic arterial blood flow distribution
measurements with 62Cu-PTSM PET.35
Ishikawa et al.36 used CT angiography to assess the effect of AT-II on the T/N blood
flow ratio in 35 patients with pancreatic cancer liver metastases (PCLM). Median
attenuation values of ROIs in tumor and normal liver parenchyma were measured
on CT angiography after hepatic arterial infusion of AT-II at a rate of 5 μg/min for
10 s, and compared to values on a baseline scan.
Tumor to non-tumor blood flow ratios
Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. Median T/N
ratios after administration of AT-II ranged from 0.8 to 7.3. All studies observed an
improvement of the T/N ratio after AT-II infusion with median improvement factors
Part IV Chapter 18
ranging from 1.8 to 3.1. The T/N ratio before and after infusion of AT-II, and the T/N
improvement factors observed in each study are summarized in Table 4.
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Table 4: T/N ratios before, during and after AT-II infusion, and T/N ratio improvement factors in
patients with hepatic malignancies
Author (year) T/N ratio T/N ratio T/N ratio T/N improvement factor
pre-infusion during infusion post-infusion
Sasaki et al. 25 median 1.36 - median 4.05 median 3.07 (1.46 – 5.33)
(1985) (0.38 – 3.36) (1.56 – 9.33) p < 0.001
Goldberg et al. 1 33
median 0.36 - median 0.75 median 2.80 (0.80 – 11.70)
(1991) (0.11 – 0.90) (0.10 – 8.11) p < 0.05
Goldberg et al. 2 34
median 3.4 - median 7.3 median 1.8 (0.5 – 3.4)
(1991) (1.3 – 6.0) (1.5 – 8.8) p < 0.05
Burke et al. 19
median 1.3 median 2.1 median 1.85 NR
(2001) (0.93 – 6.21) (0.63 – 22.86) (0.70 – 18.34) p = 0.008 and p = 0.03*
Ishikawa et al.36 median 1.03 - median 1.34 NR
(2007) (0.41 – 1.72) (0.84 – 2.09) p = 0.01
T/N ratios are described as median (range). P values correspond to reported significance levels of
Wilcoxon test for paired data. *The first p value refers to the improvement of T/N ratio during infu-
sion and the last to post-infusion. Abbreviation: NR = not reported.
Sasaki et al.25 observed a substantial (> 1.5-fold) increase of the T/N ratio after
AT-II, in all nine patients and all fourteen tumors. The T/N ratio increased from a
median value of 1.36 (range, 0.38 – 3.36) before AT-II to 4.05 (1.56 – 9.33) after the
administration of AT-II. Furthermore, the continuous radioactivity measurement
in this study revealed that the T/N ratio reached a peak at approximately 100 s after
the infusion of AT-II, and decreased gradually afterwards.
Goldberg et al. 133 found that the uptake of microspheres increased in seven
patients (78 %), and slightly decreased in two (22 %) patients. The median T/N
ratio before the administration of AT-II increased from 0.36 (0.11 – 0.90) to 0.75
(0.10 – 8.11) afterwards.
Goldberg et al. 234 also found that the uptake of radiolabeled albumin microspheres
increased in seven patients (78 %), and slightly decreased in two (22 %) patients.
In this study, the T/N ratio increased from a median value of 3.4 (1.3 – 6.0) before
AT-II to 7.3 (1.5 – 8.8) after the administration of AT-II.
Chapter 18 Part IV
Burke et al.19 determined the T/N ratio during (10 min after the start) and after
completion of a prolonged AT-II infusion of 45 min. During the infusion, the T/N
ratio was increased in 7 of 9 (78 %) patients and 7 of 11 (63 %) lesions. At the end
of the AT-II infusion, the T/N ratio was still increased in 6 of 9 (67 %) patients
- 352 -
and 6 of 11 (55 %) lesions. The median T/N ratio increased from a baseline value
of 1.3 (0.93 – 6.21) to 2.1 (0.63 – 22.86) during and to 1.85 (0.70 – 18.34) after the
prolonged AT-II infusion.
Ishikawa et al.36 observed an AT-II induced increase in median T/N ratio from 1.03
(0.41 – 1.72) before the administration of AT-II to 1.34 (0.84 – 2.09) afterwards.
Adverse effects
All studies observed a transitory AT-II induced increase in systemic blood pressure
(BP). After the infusion, blood pressure gradually decreased towards baseline
levels.
Sasaki et al.25 observed an 1.5-fold increase from 124 mm Hg (± standard deviation
31) at baseline to 186 mm Hg (± 40). Within three minutes after ceasing the AT-
II infusion, BP had returned to baseline in all patients. In one patient, different
administration strategies were employed. In this patient, hepatic arterial infusion
of AT-II did not increase systemic blood pressure as much as intravenous infusion.
Goldberg et al. 133 found a maximal increase of 40 mm Hg in systolic BP at the end
of the 100 s AT-II infusion with a gradual decrease afterwards.
Burke et al.19 observed an increase in median arterial blood pressure from 98 mm
Hg (interquartile range 97 – 108) at baseline to 114 mm Hg (interquartile range
109 – 115) after 10 min of AT-II infusion. A substantial decrease towards baseline
levels occurred in all cases within a few minutes after cessation of the infusion.
They did not observe changes in pulse rate.
Ishikawa et al.36 found an increase in systemic BP of up to 40 mm Hg in systolic
blood BP. When blood pressure was elevated, patients complained of a sense of
chest oppression and headache, but these symptoms were not severe enough to
hamper the administration of AT-II. No other adverse effects were reported.
DISCUSSION
We systematically reviewed the available evidence on the effect of intra-arterial
AT-II infusion on the hepatic T/N blood flow ratio in patients with hepatic
malignancies to determine its clinical value for radioembolization. All studies
showed a substantial increase of the T/N ratios after infusion of AT-II into the
hepatic artery. Median improvement factors of the T/N ratio ranged from 1.8 to
3.1.
Part IV Chapter 18
Whole liver external beam irradiation, instead of radioembolization, is of

limited value in the treatment of liver tumors, due to the healthy liver tissue’s low
tolerance for ionizing radiation.37 This lead to the development of selective internal
radiation therapy. During radioembolization, the predominant hepatic arterial
- 353 -
vascularization of liver tumors enables the preferential delivery of radioactive

microspheres to tumorous tissue, resulting in very high radiation doses in the
tumors while the healthy liver tissue radiation exposure remains within tolerable
limits.7,11,38 Pathological examinations of livers treated with radioembolization have
revealed that, following infusion, 90Y microspheres are preferentially deposited
in clusters within the tumor periphery, with 200-times greater microsphere
concentrations than in the tumor center and the healthy liver tissue.14,38 Perfusion
scintigraphy has been used to quantify this tumor selectivity, by calculating the T/N
uptake ratio of 99mTc-MAA. These studies have revealed a strong heterogeneity in
the T/N ratio, with reported values ranging from 0.6 – 25.9.7-9,11-12,14-17 The fact that
the hepatic arterial T/N blood flow ratio is highly variable between patients and
between different tumors within the same patient, poses a clinical problem. Kao
et al. noted that in their study in patients with inoperable HCC, the SPECT/CT
based median intra-patient difference of the 99mTc-MAA T/N uptake ratio was 1.9
(95 % confidence interval 1.1 – 2.5).17 Furthermore, Flamen et al. reported that up
to 38 % of the metastatic liver lesions in their study had an unfavorable 99mTc-MAA
T/N uptake ratio (< 1). The authors advocated the use of a 99mTc-MAA T/N uptake
ratio > 1 as a patient selection criterion, because it was demonstrated that this was
strongly predictive of metabolic posttreatment response on PET/CT. In patients
with a T/N uptake ratio < 1, tumors may receive inadequate doses of radioactivity,
while the radioactive burden on the healthy liver tissue may exceed toxic levels.
Using an intra-arterial AT-II infusion during radioembolization may prove a way to
overcome the problem of unfavorable T/N ratios, and optimize treatment efficacy.
Various studies have found an association between tumor absorbed radiation
doses, tumor response and overall survival.39-42 It can, therefore, be expected that
improved tumor selectivity of radioactive microsphere distribution will positively
affect patient outcome after radioembolization.
The selected studies showed consistent and promising effects of AT-II on the
hepatic arterial T/N blood flow ratio. There are, however, some limitations to
these studies. First, all selected studies were small non-controlled studies, prone
to selection and observer bias. Second, patients with different tumor types were
included in the selected studies. The majority of the studies included patients
with colorectal liver metastases. However, Ishikawa et al.36 only included patients
with liver metastases from pancreatic cancer, and the majority of patients in
Chapter 18 Part IV
Sasaki’s study had HCC.25 Angiogenesis of liver tumors is a complex process,

and the degree of arterial vascularization is dependent on multiple factors,
including the stage of development, grade of malignancy, tumor size and origin
- 354 -
of the primary tumor. Early stage well differentiated hepatocellular carcinoma

(HCC) for example, receives both arterial and portal blood supply through small
unpaired arteries and portal tracts within the tumor. However, during growth of
the tumor, portal tracts will be deformed and decrease in number, and arterial
tumor vessels enter the tumor. Once the tumor is encapsulated, the advanced
HCC is exclusively vascularized by arterial tumor vessels.43 The vascularity of liver
tumors is characterized by their contrast enhancement in the arterial phase on
computed tomography (CT) or magnetic resonance imaging (MRI).44 HCC is in
general hypervascular, but metastatic liver tumors can be either hypovascular,
hypervascular or display a more complex pattern of enhancement. Therefore, one
could argue that hypervascular tumors like HCC have different hemodynamic
characteristics than hypovascular liver metastases and may respond differently to
the infusion of AT-II. Hence, it is interesting to note that the study of Sasaki et al.25
(HCC) showed the greatest improvement in T/N ratio after AT-II infusion.
Third, it is currently very challenging to perform direct and accurate measurements
of the differential arterial blood flow to liver tumors and normal liver parenchyma.
Therefore, AT-II induced changes in the T/N blood flow ratio need to be estimated
by using other methods such as measurements of radioactive tracer/microsphere
uptake or contrast enhancement on CT imaging. Several challenges need to be
overcome in order to avoid biased or inaccurate estimations. T/N ratios should be
determined as the total amount of a certain agent (i.e., radioactive tracer, contrast)
in the total volume of all tumors (tumorous tissue volume) divided by the amount
of that agent in the total liver volume minus the tumor volume (i.e., healthy liver
volume). Selecting an area of tumorous and non-tumorous tissue by drawing ROIs
on planar scintigraphic imaging, or taking a biopsy of both areas may be highly
subjective and introduce bias. In addition, distinguishing healthy liver from viable
tumorous tissue and registering that spatial information with activity distribution
is a challenging task. The methods in the selected studies are somewhat outdated.
The two studies that used colloid hepatic scintigraphy to identify tumorous liver
tissue25-34, superimposed planar images of the colloid scans with those acquired
after the administration of radioactive tracers. This may result in malregistration of
images. Burke et al.19 on the other hand, did not fuse PET images with the anatomical
CT images, which in turn may result in incorrect localization of tumors.45 These
problems may be overcome by using hybrid imaging that combines functional and
Part IV Chapter 18
anatomical information, such as 18FFDG-PET-CT, and allows for the definition of

three-dimensional volumes of interest (VOIs). Furthermore, dual tracer imaging
with 99mTc-MAA-99mTc-sulfur colloid SPECT46 and dynamic magnetic resonance
- 355 -
imaging with the hepatobiliary specific contrast agent gadoxetic acid47 (Primovist,
Bayer-Schering, Berlin, Germany) are two relatively new functional imaging
strategies that may prove to be particularly useful to distinguish tumorous from
healthy liver tissue.
To determine the potential of using AT-II for the purpose of radioembolization,
the effect on the T/N uptake ratio of radioactive microspheres should be assessed.
The technological developments of the last decades enable us to perform
quantitative studies on the biodistribution of microspheres. Dosimetry after
90
Y-radioemboization, for example, used to be solely based on SPECT of indirectly
generated gamma-photons (Bremsstrahlung). Posttreatment imaging with PET,
based on the internal pair production of 90Y once every 32 million decays, has
substantially improved the posttreatment quantification of 90Y microspheres.48-50
Furthermore, our institute has developed holmium-166 (166Ho) poly (L-lactic acid)
microspheres to allow for quantitative imaging of microsphere distribution.51-52
In addition to high-energy beta radiation, 166Ho also emits gamma-radiation and
thereby facilitates imaging by gamma scintigraphy and SPECT.53,54 Moreover, the
distribution of 166Ho microspheres can be visualized by MRI due to its highly
paramagnetic properties.54-56 The overall evidence for the use of AT-II to improve
T/N microsphere uptake ratios would benefit from additional studies trying
to confirm these findings, using the above-mentioned imaging techniques for
dosimetry.
When AT-II is used in clinical practice, it may lead to a sudden rise in systemic
blood pressure. In theory, this could be accompanied by serious side effects. We
therefore screened the selected articles on any side effects of AT-II infusion. All
studies that monitored systemic blood pressure observed a transitory increase
in systolic blood pressure due to the AT-II infusion. Blood pressure returned
to baseline levels within a few minutes after the infusion was stopped, and no
relevant increase of heart rate was observed. Remarkably, only one study36 reported
on symptoms experienced by patients due to the AT-II infusion. In this study,
symptoms were not severe and all transient.
Infusion of AT-II during administration of microspheres may also influence the
total amount of microspheres that can be delivered before stasis occurs. This can be
particularly relevant for treatment with resin-based 90Y microspheres, since early
arterial stasis and subsequent inability to deliver the whole prescribed dose has
Chapter 18 Part IV
been reported in up to 20 % of cases.57 Although no early stasis was reported in the

reviewed studies, this matter deserves further study using 90Y microspheres.
AT-II infusion duration and doses differed between studies and the optimal
- 356 -
infusion strategy of AT-II remains uncertain. An infusion time of 100 s seems

justified, since in one study25 T/N ratios were continuously measured during
a 3 – 4 min infusion period of AT-II and T/N ratios were highest after 100 s of
infusion. Furthermore, the two studies33-34 that used a 100 s infusion time had
better T/N ratio improvement factors than the 10 s36 and 45 min studies19. One
study25 compared different infusion strategies in one patient and concluded that
the improvement in T/N ratio was greater with a hepatic arterial infusion of 10 μg
AT-II per minute, compared to 5 μg/min. AT-II has already been used routinely
as part of the treatment protocol of randomized controlled trials and non-
randomized studies investigating the effect of intra-arterial radioembolization
with 90Y microspheres.2,4,12,28-30 These studies used a hepatic arterial bolus injection
of 25 or 50 μg AT-II shortly (approximately 30 s) before the administration of 90Y
microspheres. Unfortunately, none of these studies reflected on the toxicity or
efficacy of the intra-arterial AT-II infusion. A comparative study (ideally a placebo-
controlled randomized trial) should determine the impact of AT-II administration
on patient outcome after radioembolization.
CONCLUSION
Infusion of AT-II into the hepatic artery leads to an increase of the tumor to
non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are
warranted to assess safety aspects, optimal administration strategy and impact on
treatment efficacy during radioembolization.
Part IV Chapter 18
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Part IV Chapter 18
1034.
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C hap ter
PART IV 19
Summary and discussion
SUMMARY
Investigations with the aim to improve radioembolization of liver tumors are pre-
sented in this dissertation, covering various aspects of this treatment, including
treatment planning, strategy and evaluation.
Treatment planning
Radioembolization treatment planning encompasses an assessment of the individ-
ual hepatic arterial anatomy, defining a treatment strategy, performing a prepara-
tory angiography to establish a safe and adequate administration, and calculating
the required treatment activity.
Understanding the hepatic arterial anatomy of individual patients plays a pivot-
al role in radioembolization treatment planning. Based on the individual hepatic
arterial configuration and segmental vascularization pattern, it must be decided
which arterial branches need to be selected for administration, which extrahepatic
side-branches should be avoided, and whether it is necessary to embolize extra- or
intrahepatic arterial branches.
Yet, in 2012, a systematic approach for anatomy evaluation on pretreatment
cross-sectional imaging was still lacking. Besides, existing classifications of hepatic
arterial variants did not include all variants relevant to radioembolization.1-3 So,
there was much uncertainty about the anatomical variants that could be encoun-
tered. Furthermore, treatment strategies were not defined ahead of the prepara-
tory angiography. This may be explained by the fact that interventional radiolo-
gists used to depend on digital subtraction angiography (DSA) – considered the
gold standard for vascular evaluation – and make ad-hoc decisions regarding the
treatment strategy during the preparatory procedure. Altogether, the workflow was
suboptimal and required improvement.
The hepatic arterial configuration and segmental vascularization pattern was as-
sessed on pretreatment liver computed tomography (CT) and DSA in radioembo-
lization candidates, as described in Chapter 3.4 We found that the hepatic arterial
configuration and segmental vascularization pattern can be assessed with confi-
dence on pretreatment liver CT. Moreover, it showed marked individual variabili-
ty beyond well-known anatomical classifications. Hence, an extended anatomical
classification was developed that can serve as a guide for the recognition of relevant
anatomical variants. Contrary to previous ones, this classification makes a clear
distinction between variants in the origin, branching pattern and segmental vas-
cularization territory of hepatic arteries.
Since no consensus existed on how to deal with anatomical variants, the use of
Chapter 19 Part IV
an individualized radioembolization treatment strategy was proposed. Risks and
- 364 -
benefits of different strategies were carefully weighed and a recommendation was

given for the most frequently encountered variants, with the aim to standardize
treatment strategies across centers. The fact that the individual hepatic arterial
anatomy can already be assessed on the pretreatment liver CT emphasizes that a
treatment plan can already be established before the preparatory angiography. This
enables discussion among peers and increases the operator’s confidence during the
procedure. Furthermore, it may reduce the procedural time, contrast- and radia-
tion burden of the preparatory angiography, by superseding extensive mapping of
the hepatic arterial vasculature with DSA. An important limitation of this study
was the unavailability of C-arm cone beam CT (C-arm CT) images. On CT, the
segmental vascularization pattern can only be estimated by tracking the course of
arterial branches towards Couinaud’s liver segments. C-arm CT, however, can re-
veal the true arterial perfusion territory of a target branch as contrast enhancement
of the liver parenchyma. In other words, CT can only show that, for example, an
arterial branch courses towards segment 4 (S4), whereas C-arm CT can depict the
true borders of the perfused area that is described as S4.
To stress the importance of using a systematic approach to identify anatomical
variants, we have retrospectively analyzed the identification rate of aberrant hepat-
ic arteries in our own clinical practice.5 From this analysis, described in Chapter 4,
we have learned that without a systematic approach, aberrant hepatic arteries will
be missed, resulting in inadequate treatment coverage. To prevent this in future
practice, potential causes for failure to recognize aberrant hepatic arteries were
determined. Based on these findings, a practical approach was formulated, consist-
ing of specific recommendations for the detection and characterization of aberrant
hepatic arteries using pretreatment liver CT, DSA, C-arm CT and scintigraphy.
Two liver segments that require special consideration during radioembolization
treatment planning are segments 1 (S1) and 4 (S4). It is important to specifically
identify the origins of the arterial branches that vascularize these segments, be-
cause these segments may need to be included in the treatment field if they con-
tain tumors. Yet, the origin of these vessels is extremely variable. Furthermore, for
treatment activity calculations, it is paramount that the total activity is fractioned
correctly when using multiple injection positions, so that the infused activity per
injection corresponds to the perfused volume.
Unfortunately, S1 is largely neglected in current radioembolization practice. This
is emphasized by the results of our study described in Chapter 5, demonstrating
that failure to target S1 occurs in up to 19 % of radioembolization patients with
Part IV Chapter 19
tumors in S1, whereas S1 is unnecessarily treated in 80 % of radioembolization
- 365 -
patients without tumor involvement.6 Considering that tumor involvement of S1

is quite common, a significant number of patients thus receive suboptimal treat-
ment. Treating S1 while unnecessary should also be avoided, since sparing of S1
was demonstrated to induce significant hypertrophy, which may help strengthen
the healthy liver reserve. Knowledge of the S1 arterial vascularization was limited
to the fact that this segment can be divided into three different parts that gener-
ally receive multiple small arterial branches from both the LHA and RHA.7-8 We
demonstrated that A1s are, with an identification rate of 12 – 17 %, seldom visible
on pretreatment CT. When A1s could be identified, it was usually in the presence
of tumor in S1, likely indicating hypertrophy of tumor-feeding vessels. Thus, now
the occurrence of unintentional under- and overtreatment of S1 has been exposed,
further research should explore ways to solve this problem.
Previous studies had already shown that the vascularization of S4 is extremely vari-
able.9-10 The segmental vascularization patterns found in our own study confirmed
that arterial branches vascularizing S4 can be either ‘distal’ branches originating
from the LHA, RHA, or LHA and RHA, or ‘proximal’ branches with a separate
origin from the CHA or PHA.4 In a comprehensive review about hepatic arterial
anatomy and its terminology, described in Chapter 6, we have proposed the use of
different terms to distinguish between these two entities; segment 4 artery (A4) for
distal branches, and middle hepatic artery (MHA) for proximal branches with an
origin that is situated in between the LHA and RHA.11 S4 has long been considered
part of the standard vascular territory of the LHA. This believe is rooted in the fact
that S4 is part of the portal venous defined left hemi-liver; in other words the portal
venous branch to S4 consistently arises from the left portal vein. However, S2-3 is
in fact the only arterial territory that is consistently supplied by the LHA. So, the
origin of the artery vascularizing S4 should always be determined in individual pa-
tients. This also implies that aLHAs only vascularize S2 per definition, while rLHAs
may vascularize S2-3 or S2-4. It remains unclear whether S4 can be subdivided into
smaller independent arterial territories.
Chapters 7 and 8 describe prospective development studies with the aim to optimize
our image acquisition protocols for pretreatment liver CT and C-arm CT for specif-
ic radioembolization purposes. The ‘Idea, Development, Exploration, Assessment,
Long-term study’ (IDEAL) recommendations provide guidelines for the systemat-
ic evaluation of innovative surgical procedures and technical interventions.12-13 The
concept of performing a prospective development study “with sequential reporting
of all cases and outcomes without omissions, and with clear explanations of when
Chapter 19 Part IV
and how technique, design, or indications were changed’’ can, however, also be ap-
- 366 -
plied to the optimization of image acquisition protocols. A benefit of this approach

is that patient selection and study procedures are standardized, thereby limiting
selection bias and improving the quality of the data collection.
In Chapter 7, a novel protocol for pretreatment liver CT was evaluated.14 The ra-
tionale for this study was that the detection of small arterial branches, such as the
right gastric artery (RGA) and A4/MHA, seemed suboptimal on CT. We hypoth-
esized that shortening the posttreshold delay of the arterial phase from 20 to 10
s could improve the detection rates of small arterial branches, through a more
favorable contrast-to-noise ratio (CNR) between the hepatic artery and portal
vein. However, no difference in RGA and A4/MHA detection rates was found
between both protocols, despite a significantly higher CNR with the early arterial
phase. A potential explanation of this discrepancy is that the CNR was measured
on maximum intensity projection images (MIP), whereas the observers assessing
the origin detection were free to use whichever settings they preferred, mirroring
clinical practice. The benefit of the early arterial phase may be diminished on non-
MIP images, since MIPs exaggerate differences in contrast enhancement between
different structures. We found that further improvement of the A4/MHA origin
detection rate is not required (range 89 – 96 %). The RGA origin identification rate
(range 54 – 69 %), on the contrary, is clearly insufficient. Perhaps, the challenge to
detect small branches like the RGA is not related to overshadowing by the contrast
enhanced portal vein, but merely a problem of the limited spatial resolution of CT,
or unfavorable blood flow dynamics. The radiologists in our center did prefer the
early arterial phase protocol, because the significantly higher CNR on MIP images
makes the evaluation of the arterial vasculature easier. It should, however, be noted
that hypervascular tumors are less well depicted on the early arterial phase. So, in
patients with this type of tumors, an additional late arterial phase or another imag-
ing modality should be considered.
The purpose of the study described in Chapter 8 was to optimize our C-arm CT
acquisition protocol for radioembolization purposes.15 Until then, C-arm CT was
used only sporadically during our preparatory angiographies, because the added
value of this imaging modality was limited to a detailed depiction of the arterial
tree. The goal was to develop an acquisition protocol that could also be used to de-
tect extrahepatic shunting and lack of target segment perfusion, as this would en-
able early recognition of technical failures during the preparatory angiography. We
started of with a protocol based on a literature review, and performed a step-wise
adjustment of acquisition parameters until optimal image quality was achieved.
Part IV Chapter 19
The diagnostic performance of C-arm CT was subsequently compared to the gold
- 367 -
standard, a single photon emission tomography (SPECT)/CT acquired after the

administration of technetium-99m macroaggregated-albumin (99mTc-MAA). The
use of a continuous contrast agent infusion, a personalized scan delay, and a 10 s
high-dose scan setting provided the best image quality, and showed contrast en-
hancement of the arterial tree, gastrointestinal shunting, as well as lack of target
segment perfusion. Furthermore, we demonstrated that the overall diagnostic per-
formance of C-arm CT is good, as gastrointestinal shunting and lack of target seg-
ment perfusion can be ruled out with confidence.
Novel treatment strategies
The current treatment paradigm for radioembolization is quite complex, and it
is not tailored to the individual patient. A safety procedure is performed in the
week(s) before the actual treatment; during which embolization of arterial branch-
es may be performed and a strategic catheter position is chosen, before adminis-
tering a (harmless) scout dose of 99mTc-MAA. Afterwards, SPECT/CT and planar
nuclear scintigraphy are obtained to exclude the presence of extrahepatic activity
and significant liver-to-lung shunting. Approximately a week later, patients need to
be readmitted again for treatment.16
The fact that the preparatory angiography and treatment procedure require two
separate hospital admissions is burdening, especially for severely diseased patients.
Gates et al. demonstrated in a small study that radioembolization can actually be
performed on an outpatient basis, with the preparatory angiography and the treat-
ment procedure taking place on the same day17. Interestingly, the authors report-
ed that the only reason to perform the preparatory angiography and subsequent
planar scintigraphy was to assess the liver-to-lung shunt fraction, since C-arm CT
was used to rule out extrahepatic shunting, and the dosimetry method used did
not require a SPECT/CT acquisition. In a letter to the editor, presented in Chapter
9, we argue in a response to this article that a true single-session treatment may
even be feasible.18 This statement is substantiated by an analysis of the estimated
absorbed lung dose in 160 patients treated with radioembolization in our center,
demonstrating that liver-to-lung shunting rarely is a limiting factor, especially not
in patients with colorectal liver metastases (CRLM).
A current challenge of radioembolization practice is that the intrahepatic distribu-
tion of therapeutic 90Y microspheres cannot be accurately predicted in advance.19-20
Unfortunately, this prohibits individualized treatment activity calculations. Since
the required activity to be infused cannot be adjusted on the basis of the expected
healthy liver dose, simplified methods have been developed that provide an ac-
Chapter 19 Part IV
tivity that is generally safe and reasonably effective. The therapeutic microsphere
- 368 -
distribution is not only unpredictable, but it also shows marked inter- and in-
tra-individual variability, with reported tumor to non-tumor (T/N) microsphere
uptake ratios ranging from 0.6 – 25.9.21 This heterogeneity is likely multifactorial,
with influences by differences in tumor angiogenesis, microsphere characteristics
and flow-bound distribution physics.22-24 Two recent investigations independently
showed that suboptimal dose delivery to at least one tumor occurs in as much as
38 – 60 % of patients treated with radioembolization.25-26 This clinical problem may
explain some of the inconsistencies in reported tumor response rates after radio-
embolization.27-28
Thus, both the predictability of the therapeutic microsphere distribution and the
treatment efficacy need to be improved before radioembolization can live up to its
true potential. Recent innovations in catheter and radioactive microsphere types
may help to achieve this goal.
Two types of administration catheters are currently available for radioemboliza-
tion procedures. The standard end-hole microcatheter remains the default cathe-
ter for all embolotherapies in interventional radiology. This may be due to its low
cost, simplicity of use, atraumatic character, and wide range of available sizes and
flexibility that allow for catheterization of small, tortuous vessels. However, the
microcatheter has no fixed support in the vessel lumen and may, therefore, deviate
towards a vessel wall during injection of microspheres. A novel catheter has specif-
ically been designed for embolotherapy. The tip of this anti-reflux catheter (ARC)
expands radially to make contact with the vessel wall during administrations to
prevent particle reflux, without blocking antegrade blood flow.
In Chapter 10, a case report is presented that provided the first-in-man evidence
for the feasibility and safety of using the ARC as a replacement to prophylactic coil
embolization of gastrointestinal side branches during radioembolization. Since
then, other studies confirmed that the use of the ARC enables a simplified injec-
tion, reduces procedure time as well as contrast agent and radiation burden, when
compared to the use of a standard end-hole microcatheter in adjunct to routine
coil embolization of gastrointestinal side branches.29-30
It remained, however, unclear whether the marked different design of the ARC
affects fluid-particle dynamics and tumor targeting during radioembolization.
Therefore, we decided to study particle-fluid dynamics and the potential effects
of catheter design in the controlled environment of a hepatic arterial vasculature
model with recreated hemodynamics. Comparative experiments were performed,
with the administration of microspheres using a standard end-hole microcatheter
Part IV Chapter 19
and the ARC in similar conditions. The results of these experiments are described
- 369 -
in Chapter 11.31 We learned that the flow pattern of blood in the hepatic arteries
is laminar under normal conditions. This means that blood flows in laminar col-
umns, parallel layers of fluid that do not cross laterally. If a microcatheter tip posi-
tion is offset in the cross-sectional vessel plane, i.e. aiming towards one of the vessel
walls proximal to a bifurcation, and microspheres are released into these blood
flow layers at the same speed as the blood flow velocities, down-stream branch tar-
geting will be skewed towards the side of catheter tip deviation. This corresponds
to our clinical experience, in which we noticed that the slightest changes in cathe-
ter position can impact flow dynamics, as visualized by DSA.32
A previous investigation had already demonstrated that deployment of the ARC
causes a blood pressure drop in the vascular compartment distal to the tip.33 This
may in theory increase tumor penetration by lowering the high interstitial pressure
in tumors with hyperpermeable vasculature.33,34 Our experiments uncovered that
the deployment of the ARC tip also converts the naturally occurring ordered lam-
inar flow pattern into a chaotic turbulent flow pattern. As a result, a more homo-
geneous particle distribution over first-order target branches was observed than
with a SMC31, which may prevent unintentional lack of tumor coverage in clinical
practice. The experiments also confirmed that, in contrast to the standard end-
hole microcatheter, the ARC tip exhibits a fixed position in the cross-sectional
vessel plane. This fixed centro-luminal position may actually enhance the ability
of a scout dose administration to predict the therapeutic microsphere distribution,
since it limits the influence of potential differences in cross-sectional catheter posi-
tion between the scout dose and therapy administration. Although a clinical study
comparing tumor targeting with a standard microcatheter and the ARC during
radioembolization recently showed promising results35, it remains unknown how
the down-stream pressure gradient, turbulent particle-outflow pattern, and tumor
vascularization would co-act to improve selective targeting of tumorous tissue.
Holmium-166 (166Ho) microspheres have been developed as an alternative for rou-
tinely used 90Y microspheres. In contrast to 90Y microspheres, these microspheres
also emit low-energy γ-radiation and have paramagnetic characteristics, allowing
for direct visualization and quantitative assessment of the microsphere distribu-
tion on SPECT and MRI. Another important benefit is that identical 166Ho mi-
crospheres can be administered in a scout dose earlier on the day of treatment to
predict the distribution of the therapeutic microspheres.25,36
So far, the use of 166Ho microspheres during radioembolization has been inves-
tigated in two clinical trials. The first clinical trial (HEPAR I) was a dose-escala-
Chapter 19 Part IV
tion study in 15 patients with unresectable chemorefractory liver metastases.37 It
- 370 -
demonstrated that 166Ho microspheres are safe to use during radioembolization,

and established a maximum tolerable whole liver dose of 60 Gy. The second clinical
trial (HEPAR II), a prospective cohort study in 38 patients with liver metastases
from various types of primary tumors, has just been finalized.38 It proves that 166Ho
microspheres can indeed be used to effectively treat liver tumors.
The study design of the next clinical trial with 166Ho microspheres is described
in Chapter 12.39 A one-day treatment approach, ARC, and 166Ho microspheres are
combined in this within-patient randomized controlled trial – the SIM trial –, there-
by aiming to optimize current radioembolization practice. The treatment strategy
in this trial is radically different from conventional practice. Twenty-five patients
with unresectable and chemorefractory CRLM will be included, to undergo radi-
oembolization treatment with 166Ho microspheres. Once patients are found to be
eligible and provided informed consent, the individual hepatic arterial anatomy
will be thoroughly evaluated on an early arterial phase liver CT. Based on this as-
sessment, a treatment plan will be discussed, and set in advance. The underlying
principle for each treatment plan is that the administration needs to include two
selective injection positions, one in the LHA, and one in the RHA. Then, the use
of an ARC will be randomly assigned to either one of the administration sites, and
a standard end-hole microcatheter will be used on the other side. Patients will
undergo a preparatory angiography in the morning, during which a scout dose of
166
Ho microspheres will be administered, followed by the actual treatment with a
therapeutic dose of 166Ho microspheres in the afternoon. SPECT/CT images will
be acquired after each procedure to compare catheter effects on the microsphere
distribution. We hypothesize that the use of the ARC further increases the pre-
dictive value of the 166Ho scout dose distribution and improves the therapeutic
T/N microsphere uptake ratio, in comparison with the standard end-hole micro-
catheter. This may also ultimately result in improved tumor response, which will
be assessed by size-based parameters on CT and metabolic activity on 18-fluo-
ro-2-deoxyglucose-positron emission tomography (18F-FDG-PET)/CT. The with-
in-patient randomized controlled trial design is an efficient way to assess local ef-
fects of treatments. A limitation of this design, however, is that effects on overall
survival cannot be assessed.
Evaluation of treatment-related toxicity and efficacy
A standardized evaluation of toxicity, therapeutic microsphere distribution, and
efficacy should, logically, be routine practice after radioembolization. Yet, it re-
mains questionable which indicators for toxicity should be screened for, what pre-
Part IV Chapter 19
cautionary measures should be taken to prevent treatment complications, how ab-
- 371 -
sorbed dose distribution relates to treatment efficacy, what the consequences are of
finding an unfavorable microsphere distribution, and which response classification
system to use.
With regard to treatment-related toxicity, it remained unclear whether laboratory
toxicity could be used for an early detection of clinically relevant toxicity. To an-
swer this question, a retrospective analysis of laboratory and clinical toxicity was
performed in all patients with liver metastases who were not enrolled in one of
our clinical trials and received radioembolization treatment in our center between
the early start in 2009 and march 2012.40 This study is presented in Chapter 13. The
observed clinical toxicity mainly consisted of the well-known symptoms related
to the postembolization syndrome. None of the patients developed radiation-in-
duced liver disease or other complications. Nevertheless, severe abnormalities in
laboratory parameters (CTCAE grade 3 – 4) were observed in 38 % of patients.
This indicates that laboratory abnormalities are part of the physiological reaction
to radioembolization treatment, and cannot be used to distinguish between nor-
mal and abnormal posttreatment courses.
Another uncertainty related to treatment complications is subject of the paper
presented in Chapter 14.32 Much controversy existed about the necessity to take
precautionary measures in order to prevent radiation-induced cholecystitis after
radioembolization. Some authors advocated routine embolization of the cystic ar-
tery during the preparatory angiography, because radiation-induced cholecystitis
can cause severe morbidity, and rarely even mortality.41-43 On the other hand, it had
also been reported that coil embolization of the cystic artery may cause ischemic
cholecystitis, with a similar poor prognosis.44 We tried to redefine the problem at
hand by pointing out what defines a radiation-induced cholecystitis on the basis
of a literature review, emphasizing the need for clinical relevance. Furthermore,
we postulated a scenario-based practical approach to guide decision-making. The
first recommendation is to place the catheter distal to the origin of the cystic artery
to avoid any problems. If that is not possible, 99mTc-MAA should first be admin-
istered in the desired injection position, and the amount of activity uptake in the
gallbladder wall should be assessed. Only if the uptake is excessive, precautionary
measures should be taken. The first thing to try is to slightly readjust the catheter
position to alter blood flow dynamics. This strategy is supported by a case that we
presented, in which we were able to reduce the estimated absorbed dose to the
gallbladder wall by more than 90 %. Only if this strategy fails, embolization of the
cystic artery should be considered.
Chapter 19 Part IV
- 372 -
Chapters 15-17 discuss three different investigations that are based on a prospective
cohort study that has been conducted in our center, the RADAR trial. A total of 42
patients with CRLM were treated with resin 90Y microspheres radioembolization
in this trial, and received extensive imaging and laboratory investigations before
and after treatment. It is the largest prospective cohort of CRLM patients treated
with radioembolization that has been reported.
A dose-response evaluation is presented in Chapter 15. Various studies had already
demonstrated associations between tumor absorbed dose and response after radi-
oembolization.26,45-55 However, none of these studies uncovered the actual nature
of the dose-response relationship for radioembolization. This is partly due to the
limited statistical analyses that had been performed. Furthermore, most studies
did not measure the actual radiation absorbed dose distribution on 90Y-PET/CT,
but merely estimated it using the distribution of 99mTc-MAA on SPECT/CT. We did
measure the tumor absorbed dose on 90Y-PET/CT, for each metastasis separately
and averaged over all metastases, and subsequently determined its relationship to
metabolic tumor response at 1 month posttreatment, using a linear mixed effects
regression analysis.56 Total lesion glycolysis (TLG) was used to indicate metabol-
ic activity. We found that there was indeed a strong and significant relationship
between tumor absorbed dose and metabolic tumor response, with higher tumor
doses generally effectuating better response. The dose-response effect, however,
depended on the baseline metabolic activity of a metastasis, which indicates that
higher doses are required for metastases with a high metabolic activity at baseline.
For the average metastasis, minimum effective tumor absorbed dose was estimated
to be 40 – 60 Gy. Interestingly, we found that tumor absorbed doses were relative-
ly low, with a mean ± standard deviation of 51 ± 28 Gy, and extremely variable.
Often times, much higher absorbed doses are proclaimed in the literature57, but
these values are based on estimations instead of actual measurements in patients
with hypervascular liver tumors. Furthermore, the relatively low absorbed doses
do explain the disappointing response rate. Thus, optimization of tumor absorbed
doses should be pursued. An important step towards achieving this goal would be
to improve current treatment activity calculations methods, since it is likely that
they curb potentially achievable tumor absorbed dose values.
Two methods for tumor response assessment are compared in Chapter 16.56 The ra-
tionale for this study was that size-based tumor response evaluations, as described
by the popular ‘Response Evaluation Criteria in Solid Tumors’ (RECIST)58, may not
be ideal for radioembolization, because this therapy, in contrast to cytotoxic drugs,
Part IV Chapter 19
does not primarily affect tumor size. Unfortunately, alternative response evaluation
- 373 -
criteria, such as modified RECIST (mRECIST)59, are not applicable in patients with
CRLM due to the hypovascular appearance of these tumors on imaging. With the
aim to develop and validate another response method for patients with CRLM that
underwent radioembolization treatment, 18F-FDG-PET derived TLG response was
compared to MRI based longest tumor diameter (LTD) response at 1 and 3 months
after radioembolization. The TLG response assessment proved valid by correlation
with LTD response. Even more so, TLG response assessment was more sensitive
to depict changes in tumor status than LTD, and total liver TLG (TL-TLG) assess-
ment showed a significant association with overall survival. It is expected that the
higher sensitivity for response detection will help early decision-making in non-re-
sponders. Further research needs to investigate whether this actually improves pa-
tient outcome. Another important benefit of the TL-TLG assessment is that it can
be done semi-automatically, making it more rapid and reproducible than RECIST.
Chapter 17 presents the main study of the RADAR trial. The embolic effect of ra-
dioembolization may stimulate angiogenesis through hypoxia, thereby, also un-
intentionally promoting tumor progression. To investigate this hypothesis, we
have explored changes in serum angiogenic factors following radioembolization,
and evaluated associations with treatment response.60 We found that significant
increases in plasma levels of angiopoeitin-2 and hepatocyte growth factor in the
first week after treatment were associated with rapid disease progression in the liv-
er. This does suggest that the embolic component of radioembolization stimulates
tumor progression through angiogenesis in certain patients. The use of an anti-an-
giogenesis drug could potentially improve treatment response in these patients.
That is, if these patients can be identified before treatment.
Interestingly, various older radioembolization studies reported routine intra-ar-
terial administration of angiotensin-II during treatment to increase the tumor to
non-tumor (T/N) microsphere uptake ratio.19,61-65 Yet, the clinical evidence sup-
porting this strategy seemed doubtful. Therefore, we decided to perform a sys-
tematic literature review on this topic, which is presented in Chapter 18. A total of
5 relevant studies, including 71 patients, were found. These studies did show that
angiotensin-II administration significantly increased the T/N ratio by a factor of
1.8 – 3.1, with reported clinical side effects being limited to transitory increase
of systemic blood pressure. However, the methodology used in these studies is
questionable, and varied heavily. Therefore, we concluded that further research is
required to assess safety aspects, optimal administration strategy and impact on
treatment efficacy, before angiotensin-II is routinely administered during radio-
Chapter 19 Part IV
embolization procedures.
- 374 -
DISCUSSION
The scientific evaluation of radioembolization has reached a critical point. Large
randomized controlled trials are now trying to prove added value of radioemboli-
zation treatment in non-salvage patients with primary or metastatic liver tumors.66
The stakes are high. Proof of added value will enable much more patients to under-
go this treatment in the future, whereas failure may demotivate clinicians to refer
patients for radioembolization treatment. So, considering the logical sequence of
evaluation, as described by the IDEAL recommendations, one would expect that
all technical aspects are already optimized at this stage.67 Yet, remarkably, many
fundamental aspects of this treatment have been somewhat neglected and still re-
quire improvement.
For outsiders, radioembolization treatment still resembles a black box. They may
falsely assume that it is a relatively straightforward treatment like radiofrequen-
cy ablation or transarterial chemoembolization. In this dissertation, we tried to
provide more insight into the many challenges that arise in clinical practice, and
provide much-needed scientific evidence for decision-making. The fact that the
preferential arterial vascularization of liver tumors drives tumor targeting provides
the advantage that patients who are ineligible for other locoregional treatments
may still be treated with radioembolization. However, it also means that tumor
targeting cannot be ‘steered’. This drawback requires a preparatory angiography
to confirm safety of treatment, while the therapeutic microsphere distribution is
unpredictable and may ultimately turn out unfavorable.
High-tech innovations follow each other at a rapid rate in the field of intervention-
al oncology. This should, however, not come at the cost of a thorough evaluation
of treatment technique. So far, most of the evidence in the radioembolization field
is either empirical, or originates from small retrospective studies, sometimes even
with flawed methodology. In our opinion, rather than focusing all of our efforts
on conducting large randomized controlled trials in the next years, we should try
to first optimize technical aspects of radioembolization. Using large, national pa-
tient registries would enable the conduct of high-quality prospective studies with
sufficient patients to build robust multivariable regression models that can help
compare the safety and efficacy of different treatment strategies.
Finding a way to predict the therapeutic microsphere distribution is presumably
one of the most important hurdles to take in the near future. As described, using
166
Ho microspheres for this purpose may be more sensible than the use of 99mTc-
MAA.36,39 Theoretically, a small dose of 90Y microspheres may, however, also be
Part IV Chapter 19
used, although it remains unclear whether the distribution of small amounts of 90Y
- 375 -
activity can accurately be quantified with PET/CT, due to the low true-coincidence
rate associated with this isotope.68 Assuming that a better scout particle would be
available, and it could be administered safely, then the individual T/N uptake ratio
can be determined and the activity to be administered can be calculated, using the
partition model method69, in a way so that the maximum tolerable healthy liver
dose is not exceeded, yet a high tumor dose is still effectuated.70
This brings out another question: What is a maximum tolerable healthy liver ab-
sorbed dose? Unfortunately, there is no clear answer yet. A mean healthy liver ab-
sorbed dose of 30 Gy is often propagated71, but this value is mainly based on ex-
perience with external beam radiation therapy.72 Thus, radioembolization specific
dose-toxicity models are needed. However, a generalized and fixed number may
not even be realistic, since the condition of the healthy liver tissue is probably also
an important factor to consider. Previous cytotoxic drug treatment and the pres-
ence of liver cirrhosis, for example, reduce the tolerance to radiation. Furthermore,
liver function should perhaps not be estimated as an average for the entire liver. If
a map of the regional liver function could be created, for example with Gd-EOB-
DTPA enhanced liver MRI73, it may be possible to predict whether a certain dose
distribution is tolerable, depending on the volume and functional status of the liver
tissue that is irradiated.
As previously outlined, estimates for minimum effective tumor absorbed dose
values remain controversial as well. We have provided first evidence that at least
40 – 60 Gy is required for resin 90Y microspheres radioembolization in patients
with CRLM, yet additional dose-response evaluations are required for other mi-
crosphere and tumor types. In fact, we believe that absorbed dose quantification
should become routine practice in centers that perform radioembolization. A shift
in treatment paradigm is required, where technical treatment success is measured
by early evaluation of the absorbed dose delivered to all targeted tumors, instead
of awaiting tumor response at 1 – 3 months after treatment. This would enable the
development of strategies for tumor dose optimization with the aim to improve
patient outcome. Various strategies may be considered. If it is already predicted
during the preparatory angiography that a tumor will receive a suboptimal tumor
dose, one may try to alter the particle-fluid dynamics by administering an intra-ar-
terial vasoconstrictor, using an anti-reflux catheter, or target the tumor-feeding
branch by separate injection. If the suboptimal tumor absorbed dose is measured
posttreatment, on the other hand, additional treatment with superselective radio-
embolization or other modalities such as transarterial chemoembolization, radiof-
Chapter 19 Part IV
requency ablation or external radiation therapy could be considered. The problem
- 376 -
with the latter strategy is, however, that it remains unknown which treatments can
be given safely and how long the interval between original and additional treat-
ment must be.
Finally, we think that we need to understand some of the physical principles that
underlie our therapy better. Fluid-particle dynamics are the main driver for tu-
mor targeting during radioembolization. Yet, they are still poorly understood. The
same is true for applied radiobiology and cancer biology. Scientific collaborations
with departments of physics and engineering, radiotherapy, and cancer biology,
could teach us valuable lessons and help us understand and recognize some of the
phenomena that we observe daily in clinical practice. Industry partnerships may
also be worthwhile to drive innovation. We predict that the development of imag-
ing tools that enable real-time visualization of the three-dimensional intravascu-
lar catheter position, and computational fluid dynamics, will have a revolutionary
impact on radioembolization treatment, as witnessed with the recent introduction
of C-arm CT.
Part IV Chapter 19
- 377 -
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liver and its variant blood supply and col- ization of the middle hepatic artery and its
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tion. Liver Transplant Transplant 736–741.
Surgical anatomy of the hepatic arteries in 11. van den Hoven AF, van Leeuwen MS, Braat
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catheter on target volume particulate dis- tery before radioembolization: Feasibility,
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37. Smits MLL, Nijsen JFW, van den Bosch 45. Lam MGEH, Goris ML, Iagaru AH, et al.
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tastases: Single-centre experience with 100
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Chapter 19 Part IV
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PART V
ADDENDUM
Addendum
PART V
Dutch summary (Nederlandse samenvatting)
Review committee
List of publications
Biography
Acknowledgements (Dankwoord)
In dit proefschrift wordt klinisch onderzoek beschreven dat aan de Afdeling Ra-
diologie en Nucleaire Geneeskunde in het Universitair Medisch Centrum Utrecht
tussen 2012 en 2015 heeft plaatsgevonden. Dit onderzoek had als doel om radio-
embolisatie als behandeling van levertumoren te optimaliseren. Het proefschrift
is als volgt opgebouwd. Deel I (Hoofdstuk 2) betreft een overzicht van de meest
belangrijke aspecten rondom radioembolisatie. Deel II (Hoofdstukken 3 – 8) bes-
chrijft overwegingen met betrekking tot anatomie en beeldvorming die van belang
zijn tijdens de voorbereiding op de behandeling. Deel III (Hoofdstukken 9 – 12)
beschrijft nieuwe behandelstrategieën. Deel IV (Hoofdstukken 13 – 18) behandelt
de evaluatie van de toxiciteit en effectiviteit van de behandeling.
INLEIDING
Levertumoren
Levertumoren zijn een belangrijke oorzaak voor ziekte en sterfte in kankerpatiënt-
en. In 2012 is naar schatting wereldwijd in 782.500 nieuwe patiënten primaire
leverkanker gediagnosticeerd. Bovendien zijn ongeveer 745.000 patiënten in het-
zelfde jaar aan de gevolgen van deze ziekte overleden. De incidentie van primaire
leverkanker is het hoogst in ontwikkelingslanden waar infecties met het hepatitis
B en C virus veel voor komen, maar ook de westerse wereld is in toenemende mate
aangedaan. Zo is de incidentie van primaire leverkanker in de Verenigde Staten
tussen 1975 en 2011 verdriedubbeld. Dit is mogelijk te verklaren door een toename
in non-alcoholische steatohepatitis ten gevolge van obesitas en diabetes mellitus.1
Levertumoren kunnen tevens ontstaan als metastasen van een kwaadaardig gezw-
el elders in het lichaam. Vooral patiënten met een colorectaal carcinoom hebben
door de directe verbinding tussen de dikke darm en de lever, via de bloedstroom
en lymfdrainage, een verhoogd risico. Dit blijkt uit het feit dat circa 20 % van de
patiënten met een colorectaal carcinoom bij diagnose al levermetastasen heeft, en
één-derde van de overige patiënten deze later in het ziektebeloop ontwikkelt.2 Bov-
endien is circa 90 % van de sterftegevallen in patiënten met een colorectaal carci-
noom toe te schrijven aan tumor-geïnduceerd leverfalen.3
Het is dan ook niet verwonderlijk dat veel aandacht wordt besteed aan de behan-
deling van levertumoren. Welke therapie geïndiceerd is hangt in sterke mate af
van het ziektestadium. Chirurgie is de behandeling van eerste keuze in patiënten
met gelokaliseerde en beperkte ziekte. Helaas is de ziekte echter bij diagnose in
een groot aantal patiënten al niet meer resectabel. In patiënten met irresectabele
levertumoren is, afhankelijk van het tumor type, systemische therapie dan wel lo-
coregionale transcatheter therapie aangewezen. Terwijl de beschikbaarheid over
Addendum Part V
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nieuwe chemotherapeutica en monoklonale antistoffen in de afgelopen jaren de

behandeling van bijvoorbeeld colorectale levermetastasen (CRLM) sterk verbeterd
heeft4, is de effectiviteit van deze middelen in andere typen metastasen5 en primaire
leverkanker6-7 teleurstellend. Bovendien gaat systemische therapie vaak gepaard
met ernstige toxiciteit. Transcatheter therapieën zoals transarteriële chemoembo-
lisatie en radioembolisatie zijn ontwikkeld als minimaal-invasieve locoregionale
behandel alternatieven.
Radioembolisatie
Radioembolisatie is een minimaal-invasieve behandeling waarbij via een kathe-
ter, onder geleide van angiografische beeldvorming, radioactieve microsferen in
de arteria hepatica geïnjecteerd worden om levertumoren van binnenuit te bes-
tralen. Levertumoren worden bijna uitsluitend door de arteria hepatica van bloed
voorzien, terwijl het grootste gedeelte van de bloedvoorziening in het gezonde
leverweefsel via de vena porta verloopt. Deze preferentiële arteriële tumor vascu-
larisatie leidt over het algemeen tot clustering van de radioactieve microsferen in
het tumorweefsel, terwijl het gezonde leverweefsel relatief gespaard wordt. In het
afgelopen decennium is radioembolisatie uitgegroeid tot een geaccepteerde, veilige
en effectieve behandeling voor zowel irresectabele chemorefractoire levermetas-
tasen als lokaal gevorderde primaire leverkanker. Desalniettemin zijn er nog steeds
aspecten die verbeterd dienen te worden voordat het ware klinische potentieel van
deze behandeling benut kan worden.8
Voorbereiding op de behandeling
Radioembolisatie behandeling vergt een zorgvuldige voorbereiding. De belangri-
jkste onderdelen van de voorbereiding zijn het in kaart brengen van de individuele
anatomie van de arteriële lever vasculatuur, een behandelstrategie definiëren, een
voorbereidende angiografie uitvoeren om (een) veilige en adequate injectie posi-
tie(s) te bepalen, en de benodigde behandelactiviteit berekenen.
De arteriële vasculatuur van de lever is complex en vertoont frequent anatomische
varianten. Derhalve dienen de individuele configuratie van de leverarteriën en hun
segment vascularisatie te worden bestudeerd, alvorens te kunnen bepalen in welke
arteriële takken de microsferen toegediend dienen te worden, welke zijtakken ver-
meden moeten worden om extrahepatische deposities te voorkomen, en of er een
noodzaak bestaat om takken te emboliseren.
In 2012 bestond er echter nog geen systematische aanpak om de anatomie op
pre-therapeutische cross-sectionele beeldvorming te evalueren. Bovendien om-
vatten de destijds bestaande anatomische classificaties niet alle varianten die van
belang zijn voor radioembolisatie.9-11 Er bestond dus grote onzekerheid over de
Part V Addendum
- 389 -
anatomische varianten die tijdens de angiografische procedures tegen konden

worden gekomen. Ook was het niet mogelijk om een behandelstrategie vooraf te
bepalen. Beslissingen werden vaak ad-hoc gemaakt op basis van digitale subtrac-
tie angiografie (DSA) beelden die tijdens de voorbereidende angiografie werden
verkregen.
Hoofdstuk 3 beschrijft een onderzoek waarin de configuratie en segment vascu-
larisatie van de arteriële lever vasculatuur op pre-therapeutische lever computed
tomography (CT) en DSA is bepaald.12 Hieruit bleek dat de individuele anatomie
van de arteriële lever vasculatuur inderdaad goed kan worden bestudeerd op de
pre-therapeutische lever CT. Op basis van de observaties in dit onderzoek werden
reeds bestaande anatomische classificaties uitgebreid met varianten die relevant
zijn voor radioembolisatie. In tegenstelling tot eerder, werd hierbij een duideli-
jk onderscheid gemaakt in varianten die betrekking hebben op de origo van de
leverarteriën (aberrante arteriën), het vertakkingspatroon (vroege vertakkingspa-
tronen) en de segment vascularisatie. In totaal werden 16 patronen voor arteriële
lever segment vascularisatie beschreven, die van elkaar verschillen ten aanzien van
de aanwezigheid van aberrante arteriën, de segment vascularisatie van aberrante
arteriën en de vascularisatie van segment 4 (S4).
Omdat er ook nog geen consensus bestond over hoe om te gaan met deze anato-
mische varianten, hebben wij een geïndividualiseerde radioembolisatie strategie
voorgesteld. Hierin werden risico’s en baten van verschillende strategieën tegen
elkaar afgewogen en per variant een aanbeveling gegeven. Het feit dat de arteriële
leveranatomie al op de pre-therapeutische lever CT kan worden beoordeeld bete-
kent dat een dergelijk behandelplan al vóór de voorbereidende angiografie kan
worden vastgesteld. Dit creëert ruimte voor intercollegiale discussie en versterkt
het inzicht van de operateur in de arteriële anatomie van de individuele patiënt
tijdens de angiografische procedures. Bovendien zou het ook kunnen leiden tot
een verkorting en vermindering van de contrast- en stralingsbelasting van de
voorbereidende angiografie, omdat de operateur gerichter kan katheteriseren.
Om te benadrukken dat een systematische aanpak noodzakelijk is voor het op-
sporen van anatomische varianten, hebben wij in Hoofdstuk 4 getoetst hoe ade-
quaat in het verleden aberrante leverarteriën in onze klinische praktijk werden
geïdentificeerd.13 Uit deze analyse bleek dat aberrante leverarteriën inderdaad kun-
nen worden gemist als geen systematische aanpak gehanteerd wordt. Dit heeft in
een aantal patiënten tot een inadequate behandeling geleid. Om dit in de toekomst
te voorkomen, hebben wij de oorzaken voor het missen van aberrante leverar-
teriën achterhaald en op basis hiervan een stappenplan ontwikkeld dat gebruikt
Addendum Part V
- 390 -
kan worden om aberrante leverarteriën met behulp van pre-therapeutische lever

CT, DSA, C-arm cone beam CT en scintigrafie te detecteren en karakteriseren.
Segment 1 (S1) en segment 4 (S4) behoeven extra aandacht tijdens de voorbereid-
ing op radioembolisatie behandeling, omdat de arteriën die deze segmenten van
bloed voorzien een opmerkelijk variabele oorsprong hebben. Qua arteriële vascu-
larisatie horen deze segmenten in tegenstelling tot de andere leversegmenten dan
ook niet per definitie bij de functionele linker of rechter hemi-lever.
Helaas blijkt uit de retrospectieve studie die in Hoofdstuk 5 beschreven staat, dat
tijdens radioembolisatie behandelingen niet voldoende aandacht wordt besteed
aan de vascularisatie van S1.14 Tumoren in S1 bleken slechts in 19 % van de be-
troffen patiënten behandeld te zijn, terwijl S1 juist onnodig wordt behandeld in
80 % van de patiënten zonder tumor(en) in dit segment. Ook overbehandeling
van S1 lijkt onwenselijk, omdat significante hypertrofie blijkt op te treden als dit
segment gespaard wordt, hetgeen de leverfunctie ten goede komt. Over de arteriële
vascularisatie van S1 was voorheen slechts bekend dat dit segment waarschijnlijk
kan worden onderverdeeld in drie gedeelten die afzonderlijk gevoed worden door
kleine segment 1 arteriën (A1s), die vanuit de arteria hepatica sinistra en dextra
ontspringen.15-16 Deze A1s bleken over het algemeen slecht zichtbaar op pre-ther-
apeutische lever CT, maar identificatie was vaker mogelijk in patiënten met tu-
mor(en) in S1. Nu wij benadrukt hebben dat S1 vaak verkeerd behandeld wordt
tijdens radioembolisatie, dient vervolgonderzoek uit te wijzen hoe dit probleem
kan worden opgelost.
Hoofdstuk 6 is een uitgebreide review over arteriële leveranatomie.17 Hierin worden
de verschillen tussen de anatomie van de arteriële en portale lever vasculatuur
benadrukt en onduidelijkheden ten aanzien van de terminologie en rapportage
van anatomische varianten besproken.
In Hoofdstuk 7 beschrijven wij een studie die als doel had om het acquisitieprotocol
voor pre-therapeutische lever CT in radioembolisatie patiënten te verbeteren. De
origo detectie van kleine arteriële takken, zoals de arteria gastrica sinistra en de
arterie die segment 4 voedt, leek suboptimaal op CT.18 Onze hypothese was dat dit
veroorzaakt werd doordat de scan delay van de arteriële fase te lang was, waardoor
contrast opname in de vena porta de origo van kleine arteriële takken overschadu-
wde. Een nieuw acquisitieprotocol werd ingevoerd met een verkorte scan delay van
de arteriële fase (van 20 seconden naar 10 seconden). Nadat 50 radioembolisatie
kandidaten deze nieuwe scan voor de behandeling hadden ondergaan, werd de
origo detectie van de arteria gastrica dextra en de segment 4 arterie vergeleken met
een historisch cohort van 50 vergelijkbare patiënten die voor die tijd een scan met
Part V Addendum
- 391 -
het oude protocol hadden ondergaan. Ondanks dat de contrast-ruis verhouding

van de arteriële lever vasculatuur significant hoger was op de scans met de verv-
roegde scan delay, leidde dit niet tot een verbetering van de origo detecties. Er lijkt
op CT nog ruimte voor verbetering te bestaan voor de origo detectie van de arteria
gastrica dextra (identificatie in 58 – 65 %), terwijl de origo detectie van de segment
4 arterie reeds goed blijkt te zijn (identificatie in 89 – 96 %).
C-arm cone beam CT (C-arm CT) is een relatief nieuwe beeldvormingsmodaliteit
die het mogelijk maakt om tijdens angiografische procedures CT-achtige beelden
te produceren. Hoofdstuk 8 behandelt een prospectieve studie waarin wij hebben
getracht om een acquisitie protocol voor C-arm CT te ontwikkelen dat geoptimali-
seerd is voor radioembolisatie.19 Voorheen was het sporadische gebruik van C-arm
CT in onze kliniek beperkt tot het drie-dimensioneel afbeelden van de arteriële
vaatboom. Ons doel was echter om een protocol te ontwikkelen waarmee ook
extrahepatische shunting en het gebrek aan target segment perfusie kan worden
gedetecteerd, zodat deze fouten reeds tijdens de voorbereidende angiografie op-
gespoord en gecorrigeerd kunnen worden. De acquisitie parameters werden in
de praktijk stapsgewijs aangepast totdat een optimale beeldkwaliteit bereikt werd.
Vervolgens werd de diagnostische waarde van de C-arm CTs vergeleken met de
goudens standaard, een single photon emission computed tomography (SPECT)/
CT na toediening van technetium-99m macroaggregated albumin (99mTc-MAA).
Hieruit bleek dat het gebruik van een continue contrast toediening, een geperson-
aliseerde scan delay, en een 10 seconden high dose scan setting resulteerden in de
beste beeldkwaliteit. Deze beelden lieten zowel contrast opname van de arteriële
vaatboom, als gastro-intestinale shunting, en gebrek aan target segment perfusie
zien. Bovendien bleek de algehele diagnostische waarde van C-arm CT goed te
zijn, met een negatief voorspellende waarde voor de detectie van gastro-intestinale
shunting en gebrek aan target segment perfusie van respectievelijk 95 en 83 %.
Nieuwe behandelstrategieën
Het huidige traject voor radioembolisatie behandelingen is erg complex en niet
afgestemd op de individuele patiënt. In de weken voor de behandeling dient een
voorbereidende angiografie plaats te vinden, waarbij eventueel arteriële takken
worden geëmboliseerd en vanuit een strategisch gekozen katheterpositie surrogaat
partikels (99mTc-MAA) worden toegediend. Na afloop worden een SPECT/CT en
planaire scintigrafie vervaardigd om extrahepatische depositie en een significante
long shunt fractie uit te sluiten. Als de voorbereidende procedure succesvol is ver-
lopen moeten patiënten ongeveer een week later opnieuw worden opgenomen om
de behandeling te ondergaan.20
Addendum Part V
- 392 -
Het feit dat de voorbereidende procedure en de behandeling minstens twee ziek-

enhuisopnames vereisen is voor zieke patiënten erg belastend. Gates et al. hebben
in een kleine studie aangetoond dat beide procedures ook op dezelfde dag kunnen
worden uitgevoerd.21 Opmerkelijk is dat de auteurs aangeven dat de voorberei-
dende angiografie uitsluitend werd uitgevoerd voor het bepalen van de longshunt
fractie, aangezien C-arm CT gebruikt kan worden om extrahepatische shunting
uit te sluiten. In een ‘letter to the editor’ als reactie op dit artikel, weergegeven in
Hoofdstuk 9, beargumenteren wij dat een echte ‘single-session’ behandeling dan
ook mogelijk zou kunnen zijn.22 Dit wordt onderbouwd door een retrospectieve
analyse van de geschatte long dosis in 160 patiënten die met radioembolisatie in
ons centrum zijn behandeld, die uitwees dat long shunting zelden een limiterende
factor is, vooral niet in patiënten met CRLM.
Een belangrijke tekortkoming van de huidige radioembolisatie toepassing met
yttrium-90 microsferen (90Y) is dat het vooralsnog niet mogelijk is om de uitein-
delijke verdeling van de microsferen in de lever met 99mTc-MAA partikels te voor-
spellen.23-24 Dit heeft ook belangrijke dosimetrische implicaties. Omdat de beno-
digde activiteit niet afgestemd kan worden op de verwachtte gezonde lever dosis,
zijn relatief simpele methoden voor activiteitberekeningen ontwikkeld, die over
het algemeen een veilige en effectieve behandeling mogelijk maken. De uiteindeli-
jke verdeling van de microsferen in de lever vertoont echter een sterke inter- en
intra-individuele variabiliteit, met een gerapporteerde range in tumor tot non-tu-
mor (T/N) microsfeer uptake ratio’s van 0.6 – 25.9.25 Deze heterogeniteit wordt
waarschijnlijk veroorzaakt door meerdere factoren, met invloeden van tumor an-
giogenese, microsfeer karakteristieken, en flow dynamica.26-28 Twee verschillende
onderzoeken hebben zelfs uitgewezen dat tijdens radioembolisatie in 38 – 60 %
van de patiënten tenminste één tumor suboptimaal behandeld wordt. Dit is een
belangrijk klinisch probleem dat mogelijk zou kunnen verklaren waarom de tumor
respons na radioembolisatie soms tegenvalt.29-30
Dus zowel de voorspelbaarheid van de therapeutische microsfeer verdeling als de
effectiviteit van de behandeling dienen verbeterd te worden. Een combinatie van
een nieuw type katheter en radioactieve microsferen zou hieraan een belangrijke
bijdrage kunnen leveren.
Momenteel worden twee type katheters gebruikt tijdens radioembolisatie proce-
dures. Doorgaans wordt een standaard microkatheter gebruikt, omdat dit type
katheter goedkoop, simpel in gebruik, atraumatisch en flexibel is. Een nadeel is
echter het gebrek aan ondersteuning in het vaatlumen, waardoor de microkath-
eter tijdens de toediening onbedoeld naar een van de vaatwanden kan deviëren
Part V Addendum
- 393 -
en daarmee een disproportionele verdeling van de microsferen kan veroorzaken.

Een nieuw type katheter, de anti-reflux katheter, is specifiek ontwikkeld voor ther-
apieën zoals radioembolisatie. De tip van de anti-reflux katheter is uitklapbaar en
maakt rondom contact met de vaatwand tijdens de toediening van microsferen,
waardoor eventuele reflux van microsferen wordt voorkomen.
In Hoofdstuk 10 presenteren wij een aantal cases die voor het eerst in patiënten
lieten zien dat de anti-reflux katheter een veilige toediening van radioactieve mi-
crosferen mogelijk maakt zonder eerst nabije gastro-intestinale zijtakken met coils
te emboliseren.31 Daarna hebben andere studies aangetoond dat een dergelijk geb-
ruik van een anti-reflux katheter de toediening simpeler maakt, en daarmee zowel
de procedure tijd verkort als de contrast en stralingsbelasting vermindert.32-33
Het was echter onduidelijk of het onderscheidende ontwerp van de anti-reflux
katheter ook invloed heeft op partikel-vloeistof dynamica en de intrahepatische
microsfeer verdeling. Daarom besloten wij het effect van de anti-reflux katheter in
een gecontroleerde experimentele setting, dat wil zeggen een artificieel lever vaat-
stelsel met gerecreëerde hemodynamica, te onderzoeken. Microsfeer toedieningen
met een standaard microkatheter werden kwalitatief en kwantitatief vergeleken
met anti-reflux katheter toedieningen onder dezelfde omstandigheden. De resul-
taten van deze in vitro experimenten zijn weergegeven in Hoofdstuk 11.34 De bloed-
stroom in de arteriële lever vasculatuur vertoont onder normale omstandigheden
een laminair patroon, oftewel bloed vloeit in geordende parallelle kolommen
die elkaar niet kunnen kruisen. Onze experimenten lieten zien dat als een stan-
daard microkatheter tijdens toedieningen een deviatie in het cross-sectionele vlak
richting een van de vaatwanden vertoont, het laminaire vloeistofpatroon ervoor
zorgt dat microsferen bij splitsing van het vat preferentieel in de dochtertak aan
de kant van de deviatie terechtkomen. Helaas is een dergelijke disproportionele
verdeling over het algemeen ongewenst en kan een deviatie in katheterpositie door
het twee-dimensionele karakter van DSA onopgemerkt blijven. Bovendien is een
deviatie in microkatheter positie soms door de geometrie van het arteriële lever-
vaatstelsel onvermijdbaar.
Voorgaande onderzoeken hadden reeds uitgewezen dat het ontplooien van de an-
ti-reflux kathetertip een daling in bloeddruk distaal van de katheter veroorzaakt.35
In theorie zou dit de tumor penetratie gedurende radioembolisatie kunnen ver-
beteren door de hoge interstitiële druk in hyperpermeabele tumoren te verlagen.36
Onze experimenten hebben voor het eerst aangetoond dat het ontplooien van de
anti-reflux kathetertip ook het geordende laminaire patroon van de bloedstroom
converteert naar een chaotisch turbulent flowpatroon. Dit resulteerde in een sig-
Addendum Part V
- 394 -
nificant homogenere verdeling van microsferen over dochtertakken, in vergeli-

jking met de standaard microkatheter toedieningen. In de praktijk zou dit kunnen
verhinderen dat bepaalde segmenten met tumoren ten gevolge van een deviatie in
katheterpositie niet worden bereikt. De experimenten bevestigden ook dat de tip
van de anti-reflux katheter zich inderdaad consequent in het centrum van het vaat-
lumen bevindt. Deze gefixeerde centro-luminale katheterpositie zou mogelijk de
voorspellende waarde van een scout partikel toediening tijdens de voorbereidende
angiografie kunnen verbeteren, door eventuele verschillen in katheterpositie tus-
sen de voorbereidende angiografie en de therapie te minimaliseren.
Holmium-166 (166Ho) microsferen zijn specifiek ontwikkeld voor radioemboli-
satie. In tegenstelling tot 90Y microsferen geven 166Ho microsferen ook γ-straling
af en beschikken ze over paramagnetische eigenschappen, hetgeen accurate
beeldvorming van de biodistributie met SPECT en magnetic resonance imaging
(MRI) mogelijk maakt. Bovendien kan een scout dosis van identieke 166Ho mi-
crosferen tijdens de voorbereidende angiografie, op dezelfde dag als de therapie,
worden toegediend.37-38 De veiligheid en effectiviteit van 166Ho radioembolisatie is
reeds in twee klinische trials aangetoond.39-40
De opzet van de vervolgstudie wordt in Hoofdstuk 12 beschreven.41 In deze ‘with-
in-patient randomized controlled trial’ – de SIM trial – worden een eendaagse
behandeling, het gebruik van de anti-reflux katheter en 166Ho microsferen gecom-
bineerd, in een poging om radioembolisatie als behandeling van CRLM te opti-
maliseren. De behandelstrategie in deze trial is erg vernieuwend. Vijfentwintig
patiënten met chemorefractoire irressectabele CRLM zullen behandeld worden
met 166Ho radioembolisatie. In geïncludeerde patiënten zal vooraf de individuele
anatomie van de arteriële levervasculatuur beoordeeld worden en op basis hiervan
een behandelplan vastgelegd worden. Als basis voor dit plan dienen in elke patiënt
twee selectieve injectieposities (in de arteria hepatica sinistra en dextra) te worden
gebruikt. Vervolgens zal het gebruik van de anti-reflux katheter per randomisatie
aan een van de twee injectieposities worden toegewezen en dient de standaard mi-
crokatheter aan de andere kant te worden gebruikt. Patiënten zullen op dezelfde
dag twee procedures ondergaan, in de ochtend een voorbereidende angiografie
met toediening van een scout dosis aan 166Ho microsferen, gevolgd door de daadw-
erkelijke behandeling in de namiddag. Na beide procedures wordt een SPECT/CT
vervaardigd om het effect van katheter type op de microsfeer verdeling te kunnen
onderzoeken. Onze hypothese is dat het gebruik van de anti-reflux katheter tot een
betere voorspellende waarde van de 166Ho scout dosis en therapeutische T/N ratio
leidt ten opzichte van het gebruik van een standaard microkatheter. Uiteindelijk
Part V Addendum
- 395 -
zou dit ook tot een betere tumor respons kunnen leiden. Dit zal door middel van
beeldvorming met lever CT en 18-fluoro-2-deoxyglucose-positron emission to-
mography (18F-FDG-PET)/CT worden onderzocht. Een ‘within-patient random-
ized controlled trial’ design is een efficiënte wijze om lokale behandeleffecten te
onderzoeken, maar effecten op overleving kunnen hiermee niet worden onder-
zocht.
EVALUATIE VAN TOXICITEIT EN HET EFFECT VAN DE BEHANDELING

Een gestandaardiseerde evaluatie van toxiciteit en behandeleffect zou onderdeel
moeten uitmaken van elke radioembolisatie behandeling. Desalniettemin bestaat
er grote onduidelijk ten aanzien van geschikte indicatoren voor toxiciteit, zinvolle
preventieve maatregelen om complicaties te voorkomen, de relatie tussen geabsor-
beerde tumor dosis en respons, de consequenties van een ongunstige post-thera-
peutische microsfeer verdeling, en het optimale systeem voor respons beoordeling.
Ten aanzien van behandeling gerelateerde toxiciteit was het bijvoorbeeld de vraag
of laboratorium afwijkingen na radioembolisatie gebruikt konden worden als in-
dicator voor klinisch relevante toxiciteit. Om deze vraag te beantwoorden hebben
wij een retrospectieve toxiciteit analyse uitgevoerd in alle patiënten die in ons cen-
trum tussen 2009 en maart 2012 behandeld zijn en geen onderdeel uitmaakten van
een klinische trial. Deze studie staat beschreven in Hoofdstuk 13.42 De klinische
toxiciteit bleek beperkt tot symptomen die passen bij het postembolisatie syn-
droom. Er werden geen gevallen van ‘radiation-induced liver disease’ of andere
complicaties waargenomen. Desondanks was er sprake van ernstige afwijkingen
in laboratorium waarden (CTCAE graad 3 – 4) in 38 % van de patiënten. Dit geeft
aan dat laboratorium afwijkingen deel uitmaken van de fysiologische reactie op
radioembolisatie en niet gebruikt kunnen worden om een normaal en abnormaal
post-therapeutisch verloop van elkaar te onderscheiden.
Er bestaat ook veel discussie over de noodzaak om voorzorgsmaatregelen te tr-
effen om ‘radiation-induced cholecystitis’ te voorkomen. Sommige auteurs raden
routinematige coil embolisatie van de arteria cystica tijdens de voorbereidende
angiografie aan, omdat het verloop van ‘radiation-induced cholecystitis’ ernstige
kan zijn, in zeldzame gevallen zelfs fataal.43-45 Daarentegen zijn er ook gevallen
gerapporteerd waarin coil embolisatie tot ischemische cholecystitis – een vergelijk-
baar ernstige complicatie – heeft geleid.46 In Hoofdstuk 14 hebben wij door middel
van een literatuur studie naar ‘radiation-induced cholecystitis’ getracht de definitie
van deze complicatie te verduidelijken door het belang van klinische relevantie te
benadrukken.47 Verder hebben wij een stappenplan opgesteld dat clinici bij hun
Addendum Part V
- 396 -
besluitvorming kan helpen. De eerste aanbeveling is om de katheter tijdens de toe-

diening distaal van de arteria cystica te positioneren. Als dit niet mogelijk is, dient
eerst 99mTc-MAA in de beoogde injectiepositie te worden toegediend en de hoev-
eelheid activiteit in de galblaaswand op SPECT te worden geëvalueerd. Alleen bij
een excessieve accumulatie raden wij voorzorgsmaatregelen aan. In een herhaalde
procedure kan dan eerst getracht worden om de flow dynamica te beïnvloeden
door een verandering in katheterpositie. Deze strategie wordt ondersteund door
een casus die wij beschrijven waarin wij de geschatte dosis op de galblaaswand met
90 % hebben kunnen reduceren. Slechts als ook deze maatregel faalt dient emboli-
satie van de arteria cystica te worden overwogen.
Hoofdstukken 15 – 17 behandelen drie verschillende onderzoeken die gebaseerd
zijn op een prospectieve cohort studie die in ons centrum is uitgevoerd, de RA-
DAR studie. In totaal zijn in deze studie 42 patiënten met CRLM behandeld met
90
Y radioembolisatie. Tevens ondergingen zij voor en na de behandeling uitge-
breide laboratorium testen en beeldvorming. Dit is het grootste prospectieve co-
hort van CRLM patiënten die behandeld zijn met radioembolisatie dat tot nu toe
is beschreven.
Hoofdstuk 15 beschrijft een dosis-respons evaluatie.48 Verscheidene studies hadden
al een associatie tussen tumor dosis en respons na radioembolisatie beschreven,
maar geen van deze studies heeft de aard van de relatie tussen dosis en respons
kunnen ontdekken.49-60 Dit valt te verklaren door de soort analyses die eerder zijn
toegepast. Bovendien hebben eerdere studies niet de daadwerkelijke post-thera-
peutische tumor dosis gemeten, maar de verdeling van 99mTc-MAA op SPECT/CT
gebruikt om de post-therapeutische tumor dosis te schatten. Wij hebben voor alle
metastasen afzonderlijk, en voor de som van alle metastasen per lever, de geab-
sorbeerde tumor dosis op 90Y-PET/CT gemeten en het verband met metabole tu-
mor respons 1 maand na behandeling onderzocht, door gebruik te maken van een
‘linear mixed effects regression analysis’. ‘Total lesion glycolysis’ (TLG) werd als
indicator voor metabole activiteit gebruikt. Hieruit bleek dat er inderdaad sprake
is van een significante relatie tussen tumor dosis en respons, waarbij hogere doses
een grotere metabole tumor respons induceren. Het dosis-effect bleek echter ook
afhankelijk van de baseline tumor TLG, hetgeen aangeeft dat metabool actievere
tumoren een hogere dosis nodig hebben om een respons te vertonen. De minimaal
effectieve tumor dosis werd voor een gemiddelde tumor geschat op 40 – 60 Gy.
Opvallend was dat de gemiddelde tumor dosis, met 51 ± 28 Gy, lager uitviel dan
verwacht en een sterke heterogeniteit vertoonde. Optimalisatie van geabsorbeerde
tumor dosis is dus vereist. Het verfijnen van methoden voor activiteitberekenin-
Part V Addendum
- 397 -
gen zouden hierin een belangrijke rol kunnen spelen, aangezien huidige methoden
haalbare tumor doses inperken.
In Hoofdstuk 17 worden twee methoden voor tumor respons bepaling met elkaar
vergeleken.61 De rationale voor deze studie is dat tumor respons evaluaties die geb-
aseerd zijn op een verandering in tumor diameter, zoals de populaire ‘Response
Evaluation Criteria in Solid Tumors’ (RECIST)62, niet geschikt zijn voor radioem-
bolisatie omdat deze therapie, in tegenstelling tot cytostatische chemotherapie,
niet primair een tumor diameter reductie veroorzaakt. Helaas kunnen alternatieve
methoden voor tumor respons bepaling zoals ‘modified RECIST’ (mRECIST)63
niet in patiënten met CRLM gebruikt worden, omdat deze tumoren relatief hypo-
vasculair zijn. Met als doel om een nieuwe methode voor responsbepaling na ra-
dioembolisatie in patiënten met CRLM te valideren, hebben wij op 18F-FDG-PET
gebaseerde TLG respons 1 en 3 maanden post-therapie vergeleken met op MRI
gebaseerde respons in langste tumor diameter (LTD). Op tumor-niveau hebben
wij, door een correlatie tussen TLG en LTD respons aan te tonen, TLG respons be-
paling kunnen valideren. Bovendien was TLG respons sensitiever voor post-ther-
apeutische veranderingen in tumor status, en bleek een ‘total liver TLG’ (TL-TLG)
bepaling significant geassocieerd te zijn met overall survival. Naar verwachting
kan de betere sensitiviteit van TLG helpen bij vroege besluitvorming in patiënt-
en met een slechte respons na radioembolisatie. Een ander voordeel van TL-TLG
respons bepaling is dat deze semiautomatisch kan worden uitgevoerd en daarmee
sneller en beter reproduceerbaar is dan RECIST.
In Hoofdstuk 18 staat het hoofdonderzoek van de RADAR studie beschreven.64 De
aanleiding voor dit onderzoek is dat het embolische effect van radioembolisatie
door hypoxie angiogenese zou kunnen stimuleren en daarmee onbedoeld tumor
progressie zou kunnen veroorzaken. Om deze hypothese te testen hebben wij de
associatie tussen veranderingen in serum angiogenese factorenen en tumor re-
spons geëvalueerd. Er bleek inderdaad een significante associatie te bestaan tussen
stijging van ‘angiopoietin-2’ en ‘hepatocyte growth factor’ levels in de eerste week
na radioembolisatie en vroege progressie van de ziekte in de lever. Dit suggereert
dat de embolische component van radioembolisatie in sommige patiënten inder-
daad tumor progressie zou kunnen induceren. Als deze patiënten geïdentificeerd
zouden kunnen worden zouden zij potentieel baat kunnen hebben bij een behan-
deling met angiogenese remmers tijdens radioembolisatie.
Opmerkelijker wijze hebben veel oudere radioembolisatie studies het gebruik van
angiotensine-II tijdens radioembolisatie gerapporteerd, met als argument dat dit
de T/N ratio zou kunnen verbeteren.23,65-68 De sterkte van de bewijsvoering voor
Addendum Part V
- 398 -
deze strategie leek echter twijfelachtig. Daarom hebben wij besloten om in Hoofd-
stuk 19 een systematische literatuurstudie naar dit onderwerp uit te voeren.25 Vijf
relevante studies, met in totaal 71 patiënten, werden gevonden. Deze studies rap-
porteerden inderdaad dat intra-arteriële toediening van angiotensine-II de T/N
ratio met een factor 1.8 – 3.1 kan verhogen, terwijl klinische bijwerkingen beperkt
waren tot voorbijgaande hypertensie. De gebruikte methoden in deze studies zijn
echter dubieus en verschilden sterk onderling. We concluderen daarom dat verd-
er onderzoek naar het veiligheidsprofiel, de optimale toedieningswijze, en de inv-
loed op het behandeleffect vereist is voordat angiotensine-II routinematig gebruikt
wordt tijdens radioembolisatie behandelingen.
In conclusie, radioembolisatie is een veilige en effectieve behandeling voor lever-

tumoren, maar er is nog ruimte voor verbetering. In dit proefschrift hebben wij
getracht inzicht te verschaffen in de vele klinische en wetenschappelijke uitdagin-
gen van radioembolisatie, en voor besluitvorming noodzakelijke bewijsvoering
aan te dragen. Grote gerandomiseerde klinische trials zijn reeds opgezet om op
groepsniveau de behandel effectiviteit van radioembolisatie met andere therapieën
te vergelijken. Om in de toekomst echter op het niveau van de individuele patiënt
een geoptimaliseerde behandeling te kunnen aanbieden, dient verder onderzoek
verricht te worden naar de verbetering van de voorbereiding op de behandeling,
behandel strategieën, en evaluatie van het behandeleffect en toxiciteit.
Part V Addendum
- 399 -
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18. van den Hoven AF, Braat MNGJA, Prince
10. Hiatt JR, Gabbay J, Busuttil RW (1994) JF, et al. (2016) Liver CT for vascular eval-
Surgical anatomy of the hepatic arteries in uation during radioembolization workup:
1000 cases. Ann Surg 220:50–52. Comparison of an early and late arterial
phase protocol. Eur Radiol.
Addendum Part V
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19. van den Hoven AF, Prince JF, de Keizer B, with colorectal liver metastases scheduled
et al. (2016) Use of c-arm cone beam CT for radioembolization with 90Y-micro-
during hepatic radioembolization: Protocol spheres. J Nucl Med 54:516-522.
optimization for extrahepatic shunting and
27. van de Wiele C, Maes A, Brugman E, et al.
parenchymal enhancement. Cardiovasc In-
(2012) SIRT of liver metastases: Physiolog-
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20. Mahnken AH, Spreafico C, Maleux G, et al. Eur J Nucl Med Mol Imaging 39:1646-1655.
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21. Gates VL, Marshall KG, Salzig K, et al. Clin Oncol 8:115–120.
(2014) Outpatient single-session yttri-
29. Vente MAD, Wondergem M, van der Tweel
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dioembolization for the treatment of liver
22. van den Hoven AF, Prince JF, van den malignancies: A structured meta-analysis.
Bosch MAAJ, Lam MGEH (2014) Hepatic Eur Radiol 19:951–959.
radioembolization as a true single-session
30. Rosenbaum CENM, Verkooijen HM, Lam
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23. Dhabuwala A, Lamerton P, Stubbs RS tal cancer liver metastases: A systematic re-
(2005) Relationship of 99mtechnetium view. J Nucl Med 54:1890–1895.
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firmed intrahepatic radioembolization per-
diation therapy (SIRT). BMC Nucl Med 5:7.
formed without coil embolization, by using
24. Wondergem M, Smits MLJ, Elschot M, et the antireflux surefire infusion system. Car-
al. (2013) 99mTc-macroaggregated albumin diovasc Intervent Radiol 37:523–528.
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25. van den Hoven AF, Smits MLJ, Rosenbaum tion with resin microspheres. J Vasc Interv
CENM, et al. (2014) The effect of intra-ar- Radiol 25:1709-1716.
terial angiotensin II on the hepatic tumor
33. Morshedi MM, Bauman M, Rose SC, Ki-
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Part V Addendum
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34. van den Hoven AF, Lam MGEH, Jernigan S, 42. Smits MLJ, van den Hoven AF, Rosenbaum
et al. (2015) Innovation in catheter design CENM, et al. (2013) Clinical and laboratory
for intra-arterial liver cancer treatments re- toxicity after intra-arterial radioemboliza-
sults in favorable particle-fluid dynamics. J tion with 90Y-microspheres for unresectable
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35. Rose SC, Kikolski SG, Chomas JE (2013) 43. Hickey R, Lewandowski RJ (2011) Hepatic
Downstream hepatic arterial blood pres- radioembolization complicated by radia-
sure changes caused by deployment of the tion cholecystitis. Semin Intervent Radiol
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vasc Intervent Radiol 36:1262–1269.
36. Ariffin AB, Forde PF, Jahangeer S, et al. W1780 yttrium-90 SIRT for the treatment
(2014) Releasing pressure in tumors: What of unresectable hepatocellular carcinoma:
do we know so far and where do we go from Outcomes of an asian cohort. Gastroenter-
here? A review. Cancer Res 74:2655–2662. ology 136:A–860.
37. Smits MLJ, Nijsen JFW, van den Bosch 45. McWilliams JP, Kee ST, Loh CT, et al. (2011)
MAAJ, et al. (2012) Holmium-166 radio- Prophylactic embolization of the cystic ar-
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Lancet Oncol 13:1025-1034.
38. Prince JF, van Rooij R, Bol GH, et al. (2015) (2013) Selective internal radiotherapy
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dioembolization with 166Ho microspheres. the cystic artery. Cardiovasc Intervent Ra-
J Nucl Med 56:817–823. diol 36:1015–1022.
39. Smits MLL, Nijsen JFW, van den Bosch 47. Prince JF, van den Hoven AF, van den
MAAJ, et al. (2012) Holmium-166 radio- Bosch MAAJ, et al. (2014) Radiation-in-
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40. Prince JF, van den Bosch MAAJ, Nijsen 48. van den Hoven AF, Rosenbaum CENM,
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with 166Ho microspheres in liver metastases. dose-response relationship of radioemboli-
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tion therapy with yttrium-90 labeled resin Post-radioembolization yttrium-90 PET/
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6603. dictive dosimetry for resin microspheres.
EJNMMI Res 3:57.
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al. (2013) Prognostic utility of 90Y radio- 57. Mazzaferro V, Sposito C, Bhoori S, et al.
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fur colloid SPECT. J Nucl Med 54:2055– carcinoma: A phase 2 study. Hepatology
2061. 57:1826–1837.
51. Lam MGEH, Banerjee A, Goris ML, et al. 58. Srinivas SM, Natarajan N, Kuroiwa J, et
(2015) Fusion dual-tracer SPECT-based al. (2014) Determination of radiation ab-
hepatic dosimetry predicts outcome after sorbed dose to primary liver tumors and
radioembolization for a wide range of tu- normal liver tissue using post-radioembo-
mour cell types. Eur J Nucl Med Mol Imag- lization 90Y PET. Front Oncol 4:1–12.
ing 42:1192-1201.
59. Eaton BR, Kim HS, Schreibmann E, et al.
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(2015) Evaluation of factors affecting tu- um-90 radionuclide therapy: Tumor dose
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primary and metastatic liver cancer treat- emission tomography response in hepatic
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53. Strigari L, Sciuto R, Rea S, et al. (2010) 60. Garin E, Rolland Y, Edeline J, et al. (2015)
Efficacy and toxicity related to treatment Personalized dosimetry and intensification
of hepatocellular carcinoma with 90Y-SIR concept with 90Y-loaded glass microsphere
spheres: Radiobiologic considerations. J radioembolization induce prolonged over-
Nucl Med 51:1377–1385. all survival in hepatocelluar carcinoma pa-
54. Riaz A, Gates VL, Atassi B, et al. (2011) Ra-
Med 56:339-346.
diation segmentectomy: A novel approach
to increase safety and efficacy of radioem- 61. van den Hoven AF, Rosenbaum CENM,
bolization. Int J Radiat Oncol Biol Phys Braat MNGJA, et al. (2016) Anatomical
79:163–171. versus metabolic tumor response assess-
ment after radioembolization treatment.
55. Garin E, Lenoir L, Rolland Y, et al. (2012)
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tumor response and survival in hepato- (2009) New response evaluation criteria in
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results. J Nucl Med 53:255–263.
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63. Lencioni R, Llovet JM (2010) Modified 66. Tebbutt NC, Wilson K, Gebski VJ, et al.
RECIST (mRECIST) assessment for he- (2010) Capecitabine, bevacizumab, and
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30:52–60. astatic colorectal cancer: Results of the
australasian gastrointestinal trials group
64. Rosenbaum CENM, van den Hoven AF,
randomized phase III MAX study. J Clin
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dioembolisation for colorectal cancer liver
metastases: A prospective cohort study on 67. Stubbs RS, O’Brien I, Correia MM (2006)
circulating angiogenic factors and treat- Selective internal radiation therapy with
ment response. [submitted] 90
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tastases: Single-centre experience with 100
65. Gray B, Van Hazel G, Hope M, et al. (2001)
patients. ANZ J Surg 76:696-703.
Randomised trial of SIR-spheres plus che-
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treating patients with liver metastases from Stubbs R (2006) Evaluation of the role of
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12:1711–1720. tive internal radiation therapy in patients
with colorectal liver metastases. Australas
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Addendum Part V
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Addendum
PART V
Review committee
Biography
Review committee
Prof. Dr. R. van Hillegersberg

Professor in Surgical Oncology
Division of Surgical Specialties, University Medical Center Utrecht
Prof. Dr. Ir. J.J.W. Lagendijk

Professor in Medial Physics
Imaging Division, University Medical Center Utrecht
Prof. Dr. O. Kranenburg

Professor in Translational Oncology
Division of Surgical Specialties, University Medical Center Utrecht
Prof. Dr. P.J. van Diest

Professor in Pathology
Division of Laboratories and Pharmacy, University Medical Center Utrecht
Prof. Dr. O.M. van Delden

Professor in Interventional Radiology
Department of Radiology, Academic Medical Center Amsterdam
Part V Addendum
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Addendum
PART V
Review committee
Biography
PEER-REVIEWED PUBLICATIONS
van den Hoven AF, Braat MNGJA, Prince JF, van Doormaal PJ, van Leeuwen
MS, Lam MGEH, van den Bosch MAAJ (2016) Liver CT for vascular mapping
during radioembolization workup: Comparison of an early and late arterial phase
protocol. European Radiology. [accepted]
Braat MNGJA, van den Hoven AF, van Doormaal PJ, Bruijnen RCG, Lam MGEH,
van den Bosch MAAJ (2016) The caudate lobe – the blind spot in radioembolization
or an overlooked opportunity? CardioVascular and Interventional Radiology.
[accepted]
van den Hoven AF, Rosenbaum CENM, Elias SG, de Jong HWAM, Koopman
M, Verkooijen HM, Alavi A, van den Bosch MAAJ, Lam MGEH (2016) Insights
into the dose-response relationship of radioembolization with resin yttrium-90
microspheres: A prospective cohort study in patients with colorectal cancer liver
metastases. The Journal of Nuclear Medicine. [Epub ahead of print]
van den Hoven AF, Prince JF, de Keizer B, Vonken EJPA, Bruijnen RCG, Verkooijen
HM, Lam MGEH, van den Bosch MAAJ (2016) Use of C-arm cone beam CT during
hepatic radioembolization: Protocol optimization for extrahepatic shunting and
parenchymal enhancement. CardioVascular and Interventional Radiology 39:64-
73.
van den Hoven AF, Lam MGEH, Jernigan S, van den Bosch MAAJ, Buckner GD
(2015) Innovation in catheter design for intra-arterial liver cancer treatments
results in favorable particle-fluid dynamics. Journal of Experimental and Clinical
Cancer Research 34:74.
Braat AJAT, Smits MLJ, Braat MNGJA, van den Hoven AF, Prince JF, de Jong
HWAM, van den Bosch MAAJ, Lam MGEH (2015) 90Y hepatic radioembolization:
An update on current practice and recent developments. The Journal of Nuclear
Medicine 56:1079-1087.
van den Hoven AF, van Leeuwen MS, Lam MGEH, van den Bosch MAAJ, (2015)
Hepatic arterial configuration in relation to the segmental anatomy of the liver;
observations on MDCT and DSA relevant to radioembolization. CardioVascular
and Interventional Radiology 38:100-111.
Addendum Part V
- 412 -
van den Hoven AF, Smits MLJ, de Keizer B, van Leeuwen MS, van den Bosch MAAJ,
Lam MGEH (2014) Identifying aberrant hepatic arteries before radioembolization.
CardioVascular and Interventional Radiology 37:1482-1493.
Prince JF, van den Hoven AF, van den Bosch MAAJ, Elschot M, de Jong
HWAM, Lam MGEH (2014) Radiation-induced cholecystitis: Do we need to
take precautionary measures? Journal of Vascular and Interventional Radiology
25:1717-1723.
van den Hoven AF, Prince JF, van den Bosch MAAJ, Lam MGEH (2014) Hepatic
radioembolization as a true single-session treatment. Journal of Vascular and
Interventional Radiology 25:1143-1144.
van den Hoven AF, Prince JF, Samim M, Arepally A, Zonnenberg BA, Lam MGEH,
van den Bosch MAAJ (2014) Posttreatment PET-CT confirmed intrahepatic
radioembolization performed without coil embolization, by using the antireflux
surefire infusion system. CardioVascular and Interventional Radiology 37:523-
528.
van den Hoven AF, Smits MLJ, Rosenbaum CENM, Verkooijen HM, van den
Bosch MAAJ, Lam MGEH (2014) The effect of intra-arterial angiotensin-II on the
hepatic tumor to non-tumor blood flow ratio for radioembolization: A systematic
review. PLoS One 9:e86394.
Smits MLJ, van den Hoven AF, Rosenbaum CENM, Zonnenberg BA, Lam
MGEH, Nijsen JF, Koopman M, van den Bosch MAAJ (2013) Clinical and
laboratory toxicity after intra-arterial radioembolization with (90)y-microspheres
for unresectable liver metastases. PLoS One 8:e69448.
Smits MLJ, Prince JF, Rosenbaum CENM, van den Hoven AF, Nijsen JFW,
Zonnenberg BA, Seinstra BA, Lam MGEH, van den Bosch MAAJ (2013) Intra-
arterial radioembolization of breast cancer liver metastases: A structured review.
European Journal of Pharmacology 709:37-42.
BOOKCHAPTER
van den Hoven AF, Sze DY, Lam MGEH (2016) Chapter 1: Introduction to hepatic
radioembolization. In: Handbook of Radioembolization: Physics, Biology, Nuclear
Medicine, and Imaging. [accepted]
Part V Addendum
- 413 -
Addendum
PART V
Review committee
Biography
Biography
Andor Franciscus van den Hoven was born on

the 19th of September 1988 in Bonn, Germany.
Ten years later his Dutch family returned to the
Netherlands. After graduating (with honors/cum
laude) at the Erasmus College in Maastricht in
2006, he started medical school at the Utrecht
University.
His profound interest in anatomy, medical im-
aging and surgical procedures motivated him
to pursue a career in interventional radiology.
During the final year of his medical study he did
a clinical internship in radiology and started a re-
search elective on radioembolization at the Department of Radiology and Nuclear
Medicine of the University Medical Center (UMC) Utrecht, under supervision of
Prof. dr. Maurice van den Bosch. After graduating from medical school in 2012, he
continued this research as a MD PhD project.
The clinical research performed by the author between 2012 and 2015 is presented
in this dissertation. During this time, he also coordinated two prospective clinical
trials (the RADAR and SIM trial), and obtained a second master’s degree (with
honors/cum laude) in Clinical Epidemiology from the Utrecht University. In Octo-
ber 2014, he performed a research internship abroad on particle-fluid dynamics at
the Department of Mechanical and Aerospace Engineering of the North Carolina
State University in Raleigh, North Carolina, USA. In 2015, he was awarded a per-
sonal travel grant by the Dutch Cancer Society and left the Netherlands again for
a half-year research internship on liver cancer imaging at the Stanford University
Medical Center in Stanford, California, USA.
In March 2016, he started his radiology training at the UMC Utrecht under super-
vision of dr. R.A.J. Nievelstein. Part V Addendum
- 417 -
Addendum
PART V
Review committee
Biography
Met dit dankwoord sluit ik mijn proefschrift af. Ik kijk terug op een periode van
vier jaar waarin ik met ontzettend veel plezier onderzoek heb kunnen doen in het
Universitair Medisch Centrum Utrecht, aan de North Carolina State University, en
in het Stanford University Medical Center. In onderstaande woorden tracht ik mijn
immense dank uit te drukken aan eenieder met wie ik heb mogen samenwerken.
Zonder jullie zou dit onderzoek niet mogelijk zijn geweest.
Proefpersonen
Lieve patiënten en familie, bedankt dat jullie aan het onderzoek hebben willen
meewerken. Ik besef mij dat dit niet altijd even gemakkelijk zal zijn geweest. Het
was heel speciaal om jullie ziekteproces en behandeling van dichtbij mee te maken.
Wij hebben samen aan een betere behandeling voor patiënten met leverkanker
gewerkt, en ik ben ervan overtuigd dat we een verschil hebben kunnen maken.
Promotoren en copromotor
Prof dr. van den Bosch, beste Maurice, mentor, mijn dank naar jou toe is onnoemeli-
jk groot. Wat ben ik blij dat ik in het laatste jaar van mijn geneeskunde studie bij
jou heb aangeklopt met de vraag of ik onderzoek in de interventie radiologie kon
doen. Vanaf dat moment heb je mij altijd het vertrouwen gegeven dat ik mijn ei-
gen toekomst, zowel binnen als buiten de wetenschap, kan vormen, en dat niets
onmogelijk is. Bedankt dat je me de vrijheid hebt gegeven om mijn eigen ideeën te
ontplooien, internationale congressen te bezoeken, en met onconventionele ideeën
naar de Verenigde Staten te vertrekken om aldaar de grenzen van onze huidige
kennis op te zoeken. Ik denk nog vaak met een grote glimlach op mijn gezicht
terug aan onze trip over de highway one in California. Dream big!
Prof. dr. Lam, beste Marnix, ik kan me nog goed herinneren hoe ons eerste contact
verliep. Tot mijn schrik voorzag jij vanuit de Verenigde Staten een van mijn eerste
artikelen van bijzonder kritisch commentaar. Wat is er veel veranderd sinds die
tijd! Ik kan mij echt niet voorstellen hoe ik dit werk ooit zonder jou had kunnen
doen. Bedankt voor het onverminderde enthousiasme en de intensiteit waarmee
jij mij in de afgelopen jaren hebt begeleid. Ik waardeer het enorm dat jouw deur
altijd voor mij open stond, en mijn mails om 23 uur nog beantwoorde, ookal was je
verschrikkelijk druk. Ik vind het ook fijn dat je mij vanaf het eerste moment bij de
kliniek hebt betrokken en als volwaardig onderdeel van het team hebt beschouwd.
Met jouw gevoel voor humor en benaderbare houding voelde werk voor mij aan
als een vrijetijdsbesteding. Gefeliciteerd met je recente benoeming tot hoogleraar!
Hopelijk mogen we nog heel lang samenwerken.
Addendum Part V
- 420 -
Dr. van Leeuwen, beste Maarten, ik heb veel aan jou te danken. Jij bent ervoor
verantwoordelijk dat mijn wetenschappelijke interesse voor de lever is uitgegroe-
id tot een passie voor hepatobiliaire en pancreatische anatomie, beeldvorming en
interventies. Het is ontzettend mooi om jou in de kliniek aan het werk te zien,
een wandelende encyclopedie met een ongeëvenaard verfijnd gevoel voor humor.
Bedankt dat je mij hebt laten zien hoe mooi het is om de ‘oude werken’ van onze
voorvaderen af te stoffen en te bestuderen. Hierdoor besef ik mij dat veel oude ken-
nis in vergetelheid is geraakt, maar in feite voor het oprapen ligt. Ook bedankt voor
jouw immer kritische blik op mijn manuscripten, je uitgesproken integere houding
ten opzichte van de wetenschap, en je bereidheid om onderwijstaken aan mij toe te
vertrouwen. Ik kijk er naar uit om veel over abdominale radiologie van je te leren.
Beoordelingscommissie
Leden van de beoordelingscommissie, Prof. dr. van Hillegersberg, Prof. dr. Lagendi-
jk, Prof. dr. Kranenburg, Prof. dr. van Diest, Prof. dr. van Delden. Ik ben u dankbaar
voor het feit dat u bereid was tijd vrij te maken en aandacht te besteden aan de
beoordeling van mijn proefschrift.
Radioembolisatie team
Alle betrokken (interventie)radiologen, nucleair geneeskundigen, verpleegkundigen,
laboranten en collega arts-onderzoekers, bedankt dat jullie altijd het onderste uit
de kan wouden halen voor onze patiënten en open stonden voor een nieuwe aan-
pak ten aanzien van radioembolisatie. Het was fijn om met jullie samen te hebben
gewerkt.
Jip, Maarten en Charlotte. Samen hebben wij radioembolisatie naar een hoger plan
getild. Wat was het een gave tijd! Jip, maatje, ik had me geen fijnere collega en vriend
kunnen voorstellen. Bedankt voor de talloze nerdie grappen, ‘work hard play good
music’ sessies, inhoudelijke gesprekken over radioembolisatie en epidemiologie,
jouw onmisbare hulp bij de echt ‘ingewikkelde zaken’, en natuurlijk de craftbeer
sessies in zowel Atlanta als New York. Je hebt een aangeboren aanleg voor de bèta
wetenschappen en wist dit op een hele natuurlijke wijze in je promotieonderzoek
te verwerken. Met een gerust hart kon ik erop vertrouwen dat de RADAR en SIM
studies in mijn afwezigheid in goede handen waren. Ik ga dit alles zeker missen,
maar wellicht worden we ooit weer directe collega’s. Maarten, jij was al geruime
tijd aan het HEPAR I onderzoek aan het werken toen ik als student begon. Ik heb
diepe bewondering voor de gedrevenheid en focus waarmee jij je dromen ver-
wezenlijkt. Zeker in het begin van mijn promotie heb je me geholpen om structuur
in mijn stukken aan te brengen. Bedankt voor al je hulp! Ik kijk er naar uit om de
Part V Addendum
- 421 -
komende tijd weer met je samen te werken in het UMC. Charlotte, dankjewel voor
de ontspannen manier waarop jij mij als student in mijn onderzoek hebt begeleid,
en bedankt dat je mij jouw studie ter overname hebt toevertrouwt. Het was heerlijk
om te zien hoe jij af en toe spontaan in een schaterlach kon uitbreken. Fijn ook dat
we het met elkaar eens waren dat ‘sommige dingen nou eenmaal zo gaan’.
Manon, Arthur en Morsal, het was een waar genoegen om met jullie te mogen
samenwerken. Het stelt me gerust dat jullie het onderzoek voortzetten. Manon en
Arthur, het blijft grappig om te bedenken dat jullie broer en zus zijn, allebei zo
extreem gedreven en vakkundig, maar net met een andere benadering ten aanzien
van de radioembolisatie wetenschap.
Drs. van Heerwaarden, beste ‘Her-ru-wie’, bedankt dat jij altijd zo grondig en re-
spectvol met patiënten communiceert. Vanaf de eerste dag op het werk was ik een
fan van je! Dank voor alle ontspanning, de grappen over bruin fruit en (tafelvoet)
ballen, de ontelbare bakken vieze en lekkere koffie die we samen hebben gedronk-
en (ben je al dispept?), de serieuze gesprekken, de bereidheid om mij altijd van
ongevraagde adviezen te voorzien, maar boven alles, je immer-gulle lach. Je bent
een gouden vent.
Dr. Zonnenberg, beste Bernard, bedankt voor alle hulp bij onder andere de RADAR
studie. Bedankt ook voor de leuke gesprekken samen, er viel altijd weer wat nieuws
te leren.
Bart en Julia, wij werkten al samen toen de nucleair geneeskunde afdeling nog
papieren statussen had. Bedankt voor al jullie hulp, inzet, en verfrissende ideeën.
Evert-Jan, Jan, Rutger, Pieter-Jan en laboranten van de angiokamer, het was een
groot plezier om met jullie aan tafel te mogen staan en mee te mogen denken over
de oneindige stroom aan anatomische en angiografische uitdagingen. ‘Uhhm…
zouden we heel misschien een C-arm CT kunnen draaien…?’ Ik kijk er nu al heel
erg naar uit om tijdens mijn opleiding met jullie aan tafel te staan.
Drs. Wessels, beste Frank, het is mooi om te zien hoe jij je ontwikkelt als expert in
de abdominale radiologie, en helemaal niet vies bent van een beetje wetenschap.
Addendum Part V
- 422 -
Dr. Nijsen, beste Frank, bedankt dat jij je blijft inzetten om de mogelijkheden van
holmium-166 microsferen te verruimen en patiënten behandelingen te verbeteren.
Gerard en Remmert, bedankt dat voor de altijd prettige en vanzelfsprekende
samenwerking. Samen hebben wij de SIM studie opgezet. De manier van werken
in deze studie is niet gemakkelijk en vraagt veel flexibiliteit van jullie. Bedankt dat
jullie hier op zo’n onverminderd enthousiaste manier mee omgaan! Remmert, jou
wil ik nog specifiek bedanken voor de nodige hulp bij de voorbereiding op onze
experimenten in North Carolina.
Dr. de Jong, beste Hugo, bedankt voor je hulp bij de onderzoeken naar beeldvorm-
ing met 90Y-PET.
Dr. Koopman, beste Miriam, ik bewonder je inzet om van radioembolisatie een

ware multidisciplinaire behandeling te maken. Dankzij jou hebben we in de af-
gelopen jaren grote stappen kunnen maken, en komen we steeds dichter bij het
aanbieden van een optimale behandeling op maat, voor alle leverkanker patiënten
in het UMC Utrecht. Bedankt hiervoor! Ook alle collega’s van de medische oncologie
en heelkunde wil ik graag bedanken voor de samenwerking.
Anneke, Saskia, Cees, Tjitske en Shanta, wat hebben jullie in de afgelopen jaren veel
waardevol werk verricht! Ik ben trots dat wij in onze afdeling zo’n sterk trialbureau
hebben. Bedankt voor alle onmisbare hulp en de plezierige samenwerking. Ik sluit
niet uit dat ik in de toekomst nog met een paar vragen langskom… Ik zal drop
meenemen!
Overige collega’s en betrokkenen
Beste Lenny en Sjoerd, ontzettend bedankt voor al jullie epidemiologische en statis-
tische hulp. Ik heb veel van jullie geleerd en ben onverminderd enthousiast om in
de toekomst te blijven werken aan de validiteit en generaliseerbaarheid van mijn
onderzoek. Hopelijk krijg ik nog vaker de kans om met jullie van gedachten te
wisselen.
Beste Annet en Marja, bedankt dat ik altijd op jullie hulp mocht rekenen! Zonder
jullie was ik kansloos. 57000: special ones, bedankt voor de IT-hulp. Beste Roy,
Chris, Karen en Jan, bedankt voor al jullie hulp bij multimedia. Roy, bedankt voor
de fraaie vormgeving van dit proefschrift.
Part V Addendum
- 423 -
Jan, bedankt voor je support en de inzicht gevende gesprekken over waar we met
radioembolisatie naartoe moeten. Quirem Medical inc., gefeliciteerd met de succ-
esvolle valorisatie van holmium-166 microsferen.
Dear Surefire Medical inc. team, especially Aravind, Jim, Rebecca, Chris and Luis,
thank you for our wonderful collaboration. I have sincerely enjoyed it! It is exciting
to see how hard you work to improve liver cancer treatments by changing the way
we use catheters during embolotherapies.
TD Medical, beste Agnes en Dirk, hartelijk bedankt voor jullie vakkundige onders-
teuning tijdens onze procedures.
Collega arts-onderzoekers
Barentszma, Lorjé, Suus, Merel, Knutteltje, Dominibar, Foppen, Brabersma, Schmit-
zel, Niesten en G, wat heb ik met jullie gelachen zeg! Natuurlijk kan onderzoek
doen soms een beetje saai zijn, maar niet met jullie in de buurt. Ik weet nog steeds
niet waar het ‘boei-me-meer’ ligt. ‘Kan dat’? ‘Dacht het wel’, ‘tik gast’! Bedankt voor
alles. Nederland, bereid je voor op deze wetenschappers en toekomstige medisch
specialisten… Do, jou wil ik specifiek bedanken voor onze gezamenlijke tijd aan
Stanford. Ik vond het heel gaaf om dat samen te kunnen doen. Zo was er altijd een
vertrouwd gezicht in de buurt, en konden we lekker tegen elkaar klagen over de
onvermijdelijke onderzoek perikelen.
Anouk, Anouk, Esther, Martin, Richard, Alex, Alexandra, Björn, Danny, Hanke,
Jan-Willem, Jennifer, Laura, Pushpa, Tom, Jill, Marlijne, Erika, Bertine en Hamza
bedankt voor de gezellige tijd. Succes met jullie vervolgtraject.
International colleagues
Professor dr. Buckner, dear Greg, thank you for giving me the opportunity to do a
research internship abroad at your facility in Raleigh, North Carolina. It was a very
interesting experience to collaborate with experts in mechanical engineering. This
multidisciplinary collaboration has redefined my idea of thinking outside the box.
Also, thank you for your outspoken hospitality, I very much appreciated the lunch-
es, drinks after work, and invitation to your home. Shaphan Jernigan, I could not
have done our experiments without you. Thank you for your remarkable patience,
expertise and willingness to adapt to unforeseen challenges.
Professor dr. Sze, dear Daniel, I feel sincere gratitude towards you. You have been a
great mentor and a very hospitable host during my six months research internship
at the Stanford University Medical Center. It was a life-changing experience for me.
Thank you for the endless sparring sessions on how to improve radioembolization.
Addendum Part V
- 424 -
Hopefully, we will be able to continue our collaboration in the future. Professor

dr. Hofmann, dear Rusty, thank you for inviting me to your division. It was great
to witness the passion for your work and your natural leadership. Dr. Louie, dear
John, thank you for letting me watch the magician at work! I have learned a lot
from you. A sincere thank you to all the attendings, fellows, residents, PA’s, techni-
cians, secretaries, and fellow visiting scholars that I’ve worked with at Stanford. You
truly are a wonderful team.
Professor dr. Alavi, dear Abass, thank you for your contributions to our work on the
dose-response relationship in radioembolization. It is truly mesmerizing to wit-
ness your undiminished passion for medical research.
Vrienden en familie
Tot slot wil ik graag mijn vrienden en familie bedanken.
Erik, Cariad and Hackman house roommates, thanks for all. I had a blast with you
while living in Palo Alto.
Sweet Lauren, thank you for showing me the true beauty of the bay. I am very grate-
ful to have met you, and I will forever cherish the memories of those happy days.
Kitesurf vrienden, het is gaaf om mijn grootste hobby met jullie te kunnen delen. Ik
kijk er alweer naar uit om na het werk met jullie het water op te gaan!
Amici, bedankt voor alle afleiding en jullie oprechte interesse in mijn onderzoek.
Vivat BOM! Hjalmar, ik kan me jouw promotie nog goed herinneren. Deze heeft
grote indruk op mij gemaakt. Bedankt voor dit goede voorbeeld. Tsjoch.
Vrienden van mijn jaarclub, bedankt dat jullie me ook na een periode van relatieve
afwezigheid weer in de groep hebben opgenomen. Ik kijk er naar uit om nog jaren
op de dinsdagen samen te eten, en met elkaar op vakantie te gaan! Sorry trouwens
dat ik nog steeds niets van Perudo bak…
Familie Moser, ik ben ontzettend dankbaar voor de warmte waarmee jullie mij in
jullie familie hebben onthaald, de mooie momenten die wij hebben gedeeld, en de
oprechte interesse die jullie in mijn onderzoek hebben getoond. Het ga jullie goed!
Lieve Anne, bedankt voor alle liefde die je mij geschonken hebt gedurende de moo-
ie jaren dat wij samen waren.
Part V Addendum
- 425 -
Ornis, Joep, beste paranimfen, bedankt voor jullie vriendschap. Soms denk ik met
weemoed terug aan onze fantastische en zorgeloze tijd in ‘Huize Casanova’, maar
het grote-mensen-leven is begonnen. Ik ben ervan overtuigd dat de toekomst ons
veel moois zal brengen. Bedankt dat jullie er voor mij zijn. Marloes en Liselotte,
topvrouwen, bedankt dat jullie mijn vrienden gelukkig maken.
Opa en Oma Douven, Monique, Jean-Pierre, Tristan en Laurens, bedankt voor jullie
liefde en steun.
Willard, amigo, wat ben ik blij dat mijn zus jou ontmoet heeft. Bedankt dat je zo lief
voor haar bent. Er bestaat niets mooiers dan samen met jou het water op te gaan.
Maisha marefu, rafiki!
Lieve Annemieke, bedankt voor je steun en oprechte interesse door de jaren heen.
Het is fijn om je steeds beter te leren kennen.
Lieve papa, ik kan me geen betere vader voorstellen. Bedankt voor je altijd aan-
wezige liefde en je wijze levenslessen. Die kritische houding in het onderzoek heb
ik vast van jou.. Bedankt ook dat je mij het vertrouwen geeft dat geen hindernis te
groot is. Ik hou heel veel van je.
Lieve mama, jouw liefde is onbegrensd. Door jouw opvoeding ben ik uitgegroeid
tot de man die ik nu ben. Het is niet in woorden te omschrijven hoe dankbaar ik
ben voor alles wat je voor mij doet en hebt gedaan. Heerlijk dat je nu zo dicht bij
mij woont. Ik hou intens veel van je.
Lieve zus, mijn maatje, met alle liefde draag ik dit proefschrift aan jou op. Sinds
mijn geboorte stond jij naast mij en heb ik altijd op jouw steun kunnen vertrouw-
en, ook in moeilijke tijden. Bedankt. Je bent uitgegroeid tot een prachtige vrouw,
een dokter waar patiënten blindelings op durven te vertrouwen. Ik ben trost op je.
Addendum Part V
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Radioembolization of liver tumors

Andor Franciscus van den Hoven

Copyright © A.F. van den Hoven 2016

Radioembolisatie behandeling van lever tumoren

ter verkrijging van de graad van doctor aan de Universiteit Utrecht

Andor Franciscus van den Hoven

Chapter 1. General introduction and outline 9

Chapter 2. Introduction to hepatic radioembolization 17

Part II: Treatment planning

Chapter 3. Hepatic arterial configuration in relation to the 59

Chapter 4. Identifying aberrant hepatic arteries prior to intra- 81

Chapter 5. The caudate lobe – the blind spot in radioembolization 105

Chapter 6. Arterial liver anatomy – introducing functional concepts 121

Chapter 7. Liver CT during radioembolization workup: Comparison 141

Chapter 8. Use of C-arm cone beam CT during hepatic 157

Part III: Novel treatment strategies

Chapter 9. Hepatic radioembolization as a true single-session 179

Chapter 10. Posttreatment PET-CT confirmed intrahepatic 185

Part IV: Evaluation of treatment toxicity and efficacy

Chapter 13. Clinical and laboratory toxicity after intra-arterial 239

Chapter 14. Radiation-induced cholecystitis after hepatic 261

Chapter 15. Insights into the dose-response relationship of hepatic 277

Chapter 16. Anatomical versus metabolic tumor response assessment 301

Chapter 17. Yttrium-90 radioembolization for colorectal cancer liver 321

Chapter 18. The effect of intra-arterial angiotensin II on the 343

Chapter 19. Summary and discussion 363

Chapter 20. Addendum

and effective treatment option for unresectable chemorefractory liver metastases

AIM OF THE RESEARCH

OUTLINE OF THIS DISSERTATION

Part I (Chapter 2) gives a comprehensive overview of hepatic radioembolization.

Finally, this dissertation is summarized and discussed in Chapter 19.

A.F. van den Hoven

Handbook of Radioembolization: Physics, Biology, Nuclear Medicine, and Imaging [accepted]

A BRIEF HISTORY OF RADIOEMBOLIZATION

to maximize treatment efficacy, to reduce treatment-related toxicity, to standardize

INDICATIONS FOR RADIOEMBOLIZATION

COMPARISON OF RADIOEMBOLIZATION AND EBRT PRINCIPLES

TYPES OF MICROSPHERES AND RADIONUCLIDES USED

Table 2: Microsphere characteristics

Figure 1: Schematic illustration of the physical properties and decay of 90

LABORATORY AND CLINICAL INVESTIGATIONS

PRETREATMENT IMAGING: LIVER CT/MRI AND 18F-FDG-PET

ASSESSING THE INDIVIDUAL HEPATIC ARTERIAL ANATOMY

PREPARATORY ANGIOGRAPHY AND INTRAPROCEDURAL IMAGING

‘Complete’ hepatic angiography requires identification of parasitized extrahepatic

Since extrahepatic deposition of radioactive microspheres may cause serious com-

IMAGING OF THE SCOUT DOSE DISTRIBUTION

PRETREATMENT ACTIVITY CALCULATIONS

after a successful preparatory angiography, but in some circumstances, can even be

MEDICATION AND PERI-PROCEDURAL CARE

CATHETER TYPES AND PARTICLE-FLUID DYNAMICS

A microcatheter specifically designed for embolotherapy, the Surefire Infusion Sys-

Introduction to hepatic radioembolization

TREATMENT-RELATED LABORATORY AND CLINICAL TOXICITY

ANATOMICAL TUMOR RESPONSE ASSESSMENT

FUNCTIONAL TUMOR RESPONSE ASSESSMENT

A.F. van den Hoven

CardioVascular and Interventional Radiology 2015

tomography (MDCT). Consequently, a treatment strategy, tailored to the patient’s

PATIENTS AND METHODS

Figure 1: Patient inclusion

Hepatic arterial configuration and segmental vascularization pattern

Table 2: Observed early branching patterns