1. pERSpECTivES
opinion
intra-arterial brachytherapy of hepatic
malignancies: watch the flow
Bruno Morgan, Andrew S. Kennedy, Val Lewington, Bleddyn Jones
and Ricky A. Sharma
abstract | Although the liver possesses a dual blood supply, arterial vessels deliver
only a small proportion of blood to normal parenchyma, but they deliver the vast
majority of blood to primary and secondary cancers of the liver. This anatomical
discrepancy is the basis for intra-arterial brachytherapy of liver cancers using
radioactive microspheres, termed radio-embolization (RE). Radioactive microspheres
implant preferentially in the terminal arterioles of tumors. Although biological models
of the flow dynamics and distribution of microspheres are currently in development,
there is a need to improve the imaging biomarkers of flow dynamics used to plan RE.
Since a direct consequence of RE is vascular disruption and necrosis, we suggest that
imaging protocols sensitive to changes in vasculature are highly likely to represent
useful early biomarkers for treatment efficacy. We propose dynamic contrast-enhanced
CT as the most appropriate imaging modality for studying vascular parameters in
clinical trials of RE treatment.
Morgan, B. et al. Nat. Rev. Clin. Oncol. 8, 115–120 (2011); published online 5 October 2010;
doi:10.1038/nrclinonc.2010.153
Introduction
radio-embolization (re), consisting of
intra-arterial brachytherapy with yttrium-90
(90Y) microspheres allows the delivery of
high-dose selective internal radiotherapy to
malignant tumors of the liver. re involves
intra-arterial injection of radioactive resin
or glass microspheres via endovascular
catheters selectively placed in branches
of the hepatic arterial vasculature.1 90Y is
a pure-beta emitter that decays to stable
zirconium-90 with a half-life of 64 h (Box 1).
90
Y microspheres preferentially lodge within
the neovascular rim of tumors,2 confining
the radiation dose delivered to the immediate proximity of the active tumor and thus
sparing normal liver parenchyma.3 unlike
other forms of brachytherapy, in which
sealed radioactive sources are placed within
or immediately adjacent to tumor tissue,
injection of microspheres via the hepatic
competing interests
A. S. Kennedy and R. A. Sharma declare
associations with the following company: Sirtex
Medical. See the article online for full details of
the relationships. The other authors declare no
competing interests.
artery branches results in primary and
metastatic tumors of the liver being targeted
irrespective of their number, size or location
within the liver.4
in this article, we argue that the currently
applied surrogate test of flow dynamics
used to plan re, that is, the distribution of
technetium-99m labeled macro-aggregated
albumin, cannot be used to predict the efficacy of the treatment and there is a need
for biological models of flow dynamics to
better predict microsphere distribution. we
propose that imaging protocols sensitive to
changes in vasculature are likely to represent useful predictive markers of malignant
lesions that could benefit from re and, in
patients who have received this treatment,
they may be useful early biomarkers of
treatment efficacy.
Deficits in imaging used to plan
the distribution of technetium-99m labeled
macro-aggregated albumin [99mtc-maa] following direct injection into the hepatic artery
(Figure 1) has been used as a surrogate of the
distribution of microspheres. Historically,
99m
tc-maa was developed as an imaging test
to quantify non-target flow of microspheres
nature reviews | clinical oncology
beyond the liver. the particle diameter range
for maa is 10–150 µm,5 whereas resin microspheres are invariably 20–60 µm in diameter
with >85% of resin microspheres 30–35 µm.1
Quantitative gamma camera imaging provides a reasonable estimate of the distribution of 99mtc-maa. moreover, the assessment
of intra-hepatic arterio-venous shunting and
the exclusion of significant non-target uptake
following vascular coiling procedures to electively embolize arteries is critical to the safety
of the re procedure.4
although essential to determine the safety
of the subsequent re procedure, 99mtc-maa
imaging should not be viewed as an exact
surrogate for microsphere particle delivery
in vivo. Considerable differences in flow
dynamics exist between 99mtc-maa and 90Y
microspheres, which result from disparities
in particle size and vascular caliber; these
disparities exist even if the precise site of
injection (the main hepatic artery or selectively into right, left or segmental arteries)
is exactly the same as it is will be for the
intended re treatment. Flow dynamics will
be altered further by differences in injection
technique, injection velocity and injectate
viscosity between 99mtc-maa and the suspension of 90Y microspheres. while maa is
administered as an injection over 2–3 min,
microspheres are injected in short bursts
chased through with water and contrast
medium. the typical number of particles
administered during a maa procedure is
100,000–250,000 per injection. By contrast,
resin microspheres, which tend to sediment
out and are resuspended repeatedly by agitation and water flush, are administered as
approximately 30–60 million particles during
one treatment procedure.1
Glass 90Y microspheres have a high specific
activity and typically between 1–8 million
microspheres are delivered in a standard
treatment.1 a study of 99mtc-maa injected
into the hepatic arterial circulation showed
that, although the majority of CrC liver
metastases do have greater arterial blood
flow than normal liver, the tumor to normal
liver ratio varied greatly, ranging from 0.1 to
9.7. However, the investigators found that
this ratio did not predict tumor response
after treatment by re.6 a previous study in
patients with hepatocellular carcinoma, generally characterized by more hypervascular
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2. perspectives
Box 1 | Explanation of radiology terms
■ Radio-embolization: a therapeutic procedure that allows the delivery of high-dose selective
internal radiotherapy to malignant tumors of the liver by injection of radioactive microspheres
into hepatic arterial vessels.
■ Brachytherapy: a form of high-dose radiotherapy where a radioactive source is placed inside
or immediately adjacent to the lesion requiring treatment.
■ Yttrium-90: an electron-emitting isotope produced by bombardment of yttrium-89 with
neutrons in a nuclear reactor.
■ Response evaluation criteria in solid tumors (RECiST): internationally recognized criteria for
assessing both tumor response and progression in clinical trials. Despite an updated version
in 2009,12 these criteria are still heavily dependent on anatomical tumor assessment.
imaging assessments are available based on metabolism, physiological function and tissue
structure but these are not yet sufficiently validated to be included as part of the criteria.
■ CT: CT scanning is used in all stages of cancer management. intravenous contrast is given
routinely to improve tumor delineation.
■ Dynamic contrast-enhanced CT (DCE-CT): Dynamic scanning refers to the rapid acquisition of
images and how they evolve while contrast enhancement is administered intravenously. The
quantification of enhancement parameters may be used to study vascular parameters such
as blood flow and vessel permeability.
◀ Figure 1 | Macro aggregated albumin scan.
Coronal (antero-posterior) view of a patient
with metastatic colon cancer to the liver.
White spots represent high uptake of the
tracer following injection directly into the
hepatic arterial circulation. The carrier of the
radionuclide is macro-aggregated albumin
(MAA). prior to administration, MAA is
complexed with the gamma emitter, 99mTc, to
permit imaging of uptake in vivo.
lesions than metastatic colorectal cancer, did
suggest a better response to re. this finding
supported the hypothesis that ‘hot’ lesions on
99m
tc-maa scan respond better than ‘cold’
lesions to re treatment.7
the sensitivity of detecting the distribution of 99mtc-maa has been considerably
improved by tomographic imaging with
single photon emission computed tomography (sPeCt) fused with Ct, a technique
increasingly being adopted by centers offering re treatment. in a study of eight patients,
a mathematical model was developed for
converting all liver voxel maa–sPeCt
uptake values to the absolute 90Y activity
administered, with a view to finding potential correlations with metabolic response on
18
F-fluorodeoxyglucose (FDG) Pet scans
in patients with liver metastases treated
with microspheres. 5 although this study
was limited by the use of Pet scan 6 weeks
post-re as the only clinically relevant end
point, the researchers found that maa
uptake could predict subsequent response
on FDG-Pet, but only for the metabolically
active parts of liver lesions.5
in short, 99mtc-maa imaging provides a
broad indication of tumor bed vascularity
116 | FEBRUARY 2011 | volUmE 8
and non-target uptake of particles of a similar
size, but it is of limited utility as a predictor of
intra hepatic 90Y microsphere particle deposition and is not useful as a marker of the
potential efficacy of this treatment.
Flow characteristics in planning
Y microspheres of 20–60 µm in diameter
(considerable smaller than particles used for
transarterial embolization (tae) or transarterial chemoembolization [taCe]) are
used for re, which cause less direct embolization of the macrovasculature.1 indeed,
one important distinction between the tae
or taCe and re is that blood flow to tumor
and normal liver is affected in fundamentally
different ways. non-radioactive embolization
uses larger particles that become irreversibly
lodged upstream from tumors in the liver,
which blocks blood flow to tumor tissue and
some of the nearby normal liver parenchyma.
although important to successful embolization proximal to the tumor, the subtleties of
blood flow dynamics may be less important
for tae or taCe than they are for the efficacy of re.8 in addition to being smaller,
radioactive 90Y microspheres have a lower
specific gravity compared with particles used
for tae or taCe.9
since blood flow parameters are important to the ultimate placement of 90Y microspheres, a greater understanding of hepatic
artery fluid dynamics that impact microparticles may optimize safety and efficacy of
re. Computational models of blood flow in
the major mesenteric arteries under normal
conditions have been developed,10 but the
hepatic arterial system was not part of that
model. research using three-dimensional
computational flow modeling of microsphere distribution has shown that terminal
artery microparticle deposition in the tumor
is greatly affected by the position within the
lumen, specifically within laminar flow
columns, into which the microspheres are
released (Figure 2).8 Furthermore, computational modeling of a representative hepatic
artery system, with simulation of laminar
transient particle hemodynamics, has illustrated the influence of a curved geometry
of the arterial vessels on the velocity field
and the particle trajectory dependence on
spatial and temporal particle injection conditions.11 interestingly, particle characteristics
and inelastic wall collisions had little effect
on particles released during the accelerating
phase of the arterial pulse, that is, both resin
and glass microspheres followed organized
paths to predetermined outlets. we propose
that there is a need for further computer
90
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3. perspectives
simulations of blood flow and micron particle
transport applied to a representative hepatic
arterial system to provide new insights, with
regard to pressure boundary conditions and
the effects of transient changes.
a
How perfusion imaging improves RE
there are two well established roles for
diagnostic imaging in re. First, imaging
is essential to the planning of the radiation dosage by determination of the ratio
of malignant disease to whole liver volume,
careful delineation of the arterial anatomy
and exclusion of significant shunting that
may lead to radiation pneumonitis, gastritis
or duodenitis.1,4
the second role of imaging is to predict or
monitor the efficacy of re. when evaluating
a therapy in a clinical trial, objective end
points of successful therapy are required.
an end point currently preferred for largescale oncology trials conducted in patients
with metastatic disease is progression-free
survival or time to progression, generally
measured using cross-sectional imaging
and the response evaluation criteria in solid
tumors (reCist). 12 with regard to re,
local edema post-treatment makes accurate
analysis of response to therapy (Box 1) difficult in the early stages of treatment, which
may not necessarily reflect successful treatment as measured by tumor shrinkage at
later time points.
imaging evaluation of response
reCist is the gold standard criteria for
monitoring treatment response in oncology trials. these criteria use anatomical
response related to changes in tumor size
and the presence of new lesions. 12 such
anatomical-based criteria have provided
an international standard and, for many
solid tumors treated by cytotoxic chemotherapy, the criteria represent a robust end
point to determine time to progression. in
the past few years, however, the anatomical
approach to measuring response has been
criticized.13 Firstly, there is a poor correlation between anatomical response and
patient benefit in tumors treated by radiotherapy or biological agents. secondly, for
certain therapies including radiotherapy,14
chemoradiotherapy,15 radiofrequency ablation16 and immunotherapy,17 there may even
be a small increase in tumor size or even the
appearance of new lesions (due to better
detection of small lesions on treatment) in
the presence of a favorable patient outcome
to the treatment. this has been well documented following re therapy, probably
Tumor
Blood flow
b
1
Necrosis
‘Radiation cloud’
killing all tumor cells
Missed area where
tumor cells did not
receive enough X-ray
therapy and will
survive and grow
2
Necrosis
Overlapping radiation
clouds ensuring no
surviving tumor cells
Figure 2 | Geometry of microspheres relative to the hepatic arterial system. a | The potential
distribution map of deposition of ionizing radiation depends on injection sites for yttrium-90
microspheres. Different laminar flow channels occur in larger arteries, which predominately flow
to specific daughter vessels in the liver.8 b | Microparticles flowing in a daughter vessel to a
solid tumor in the liver implant in the growing outer rim, which is hypervascular. panel 1 shows
incomplete coverage of the active tumor edge with gaps in tumoricidal X-ray therapy (XRT) dose
cloud. panel 2 demonstrates optimal radiation coverage of tumor cells with adequate targeting
and sufficient numbers of microparticles implanting in and around the tumor.
because of intra-tumoral and peri-tumoral
edema and hemorrhage. 18,19 therefore,
although high partial response rates have
been seen in patients undergoing re, particularly with concomitant radiosensitizing
chemotherapy,20 other methods of response
nature reviews | clinical oncology
assessment early in treatment may have a
better association with patient outcome.
an ideal surrogate clinical end point measures an effect of therapy that is linked to
both the desired action on the target and the
intended benefit for the patient. in the case
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4. perspectives
a
b
Figure 3 | Changes in tumor perfusion detected by DCE-CT. CT scan images of a liver metastasis
from renal call carcinoma (arrow) a | before and b | 6 months after commencement of therapy
with the anti-angiogenic drug, sunitinib. Both images were performed 70 seconds after bolus
injection of a standard intravenous contrast agent. panel b shows not only a reduction in tumor
size but also a visible reduction in contrast enhancement.
of re, the principal objective is to selectively
irradiate liver tumors by delivering high
radiation dose to malignant lesions while
minimizing dose to normal tissues. this is
achieved by injecting 90Y microspheres into
the source of the preferential blood supply to
tumors and preferential placement of microspheres based on size is determined by the
disordered microvasculature in tumors.4 re
results in steep physical dose gradients: 1 GBq
(27 mCi) of 90Y delivers a localized dose of
beta radiation with a mean tissue penetration
of 2.5 mm and a maximum range of 11 mm.1,2
this mean tissue value suggests that if most
radioactivity is sequestered within the circumferential hypervascular rim of malignant
liver lesions, then the high local dose and
dose rate to this region may be responsible
for most of the biological antitumor effects.
thus, re therapy has a predominant radiation effect on tumors rather than significant
embolism. therefore, we believe that significant changes in tumor perfusion observed
post-re should be consistent with those
observed during and after radiotherapy.21
a common histological feature of successful radiation therapy and effective re
is tumor necrosis.2,22 this form of cell death
may not be associated with rapid reductions
in size on cross-sectional imaging, probably because of the inflammatory responses
associated with necrosis and resulting local
edema. this observation has led to proposals to modify standard criteria to monitor
responses to radiation therapy. imaging
protocols sensitive to changes in vasculature
may be a useful early biomarker for treatment
efficacy. some success has been achieved by
combining anatomical tumor response with
a measure of tumor necrosis using intravenous contrast- enhanced Ct scans for
both primary and secondary liver tumors.23,24
this interesting approach may show better
correlation with patient outcome than tumor
size alone. in these studies, necrosis detected
on imaging has been assessed in a semiquantitative fashion using arbitrary criteria.
this approach has been successfully applied
in the treatment of gastrointestinal stromal
tumors (Gist) with imatinib25 and the treatment of patients with other malignancies
using anti-angiogenic agents (Figure 3).
we suggest that the assessment of necrosis
may be improved by stipulating contrast
injection protocols and imaging timings or
applying physiological models to the contrast
enhancement kinetics in an attempt to quantify physiologically relevant parameters, such
as tissue perfusion or vascular permeability.
tumor enhancement by contrast media
is multi-factorial (Box 2).26 although the
liver has a dual blood supply, quantitative
imaging techniques model tumor enhancement based on the arterial blood supply and
ignore the portal blood supply to the rest of
the liver, which is assumed to be a separate
part of the whole body circulation. although
standard dynamic Ct is often referred to as
arterial (early), portal (middle) and equilibrium (delayed) phase, this terminology is
used to describe the difference in enhancement between liver tissue and tumors. the
tumor itself is essentially being imaged in
early, middle and delayed arterial phase.
large tumors will receive a minor variable portal vein supply, but this is unlikely
to affect follow-up studies. likewise, there
may be variation in vascular flow due to pretreatment embolization, but rapid development of collaterals is unlikely to affect
follow-up perfusion studies.
During re, modern angiography suites
can use software analysis of rotational
angiography to obtain 3D information of the
target organ with images similar to Ct scans.
this system provides good spatial accuracy
118 | FEBRUARY 2011 | volUmE 8
but contrast sensitivity is lower than for
standard Ct.27 this technique can provide
qualitative information regarding the distribution of injected tracers and may be
useful to identify areas of necrosis within the
tumor.28 However, this technique is unlikely
to be helpful in monitoring tumor response
as quantification of contrast enhancement
curves and reproducibility are likely to be
problematic.
most of the published research on
tumor perfusion characteristics has used
dynamic-contrast enhanced mri (DCemri). iodinated contrast agents used in Ct
scanning have similar pharmacokinetics to
gadolinium chelates used in DCe-mri and,
therefore, DCe-Ct may be equally useful in
assessing tumor perfusion characteristics.
DCe-mri normally provides more time
points to allow detailed modeling of vascular
parameters. However, as we have proposed
that the mechanism of response to re is
predominantly radiation cell kill resulting
in necrosis, there is likely to be a reduction in
all of these factors as there is limited perfusion. this reduction could be measured
in a model based system using ve, but the
semi quantitative ‘area under the contrast
enhancement curve’ or maximum relative
signal intensity measurements are probably adequate, requiring fewer time points.
DCe-mri has the advantage of having more
sensitivity to contrast enhancement with a
greater dynamic response of signal intensity to changing concentrations of contrast.
However, quantification of signal change
is more problematic than for Ct scanning. intra-patient reproducibility is crucial
for follow-up studies and can be affected
by patient factors (for example, level of
hydration, posture) and affected by hemodynamics and scanner issues. in practice, the
reproducibility of Ct and mri are similar in
this context.29
although repeated Ct scanning exposes
patients to ionizing radiation, the absorbed
dose received is very low compared with
doses delivered with re, and is measured
in units of milli-Gray rather than Gray.1
as Ct scanning is likely to be incorporated
into imaging protocols for assessment of
tumor response by reCist, this modality may prove the most practical for perfusion imaging. we propose that DCe-Ct
studies could be performed at baseline
and at 2 weeks to 2 months post treatment.
moreover, per fusion indices measured
at these early time points post-re may
predict the results of anatomical imaging
at 6–9 months post-re, as well as more
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5. perspectives
clinically relevant end points such as time
to progression in the liver. Perfusion Ct
scanning at an early time point post-re
may allow the patient’s management to be
planned in advance, rather than relying
on the results of a scan ≥6 months later.
However, we caution against DCe-Ct scans
being performed too early post-re (within
the first week) when perfusion results could
be confused by radiation causing an early
inflammatory response, which paradoxically
increases perfusion. investigators should
also note that interpretation of enhancement may also be complicated by the hyperenhancement seen in normal liver around
tumors treated by ablative techniques
including re.21,30,31
another mri technique reported to be
sensitive for the detection of necrosis is
diffusion weighted (Dw-) mri.21 in the
particular case of re, it should be noted
that these protocols normally involve echoplanar sequences, which are particularly
sensitive to artifacts from magnetic field
irregularities. therefore, the presence of
embolization coils in these patients, may
make Dw-mri impractical for tumors
in the central and left parts of the liver
(Figure 4). DCe-mri and mr spectroscopy
studies are also likely to be compromised by
these embolization coils. However, the combination of DCe-mri and Dw-mri would
be a useful method of monitoring therapy in
patients where embolization coils have not
been used extensively.21
as successful therapy leads to necrosis,
it is not surprising that FDG–Pet scans
have shown promise as an early marker of
therapeutic success.21,32,33 the functional
information obtained from DCe-Ct will be
complemented and augmented by metabolic
information acquired on FDG-Pet scans.
in particular, the differentiation between
active malignancy and necrotic tissue will
be important in research studies.
imaging as a predictive marker
as several effective systemic treatments are
now available for patients with liver metastases from colorectal cancer, clinical trialists
should identify whether re is an appropriate
treatment for individual patients. the arterial hypervascularity of lesions is important
as the response to re relies on adequate
vascular delivery of 90Y microspheres as
well as perfusion of oxygenated blood to
exert direct and indirect radiation cell kill.
Preliminary validation of the technique
of measuring perfusion as a predictor of
response to external-beam radiotherapy
Box 2 | Tumor enhancement by imaging contrast agents26
Tumor enhancement, as measured using iodinated contrast in CT or gadolinium-based chelates in
MRi, is multi-factorial. Both types of contrast agent rapidly disperse in the plasma compartment
after intravenous injection and then into the extravascular extracellular (interstitial) space.
Most of the image enhancement seen and measured is due to contrast accumulating in the
interstitial space. This accumulation in a tissue or tumor depends on an intact blood supply and
tissue circulation, permeability of the vessel wall, and the size of and osmotic pressure within
the interstitial space. various models have been used to measure tissue enhancement-defining
terms such as tumor blood (plasma) volume (vp), vascular surface area and permeability (Ktrans)
and the extravascular extracellular volume available to contrast (ve).
has been demonstrated for perfusion indices
derived from DCe-mri.34 Paradoxically,
although increased enhancement may
predict response to radiotherapy, indicating
good perfusion and therefore oxygenation, it
may also be a poor prognostic marker, indicating increased tumor angiogenesis, such as
in cervical carcinoma.35
Consistent with the observation that colorectal liver metastases often have necrotic
centers with poor vascularity, direct tissue
sampling following re has shown that the
enhancing periphery of the tumor shows
high accumulation of re particles but the
necrotic center does not.36 we suggest that
there is likely to be considerable variation in
inter-tumoral and intra-tumoral dispersion
of microspheres in primary and secondary
liver malignancies and that this variation
will affect therapeutic delivery and clinical
outcome. although there is a theoretical
basis and clinical evidence that pre-treatment
tumor vascularity affects response to therapy
in HCC,7 a study of 137 patients with liver
metastases from a variety of primary tumor
sites failed to show a correlation of tumor
vascularity on Ct compared with clinical
end points.6,21 However, in this study visual
assessment was made against normal liver at
40 s post enhancement when the liver would
already be expected to enhance well, perhaps
explaining the low percentage (18%) of
cases of ‘hypervascularity’. Furthermore, no
assessment was made of areas of the heterogeneity of enhancement on Ct or angiography. the clinical end points could also
be affected by primary tumor type, which
would likely affect vascularity as an independent variable. in these studies dosing may
have been optimal for necrotic tumors and
could therefore be reduced in hypervascular
tumors without necrotic centers. the extra
information available from a DCe-Ct perfusion study with multiple time points would
be more informative than the qualitative
information from arterial and portal phase
Ct in recently published studies,6,21 because
it will provide analysis of the heterogeneity
nature reviews | clinical oncology
Figure 4 | DW-MRi artifacts that make image
interpretation difficult. A diffusion weighted
(DW)-MRi showing a 9 cm liver metastasis from
colorectal carcinoma. The high signal is due to
restricted diffusion (arrows). The sequence is
particularly sensitive to artifacts from metallic
foreign bodies. There is a 4 cm signal deficit
due to small surgical clips at the edge of the
tumor (arrowheads). Surgical clips were
inserted during previous hepatic resection.
of enhancement and better assessment of the
early phase of enhancement.
we propose that perfusion indices derived
from DCe-Ct scanning, preferably interpreted using models of blood flow and
pressure boundary conditions specific to
re therapy, may predict which individual
patients are likely to benefit most from re.
we also advocate the use of these indices in
clinical trials to show either the presence or
development on treatment of central hypovascular necrotic areas,22 which may benefit
from fractionated therapy—such as re performed in two or three sessions with at least
4–6 months between fractions.
Conclusions
although essential for the determination of
the safety of the subsequent re procedure,
gamma scanning with 99mtc-maa should
not be viewed as a predictor of microsphere
particle delivery in vivo and certainly not a
surrogate biomarker of efficacy. we believe
that there currently exists a need for biological models of flow dynamics to better predict
particle distribution from re treatment.
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© 2011 Macmillan Publishers Limited. All rights reserved

6. perspectives
Computer simulations of blood flow and
micron particle transport should be developed for re with specific regard to vessel
geometry, particle inlet distribution and
pressure boundary conditions. moreover,
we suggest that imaging protocols sensitive
to changes in vasculature may predict which
individual patients may benefit from re and,
in patients who have already received this
treatment, the same indices may be useful
early biomarkers of treatment efficacy. Based
on these opinions, we have suggested how
DCe-Ct should be incorporated into clinical trials of re and how the treatment may
be modified in future trials according to
imaging results.
Department of Cancer Studies and Molecular
Medicine, University of Leicester, Leicester
Royal Infirmary, Leicester LE1 5WW, UK
(B. Morgan). Mechanical and Aerospace
Engineering Department and Biomedical
Engineering Department, North Carolina State
University, Raleigh, NC 27695, USA
(A. S. Kennedy). Nuclear Medicine Department,
Royal Marsden Hospital, Sutton, Surrey
SM2 5PT, UK (V. Lewington). Cancer Research
UK—Medical Research Council Gray Institute
for Radiation Oncology and Biology, Old Road
Campus Research Building, University of Oxford,
Oxford OX3 7DQ, UK (B. Jones, R. A. Sharma).
Correspondence to: R. A. Sharma
ricky.sharma@rob.ox.ac.uk
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acknowledgments
The concepts presented in this article were
developed at the Tryst of Radio-Embolization
Brachytherapy Leading Experts (TREBLE) meeting
held in Trinity College, Oxford on 26 October 2009.
The authors wish to thank the TREBLE participants:
Boris vojnovic, John primrose, Eli Glatstein, David
Berry, peter Gibbs, Denny Liggitt, David Liu, Marc
peeters and Bruno Sangro. R. A. Sharma is funded by
the Higher Education Funding Council for England
and the Bobby Moore Fund of Cancer Research UK.
R. A. Sharma and B. Jones acknowledge the support
of the NiHR Biomedical Research Centre, Oxford, UK.
author contributions
B. Morgan, A. S. Kennedy and R. A. Sharma
contributed to the data research, discussion, writing
and reviewing/editing of the manuscript.
v. Lewington and B. Jones contributed to the
discussion and writing of the manuscript.
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