Download Molecular imaging of gliomas with PET

Neuro-Oncology 13(8):806 – 819, 2011.
doi:10.1093/neuonc/nor054
Advance Access publication July 13, 2011
N E U RO - O N CO LO GY
Molecular imaging of gliomas with PET:
Opportunities and limitations
Christian la Fougère, Bogdana Suchorska, Peter Bartenstein, Friedrich-Wilhelm Kreth,
and Jörg-Christian Tonn
Department of Nuclear Medicine (C.F., P.B.); Department of Neurosurgery (B.S., F.-W.K., J.-C.T.), University
of Munich – Campus Grosshadern, Marchioninistr 15, 81377 Munich, Germany
Neuroimaging enables the noninvasive evaluation of
glioma and is considered to be one of the key factors for
individualized therapy and patient management, since
accurate diagnosis and demarcation of viable tumor
tissue is required for treatment planning as well as assessment of treatment response. Conventional imaging
techniques like MRI and CT reveal morphological information but are of limited value for the assessment of
more specific and reproducible information about
biology and activity of the tumor. Molecular imaging
with PET is increasingly implemented in neuro-oncology,
since it provides additional metabolic information of the
tumor, both for patient management as well as for evaluation of newly developed therapeutics. Different molecular
processes have been proposed to be useful, like glucose consumption, expression of amino acid transporters, proliferation rate, membrane biosynthesis, and hypoxia. Thus,
PET might help neuro-oncologists gain further insights
into tumor biology by “true molecular imaging” as well
as understand treatment-related phenomena.
This review describes the method of PET acquisition as
well as the tracers used to image biological processes in
gliomas. Furthermore, it considers the clinical impact of
PET on the use of currently available radiotracers,
which were shown to be potentially valuable for discrimination between neoplastic and nonneoplastic tissue, as
well as on tumor grading, determinination of treatment
response, and providing an outlook toward further
developments.
Keywords: glioma, molecular imaging, PET.
A
dvances in neurosurgical techniques, radiotherapy planning, and novel chemotherapeutics for
glioma treatment go hand in hand with an
Received October 19, 2010; accepted March 28, 2011.
Corresponding Author: Jörg-Christian Tonn, Department of
Neurosurgery, University of Munich, Marchioninistr 15, D-81377
Munich, Germany ([email protected]).
increasing demand for noninvasive, quantitative
imaging techniques. Whereas structural imaging such
as conventional MRI provides information on the size
and localization of tumors and delineates secondary
phenomena such as mass effect, edema, hemorrhage,
necrosis, and signs of increased intracranial pressure,
PET is expected to characterize the tumor on a metabolic
and molecular level; these new imaging data might
improve noninvasive tumor evaluation, promote the
development and application of tailored treatment concepts, and facilitate prognostic assessment before and
after treatment. Since its advent in 1970, PET has
gained an additional value in evaluation of patients
with gliomas,1 which represent the most frequent
primary brain tumors, being most difficult to treat.
Depending on the radiotracer used, various molecular
processes can be visualized; the vast majority of these
agents are related to increased intratumoral cell proliferation. However, the increasing variety of radiotracers
implemented for glioma evaluation and the lack of standardized analysis as well as mostly retrospective reports
based on single-institution low case numbers constrain
the potential informative value of PET-based investigations. This review attempts to give an overview of
the radiotracers currently utilized in view of their applicability for diagnostic purposes, treatment planning, and
therapy monitoring, as well as to provide an outlook for
the future development of PET imaging in glioma.
Molecular Imaging with PET
Principles of PET
PET imaging allows highly sensitive measurements (in
the picomolar range) of biochemically active molecules
labeled with short-lived positron-emitting radionuclides
(radiotracers). Positrons emitted from the nucleus of
radioisotopes subsequently annihilate on contact with
electrons after traveling a short distance within the
tissue (mean range, 0.2 up to 1.5 mm, depending on
# The Author(s) 2011. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
All rights reserved. For permissions, please e-mail: [email protected].
la Fougère et al.: PET in Glioma
the mean energy of the positron). Each annihilation
results in a pair of 511 keV photons traveling in opposite
directions that can be counted by detector units, which
commonly are arranged in a ring surrounding the
subject. When 2 opposing detectors simultaneously register a pair of photons (time window, 15 – 20 ns), the
annihilation event is counted and assigned to a line of
response joining the 2 relevant detectors. Accordingly,
a PET scan consists, in essence, of the acquisition of a
large number of lines of response, which are used to
reconstruct 3D images by means of standard tomographic techniques that also include scatter correction,
random correction, and the effects of attenuation in
order to obtain an accurate quantification. The physics
of coincidence detection enable high spatial resolution
and high sensitivity, which are necessary to perform
dynamic data acquisition. The spatial resolution currently is about 1.5 mm at its best.
Basically, different positron-emitting isotopes can
potentially be used, which are produced in a cyclotron
(e.g., carbon-11 [11C], nitrogen-13 [13N], oxygen-15
[15O], fluorine-18 [18F]) or with a generator (e.g.,
gallium-68 [68Ga]). While isotopes with very short
half-lives (15O: 2 min; 13N: 10 min; 11C: 20 min)
permit multiple studies in a single setting, their use is
restricted to centers with an adjacent cyclotron unit,
and they therefore can hardly be implemented for clinical practice. The use of 18F (half-life, 110 min) enables
more complicated and time-consuming labeling processes and permits the commercial distribution of radiotracers by PET radiopharmacies at offsite locations.
Useful radiotracers should have unaltered biological
properties when compared with the unlabeled molecule,
should not be easily dissociable from the radionuclide,
and should ideally come with low unspecific uptake in
the background or blood in order to obtain highercontrast images. Several hundred million cells in relatively close proximity must accumulate the radiotracer
to visualize them against the background.2
Radiotracers are typically injected intravenously. The
tracer uptake into targeted structures within the brain
depends on different parameters, like regional perfusion,
individual pharmacokinetic and pharmacodynamic
properties, and permeability of the blood-brain barrier.
PET Data Acquisition and Analysis
Different strategies are necessary for PET data acquisition (simple static scan for the assessment of the
tracer uptake in steady-state versus dynamic image
acquisition in order to obtain the molecular information
as a function of time), leading to more sophisticated PET
data analysis. Ideally, this analysis should be performed
after co-registration with high-contrast anatomical
images (e.g., MRI) in order to combine the functional
and morphological information, a procedure that can
be done easily also in clinical practice.
Assessment of the maximal or mean standardized
uptake value (SUV) is the most widely used procedure
for a semiquantitative measurement of the radioactivity
in the target. It can be calculated as a ratio of tissue
radioactivity concentration at time t (C(t)) and injected
dose(t0) at the time of injection divided by patient’s
body weight. This can be performed voxelwise as well
as by means of regions or volumes of interest.
Additionally, these values have to be corrected for the
unspecific uptake in the background.
Dynamic PET data acquisition obtains time activity
courses to get additional information about uptake,
metabolism, and wash out of the tracer. This procedure
is necessary for radiotracers with more complex pharmacokinetic properties that do not reach steady state
after uptake into the cells or by irreversible binding to
a target structure. Time activity courses are assessed in
predefined regions (e.g., in the tumor) or by each pixel
of the image sequence. They can be used to extract quantitative parameters through their mathematical description by means of kinetic or compartmental models,
which in some cases do necessitate blood samples for
the correction of tracer metabolites. However, the
latter can hardly be performed in clinical routine.
Available PET Radiopharmaceuticals for Glioma
Imaging
For imaging of gliomas, several radiotracers have been
suggested as useful for different purposes, like diagnosis,
grading, assessment of recurrence, and treatment planning and monitoring. In the following, the most important or promising approaches are presented.
Glucose metabolism—The glucose analogue 2-[18F]
fluoro-2-deoxy-D-glucose ([18F]FDG) is the most frequently used radiotracer for PET3 to measure the local
metabolic rate of glucose that represents a common
pathway of neurochemical activity in the brain.4,5
Intravenously injected [18F]FDG is rapidly cleared
from vascular to interstitial space and is afterward
actively transported through cellular membranes into
the cells by glucose transporter proteins (GLUTs).
According to the first step of the glycolysis, [18F]FDG
is phosphorylated by the enzyme hexokinase to
[18F]FDG-6-phosphate, which cannot further act as a
surrogate for the glycolytic pathway. This results in
metabolic trapping in the cells. Due to the pharmacokinetic properties (high early uptake and trapping in the
cell within the first 10 minutes and quite fast blood clearance and renal elimination) steady-state images can be
obtained 30 min postinjection (p.i.). The physiological
brain glucose metabolism and consequently the
[18F]FDG brain uptake is very high, because glucose provides approximately 95% of the required ATP and is
also tightly connected to neuronal activity.
[18F]FDG PET was proposed to be useful for imaging
gliomas because of an increased glucose metabolism in
high-grade glioma as well as a positive correlation
between the glycolysis rate and malignancy.5,6 The
increased uptake was suggested to be related to
changes in transport rate via modulation of GLUTs.7
However, the diagnostic accuracy of [18F]FDG PET is
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hampered by the high physiologic glucose metabolism in
different brain areas, such as the cerebral cortex, the
basal ganglia, and the thalamus, which significantly
limits the sensitivity for detection as well as the specificity for delineation of adjacent glioma tissue. The
demarcation of glioma is most notably impeded in lowgrade gliomas, which show mostly only modest uptake,
similar to that of white matter and decreased uptake
when compared with grey matter.8,9 Low contrast to
background can also be found in some high-grade
gliomas, where [18F]FDG uptake was found to be
similar to or less than in the cerebral cortex.10 Finally,
[18F]FDG is known to accumulate in macrophages and
inflammatory tissue, making distinction between
glioma and acute or chronic inflammatory process
often difficult.
Amino acid transport and protein synthesis—
Radiolabeled amino acids were introduced in 1982 as
suitable PET tracers in brain tumors.11 The use of
amino acids is based upon an increased amino acid utilization, which is known to play a key role in cell proliferation, as well as extracellular matrix growth production
in glioma.12 Amino acid transport as well as protein
synthesis were both demonstrated to be enhanced in
most gliomas and can potentially be used as targets
for imaging.13 For this purpose, a variety of radiolabeled
amino acids, like [11C]methionine ([11C]MET),14 and
aromatic amino acid analogues, like [18F]fluorotyrosine
([18F]TYR),15 [18F]fluoroethyltyrosine ([18F]FET),16,17
[18F]fluoromethyltyrosine
([18F]FMT),13
and
18
18
[ F]fluorodopa ([ F]DOPA),18 were proposed.
Comparable uptake in cerebral gliomas, at least for the
most widely used radiotracers like [11C]MET and
[18F]FET,19,20 has been shown. The artificial analogues
of the amino acids, in contrast to the acids themselves,
are not incorporated into proteins.21 Active amino acid
transport in tumor cells is supposed to be one of the ratelimiting factors of amino acid imaging22 and has been
shown to be upregulated in the cell membranes of
tumor cells, especially when their growth conditions
become adverse, regardless of the phase of the cell
cycle.23 However, possible bias may be caused by unspecific increase of amino acid uptake due to damage of the
blood-brain barrier in glioma.24 High-contrast images
can be acquired due to high amino acid uptake in both
low- and high-grade glioma and low uptake in normal
brain tissue. Using the conventional uptake ratio-based
approach (e.g., SUVmax/background, where SUV ¼
standard uptake value) does not provide a reliable
grading on an individual level, because of quite high
interindividual variability in amino acid uptake in
gliomas, which can be attributed mainly to differences
in amino acid transport characteristics.14,25 However,
recently published data have shown that the use of
dynamic analysis of [18F]FET uptake (zero to 40 –
50 min) to obtain the time course of the radioactivity
does allow a differentiation between low- and highgrade gliomas with high diagnostic power because of
different FET kinetic uptake behavior.26 Plotting analysis of uptake activity over time shows a slight increase in
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low-grade gliomas, whereas high-grade tumors present
with an early peak followed by a decrease (Fig. 1).
Proliferation rate—Increased cell proliferation and
DNA replication is a characteristic of malignant transformation. Therefore, the assessment of cellular proliferation was suggested to be useful for therapy guidance as
well as for early evaluation of treatment response,
because a decrease in cellular proliferation precedes
morphological changes.27 In order to image the proliferation rate by means of PET, radiolabeled nucleosides like
the
thymidine
analogue
[18F]fluorthymidine
18
28
([ F]FLT)
have been developed and validated.
Thymidine is rapidly transported into the cells by
means of a nucleoside transporter and can be phosphorylated by the enzyme thymidine kinase (TK)-1 to
thymidine nucleotides, which are among the molecular
building blocks of DNA but not of RNA.28 TK-1 is
highly expressed during DNA synthesis of proliferating
cells28 and leads to intracellular trapping of the radiotracer.29 Therefore, the retention of [18F]FLT within the
cell provides a measure of cellular TK-1 activity.
[18F]FLT was thought to be a helpful predictor of
tumor progression and useful for the monitoring of
treatment response.30,31 In gliomas, elevated [18F]FLT
uptake was associated with increased expression of
antigen Ki-67, an index of mitotic activity.30 In addition,
the use of [18F]FLT was suggested to be beneficial
because it accumulates at lower levels in most of the
brain regions due to a lack of significant neuronal cell
division.2 However, the value of this tracer in gliomas
needs further evaluation in prospective studies.
Membrane biosynthesis—Choline is a precursor for the
biosynthesis of phosphatidylcholine and other phospholipids, which are major components of cell membrane.32
Because cell proliferation can be associated with
increased metabolism of cell membrane components,
choline was proposed to be useful for imaging in oncology. Radiolabeled choline was previously demonstrated
to be rapidly cleared from blood within a few minutes
and to show increased uptake in different tumor entities.33 In brain tumors, the choline analogue
[18F]fluorocholine was considered to distinguish highgrade gliomas, metastases, and benign lesions on the
basis of the measured uptake. In addition, increased
peritumoral [18F]fluorocholine uptake was suggested as
a discriminating characteristic of high-grade gliomas.34
However, [11C]choline uptake was reported to be extremely high in the choroid plexus, the venous sinuses, and
the pituitary gland, which limits its use for the demarcation of tumor border in the vicinity of these structures.
Therefore, amino acid tracers were supposed to be
superior for the evaluation of tumor extension,35 even
if radiolabeled choline was suggested to be useful in evaluating the potential malignancy of oligodendroglial
tumors.
Oxygen metabolism—Tumor hypoxia results from
rapid tumor growth and concomitant insufficient
blood supply that comes along with significantly
la Fougère et al.: PET in Glioma
Fig. 1. Transversal [18F]FET PET, fused PET MR, and contrast-enhanced T1-weighted MR images are shown. Similar increased tracer uptake
was found in a patient with oligoastrocytoma WHO II (OA) (upper row) and glioblastoma (GBM) (lower row) that did not allow the
differentiation between low- and high-grade glioma. However, additional assessment of tracer kinetics enabled the right diagnosis, by
showing increasing activity in the low-grade glioma and an early peak followed by a decrease in the high-grade glioma.
lower oxygen concentrations in parts of the tumor
compared with normal tissue. Hypoxia may drive
the peripheral growth of a tumor and is
associated with tumor progression and resistance to
radiotherapy.36
The
nitroimidazole
derivatives
[18F]fluoromisonidazole ([18F]FMISO)37 and [18F]
FAZA38 have been shown to be suitable markers for
hypoxia, since their metabolites are trapped exclusively
in hypoxic cells.39 After diffusion into all cells, the
nitroimidazole derivatives are reduced, reoxidized,
and finally slowly cleared from tissue in normal cells
but not in hypoxic cells, where these substances are
further reduced and finally retained.
[18F]FMISO uptake was observed in high-grade but
not in low-grade gliomas, and a significant relationship
was found between [18F]FMISO uptake and expression
of vascular endothelial growth factor receptor– 1 and
antigen Ki-67.40 Generally, increased [18F]FMISO
uptake is found in the periphery but not in the center
of a glioblastoma, since only viable cells are able to
accumulate the tracer, and enrichment in necrotic
tissue is low.41 On the basis of the biological links
between hypoxia and the aggressiveness of disease,
including tumor-induced neoangiogenesis, it is instructive to compare images of hypoxia with MRI scans to
reveal aspects of new vasculature and invasion.42
However, only limited data investigating the role of
hypoxia markers for glioma in clinical settings are
available at present. Despite the encouraging preliminary results, suboptimal imaging properties (low
target-to-background ratio as well as slow uptake in
malignant tissue) have limited the use of [18F]FMISO
in routine clinical practice so far.43
Perfusion—Pathological angiogenesis is a hallmark of
malignant gliomas, as it is one of the most prominent
mechanisms driving tumor development and progression. Several efforts in this area of research are
leading to the development of antiangiogenic molecules
for cancer treatment.44 The ability to measure blood
flow noninvasively may be of importance in monitoring
glioma therapies. Suitable perfusion tracer should come
with high extraction from the blood and high diffusion
into the tissue that is proportional to delivery and
should not participate significantly in metabolic processes.45 However, reliable quantification of perfusion
requires arterial blood samples and is performed
mostly with very short-lived 15O-labeled water, which
definitively restrains its use for research purposes only.
Clinical Applications
Grading and Differential Diagnosis
Management and prognosis of gliomas highly depend on
histological grading. The value of conventional MRI
may be limited to differentiation between low-grade
gliomas and benign nonneoplastic lesions or to detection
of high-grade gliomas without obvious MR-morphological signs of malignancy. Currently, evaluation
based on PET imaging of glioma-suspicious lesions is
conducted by means of mainly 4 radiotracers: the
glucose analogue [18F]FDG and the radiolabeled
amino acids [11C]MET, [18F]FET, and [18F]DOPA.
The first and the most widely used radiotracer for
brain tumors is [18F]FDG. [18F]FDG uptake was
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shown to be correlated with tumor cell density,46 the
grading and malignancy of glioma,5,47,48 and survival
prognosis.6,49,50 However, the sensitivity of [18F]FDG
PET was found to be limited in primary diagnosis of
glioma, because only 3% to 6% of patients with lowgrade gliomas and 21% to 47% of patients with highgrade gliomas presented with increased tracer
uptake.35,51 To overcome the slight contrast between
glioma and normal grey matter tissue, delayed scanning
intervals up to 7 h p.i. have been proposed.52 However,
this procedure is hardly applicable in a clinical setting.
For the past few years, PET using radiolabeled amino
acids has gained increasing importance in the diagnostic
workup of glioma, since it overcomes the limitations of
[18F]FDG by showing a much higher tumor/nontumor
contrast. [11C]MET PET was shown to permit a better
delineation in gliomas that were iso-/hypometabolic
on [18F]FDG PET and to provide a sufficiently high sensitivity in differentiation between nonneoplastic lesions
and low-grade gliomas (up to 79% positive predictive
value).53 Thus, increased amino acid uptake can be
found in 72% to 76% of low-grade and 95% to 100%
of high-grade gliomas for both [11C]MET and
[18F]FET35,51 (Fig. 2). A recently developed dynamic
analysis of [18F]FET uptake enables the differentiation
between low- and high-grade gliomas with high diagnostic power (sensitivity, 94%; specificity, 100%)26 (Fig. 1).
In addition, recently published data show that
[18F]DOPA PET was able to differentiate between lowand high-grade gliomas and that the tracer uptake correlated with tumor proliferation in newly diagnosed
gliomas but not in previously treated recurrent
tumors.54 Preliminary data also suggest that dynamic
analysis of [18F]FET PET might enable the differentiation between highly vascularized low- and high-grade
oligodendrogliomas, which display both increased
amino acid uptake26 and [18F]FDG uptake, independent
of World Health Organization (WHO) grading. This has
to be confirmed in ongoing studies. Furthermore, the
combination of static uptake evaluation together with
the proposed dynamic approach can be implemented
for identification of anaplastic foci within a heterogeneous glioma.55 Thus, for noninvasive grading of
primary gliomas, the standard method should be supplemented by the dynamic approach. A similar kinetic
analysis has been attempted for [11C]MET; however,
the uptake characteristics of this tracer do not allow
differentiation between low- and high-grade gliomas
on an individual patient basis.56
Because differential diagnosis of newly diagnosed
masses with ring enhancement on MRI includes neoplastic (e.g., gliomas, brain tumors, metastases) as well as
nonneoplastic entities such as abscesses, parasitic
lesions, demyelinating and reactive lesions, infarction,
and resolving hematoma, a noninvasive pretherapeutic
identification is highly desirable. PET with [18F]FDG
was previously shown to be of limited value to reliably
predict whether a lesion was malignant, due mainly to
unspecific tracer uptake related to a higher metabolic
rate and increased density of inflammatory cells,57 – 60
as well as the very heterogeneous uptake in cerebral
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metastases. Furthermore, relatively benign tumors,
including pilocytic astrocytoma and ganglioglioma,
often present with increased [18F]FDG uptake that is
caused by presence of metabolically active endothelial
cells.61 Even if considered to be more specific, currently
available data show false positive findings in benign or
inflammatory processes (mainly in abscesses but also in
demyelinating lesions) for choline (5/110; 4.6%)62 as
well as amino acid PET (up to one-third of newly diagnosed solitary intracerebral lesions showing ring
enhancement on contrast-enhanced MRI).57,60,63 In
addition, from our own experience cerebral metastases
are associated mostly with increased amino acid
uptake that does not allow the differentiation of
gliomas.
In conclusion, the use of [18F]FDG PET is of questionable value for initial diagnosis, especially when amino
acid tracers are available, but it might provide some
helpful information—for instance, for the differentiation
of low-grade gliomas (low [18F]FDG uptake) from
inflammatory lesions (slightly increased [18F]FDG
uptake). In addition, due to its limited accuracy for
differential diagnosis, PET cannot be considered to be
a sufficient alternative to histological diagnosis provided
by means of biopsy or resection.
Tumor Extension and Treatment Planning
PET guidance for biopsy planning in low- and highgrade gliomas—Biopsy is performed to obtain a diagnosis in de novo cases when the tumor is located in an eloquent brain region and resection cannot be performed
without compromising normal function, or when the
patient’s general condition or refusal to undergo
surgery does not allow an open resection. In addition,
it constitutes a safe and reliable method to disclose
tumor recurrence or progression following previous
multimodal treatment, as well as malignant transformation of a glioma previously classified as low grade.
Most widespread, the procedure for stereotactic biopsy
involves contrast-enhanced morphological (MRI)
imaging.
Although contrast enhancement, among other criteria, has been shown to be the strongest predictor of
malignancy, up to 10% of all high-grade gliomas64
and approximately one-third of anaplastic astrocytomas65 do not present with contrast enhancement on
gadolinium T1 images. Conversely, low-grade gliomas
can sometimes demonstrate peritumoral edema as well
as contrast enhancement and, therefore, be mistaken
for high-grade gliomas.66 Thus, target selection for
stereotactic biopsy based on MRI/CT guidance alone
has been regarded with controversy, since the degree of
malignancy might be underestimated, especially in
gliomas with a rather “benign” appearance on MRI.67
Taking into consideration the often encountered interand intratumoral heterogeneity, PET might be a valuable
additional tool for exposure of the most malignant areas
of the tumor, ensuring correct evaluation of the biopsy
site.
la Fougère et al.: PET in Glioma
Fig. 2. Transversal MR, fused PET MR, and [18F]FET PET images are shown. Upper row: diffuse T2-hyperintensity in the left insula with focal
and moderate [18F]FET uptake in a patient with astrocytoma WHO II. Middle row: MRI shows a diffuse T2-hyperintensity, without contrast
enhancement in T1-weighted MR images (not shown), and [18F]FET PET demonstrates significant tracer uptake in a patient with
histologically proven anaplastic astrocytoma WHO III. Lower row: a patient with glioblastoma without contrast enhancement in
T1-weighted MR but markedly increased [18F]FET uptake.
Despite its limited validity in low-grade glioma,
[ F]FDG, being the most widely applied radiotracer,
was shown to be superior for stereotactic biopsy target
selection compared with CT or MRI alone.68,69
However, its additional value for biopsy guidance in
lesions already highly suggestive on MRI of a high-grade
glioma remains limited.
In a prospective study combining amino acid PET
([18F]FET) and MRI, the use of both modalities was
shown to enhance the accuracy significantly (sensitivity
93%; specificity 94%) compared with MRI alone (sensitivity 96%; specificity 53%)70 and to be more accurate
in identifying active tumors than [18F]FDG PET,47,71
indicating that amino acid PET is better suited for
biopsy target selection than [18F]FDG, especially in lowgrade gliomas. As nonenhancing lesions tend to exhibit
malignant histopathological features within a presumed
WHO II glioma, the diagnostic and prognostic assessment most notably depends on the sampling location.
18
Recently, [18F]FET PET was demonstrated to reliably
detect anaplastic foci and to be able to differentiate
between grade II and grade III histopathology within
one and the same lesion (sensitivity 92%; specificity
82%) when the dynamic analysis was applied55 (Fig. 3).
While there is growing evidence for the implementation of PET for biopsy planning in low-grade
gliomas, the necessity of PET guidance in high-grade
gliomas is arguable. Due to their metabolic and vascular
properties based on increased proliferation, high-grade
gliomas generally effectuate high uptake values of all
well-established radiotracers. Therefore, [18F]FDG,69
[11C]MET,71 and [18F]FET,70 as well as [18F]FLT,
which can identify regions of tumor with increased proliferation rate,72 could be implemented for combined
PET/MR guidance in a high-grade glioma.
PET guidance for surgery planning—Due to its ability
to reveal the most malignant areas within a gliomatous
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Fig. 3. Combined [18F]FET PET MR clearly demarcate the anaplastic focus in a patient with heterogeneous glioma. Slightly increased contrast
enhancement but highly increased tracer uptake proved this to be an anaplastic oligoastrocytoma WHO III (A), whereas nonenhancing
tumor parts without significant tracer uptake were shown to constitute an astrocytoma WHO II (B).
tumor, PET might potentially help to plan the resection
and to guide the surgeon. Especially in heterogeneous
gliomas consisting of high- and low-grade components,
resection including the most malignant parts of the
tumor should be aimed for, in order to ensure a
correct histological evaluation. However, only 2
studies have investigated the value of a PET-guided
resection so far. The multimodal navigation system
including amino acid PET was suggested to be more
useful than the conventional navigation system in
determining the resection area by providing a clearer discrimination of tumor boundary, which resulted in
decreased remnant tumor mass and was associated
with improved postsurgical survival73,74 (Fig. 4). In
addition, preoperative [18F]FET uptake highly correlates
with the degree of intraoperative 5-aminolevulinic acid
fluorescence in glioma.75 However, the significance of
this finding remains limited as far as patient selection
for surgical treatment is concerned. Further investigations are necessary to evaluate the relationship of a
PET-guided extent of resection with patients’ outcomes,
as well as procedure-related morbidity compared with
MRI-based resection.
PET guidance for radiation therapy planning—
Stereotactic radiotherapy, radiosurgery, intensitymodulated radiotherapy, and 3D planning of brachytherapy enable a highly precise delivery of radiation
in glioma. Even if the target volume definition is currently based on CT and MRI techniques, additional
information from molecular imaging techniques to visualize biological pathways is expected to have a major
impact on radiation oncology.76 As a consequence, the
concept of biological target volume (BTV) was proposed
in addition to the concepts of gross tumor volume
(GTV), clinical tumor volume (CTV), and planning
target volume (PTV).77 In high-grade gliomas, early
recurrence after local treatment is a common feature,
and relapse occurs in terms of continuous growth
within 2– 3 cm from the margin of the original lesion
in approximately 80% of cases.78
Recent studies claim the usefulness of PET-based
BTV for radiation therapy planning. In high-grade
gliomas, amino acid– based assessment of BTV was
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supposed to be more accurate than morphological
GTV,79,80 which in several cases was shown to differ
substantially in size. The inadequate coverage of BTV
by morphological GTV was linked with increased risk
of noncentral failures, and therefore amino acid– based
BTV was suggested to be useful for identifying areas
for conformal boost.81 In addition, a nonrandomized
study dealing with patients with recurrent high-grade
gliomas showed that treatment planning based on radiolabeled amino acids combined with CT/MRI was also
associated with improved survival in comparison with
treatment planning using CT/MRI alone (median survival time, 9 months vs. 5 months).78 Therefore, in order
to spare normal tissue, reduce toxicity, and decrease
the likelihood of geographical misses in target volume
definition, biological treatment planning seems to be
very promising. However, this has to be validated in prospective studies in order to assess both the impact of
amino acid PET for target volume definition and the
importance of biological tumor tissue definition for
patients’ overall survival. In contrast to amino acid
PET, the use of [18F]FDG PET does not appear to have
a major additional impact for the delineation of target
volume, as the area of increased [18F]FDG uptake has
been shown to correlate closely with contrast enhancement in MRI.82
Assessment of tumor hypoxia prior to radiotherapy is
also expected to be beneficial, as it would provide a
rational means of demarcating radio-resistant hypoxic
zones within the treatment volumes in glioma and therefore could lead to an adaptation of individual treatment
strategies by increasing the dose deposition in hypoxic
areas and minimizing the doses in well-oxygenated
areas or by using radiosensitizing drugs in well-selected
patients.40 However, to the best of our knowledge, no
clinical study assessing the hypoxia-marker uptake and
treatment response to radiotherapy has yet been
published.
Value of PET for Follow-up of Glioma
The use of multimodal individual therapy strategies,
including surgery, radiotherapy, and chemotherapy, as
well as therapies involving antiangiogenic substances
la Fougère et al.: PET in Glioma
Fig. 4. Tumor delineation and target volume definition for treatment planning substantially differs, depending on the image modality used.
Highest tumor volume is suggested on T2-weighted MRI. [18F]FET uptake considerably exceeds the contrast enhancement in T1-weighted MRI.
and other biologically targeted therapies, necessitates an
accurate and early assessment of treatment response,
particularly in high-grade glioma, in order to optimize
patient care and treatment. Current standard therapeutic
regimen in high-grade glioma, notably glioblastoma
multiforme, involves a combination of radio- and chemotherapy with temozolomide followed by adjuvant
temozolomide monotherapy according to the protocol
of the European Organisation for Research and
Treatment of Cancer.83
Assessment of treatment response is very challenging,
because posttherapeutic changes reflected by contrast
enhancement or changes in tumor size obtained with
conventional MRI and CT techniques are of limited
value61 and often fail to detect early treatment response,
as they occur with a delay of weeks up to months.84,85
In addition, posttreatment MRIs often show
contrast-enhancing lesions that can be associated either
with tumor relapse or with treatment-induced changes.
These changes, which are attributed mostly to
radiation-induced damage of neural and vascular
tissue, can be classified as pseudoprogression (early
radiographic changes, reversible) or radiation necrosis
(subacute radiographic changes, irreversible). In contrast
to genuine tumor recurrence, these treatment-related
alterations can be asymptomatic, especially in case of a
pseudoprogression, usually fail to progress, and are
associated with prolonged survival.86 As a consequence
of temozolomide treatment, the incidence of pseudoprogression has increased, mainly in glioblastoma with a
methylated O(6)-methylguanine-DNA methyltransferase status. As the discrimination between contrast
enhancement related to tumor recurrence and
treatment-related effects is quite challenging, the accuracy of MRI-based predictions of patient’s disease
status remains limited.87 Although the recently introduced criteria of the Response Assessment in
Neuro-oncology for assessment of treatment response
by MRI address pseudoprogression or pseudoresponse
phenomena, proposing a reevaluation of diagnosis by a
subsequent MRI scan after a time period of 4 weeks,88
the additional evaluation by means of magnetic resonance spectroscopy (MRS) and PET prior to imaging or
as a supplementary imaging modality has been suggested
as a valuable tool for subsequent therapy monitoring
and adjustment.
With regard to standard therapy regimens in
glioma, [18F]FDG PET was able to predict response
to temozolomide but not to temozolomide plus radiotherapy,89 probably due to energy-dependent apoptosis
of tumor cells, rapid infiltration of tumor by inflammatory cells after radiotherapy,90 or alterations in
the
blood-brain
and
blood-tumor
barriers.91
18
Currently available data on [ F]FDG PET are quite
inconsistent and show limited accuracy for the differentiation of recurrence from radiation necrosis, with
sensitivities between 40% and 90% and specificities
between 40% and 80%, respectively,8,92 – 94 which
could lead to an inappropriate treatment in up to
one-third of patients.
In contrast, radiolabeled amino acid tracers are not
taken up by glycolytic inflammatory cells and therefore
have been suggested to be more appropriate for discrimination between recurrence or progression versus unspecific therapy-related changes.95 However, the
experience for treatment monitoring is still comparably
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limited. Higher diagnostic power was confirmed in
different studies with [11C]MET (sensitivity, 75% –
90%; specificity, 75% –92%)96 – 98 as well as with
[18]FET (positive predictive value, 84%; sensitivity,
82%; specificity, 100%).99,100 Slightly increasing and
homogeneous uptake around the tumor cavity pointed
to benign therapy-related changes, whereas focally
increased [18F]FET uptake was shown to be an early
and reliable indicator of tumor progression100 (Fig. 5).
However, the diagnostic power was higher in an MRS
study based on multivoxel 3D acquisition (sensitivity,
94%; specificity, 100%).101 Comparable diagnostic
accuracy was found for [18F]FET PET when additional
dynamic data analysis was applied (sensitivity, 100%;
specificity, 93%),102 which was significantly superior
to conventional MRI (sensitivity, 94%; specificity,
50%) in discriminating tumor recurrence from posttherapeutic changes. However, the accuracy of amino acid
PET is not yet high enough to replace histological verification in patients with MRI-based suspicion of a glioma
recurrence or progression but seems to be a useful tool
for biopsy planning and patient selection. In this light,
a significant decrease of amino acid uptake, correlated
with effectiveness of radiotherapy and chemotherapy103
and postoperative elevated amino acid uptake,
suggesting remnant glioma tissue is associated with
worse survival in malignant glioma.104
Limited data on [18F]FLT indicates that this marker
for cell proliferation might also be superior to
[18F]FDG in evaluating recurrent high-grade gliomas.30
In an animal model of glioma, [18F]FLT uptake correlated with changes in tumor growth as well as expression
levels of therapeutic genes and has been suggested to be a
promising noninvasive parameter to monitor effects of
antiproliferative therapy, as [18F]FLT uptake levels
could be assessed as early as 3 days after therapy
onset.105 However, these results have to be confirmed
in humans.
New treatment strategies with antivascular agents
(e.g., the antivascular endothelial growth factor receptor-1 antibody bevacizumab) are difficult to monitor
reliably by conventional imaging techniques, since
treatment-induced reduction of contrast enhancement
represents predominantly reduced vascular permeability.106 Therefore, contrast-enhanced MRI is considered to be of only limited value to quantify tumor
burden after treatment with antivascular agents.86
However, to date none of the current radiographic modalities, neither conventional or diffusion-weighted
imaging-based MRI nor MRS, has proven sensitive
enough to assess post-bevacizumab treatment effects.
Metabolic imaging has been proposed to be an
alternative therapy-response assessment tool. [18F]FLT
PET proved to be superior compared with
contrast-enhanced MRI in predicting treatment response
of malignant gliomas to bevacizumab plus chemotherapy,107 albeit in a small group of patients with recurrent
malignant gliomas (n ¼ 21). Yet, the experience to date
remains limited, and further prospective studies have to
be performed.
PET based on markers of hypoxia like [18F]FMISO
might be helpful to detect hypoxic areas, which were
shown to be associated with poorer therapy response
to antiangiogenic treatment.108 However, this assumption remains speculative and has to be proven by prospective studies.
Fig. 5. Postradiogenic contrast enhancement on MRI coupled with pathologically increased tracer uptake on PET were highly suggestive for
glioblastoma progression, which was confirmed by means of histology (upper row), whereas contrast enhancement on MRI with only slightly
increased and homogeneous [18F]FET uptake (lower row) was shown to be treatment associated by follow-up examinations.
814
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Altogether, amino acid PET with dynamic analysis
seems to provide additional information, compared
with morphological imaging techniques, for the sensitive
and specific detection of glioma recurrence. Moreover,
PET-based imaging might help to monitor new treatment modalities like antiangiogenic therapies.
Impact of PET-Based Evaluation on Patient Prognosis
Several prognostic factors have been identified in
glioma, including patient’s age, location and size of
the lesion, histology and grade of the tumor, and
neurological status.109 The clinical course of patients
with low-grade gliomas can vary considerably, and
valuable tools for an accurate identification of patients
with a poor or a favorable prognosis is highly desirable to adjust treatment strategies. A treatment that
is too aggressive may cause treatment-related morbidity, whereas insufficient treatment of progressive
lesions may significantly decrease overall survival
time. [18F]FET PET in combination with MRI was
suggested to be a strong predictor in determining the
clinical course and outcome in nonenhancing lowgrade gliomas. Within the observation period of the
study (up to 65 months), the best outcome was
found in circumscribed lesions without tracer uptake
(18% progression), which was followed by those
with tracer uptake (46% progression). The worst
outcome was shown in diffuse glioma with high
uptake (100% progression).110 [18F]FDG PET uptake
was also shown to predict malignant transformation
and to correlate with overall survival in a large retrospective study including 331 patients, since 71% of
patients with initially high [18F]FDG uptake survived
for less than 1 year (22% less than 3 years),
whereas 94% of patients with initially low [18F]FDG
uptake had a median survival of more than 1 year
(63%; and 39% more than 2 and 3 years
respectively).111
Potential New Targets for Glioma Imaging
Several molecular markers involved in glioma progression have recently been characterized.112 A true
molecular imaging would allow visualization of these
molecules in situ. This could have a major impact
on the understanding of glioma biology, as well as
on selection and monitoring of therapies against
these targets.
The use of radiolabeled biomolecules such as monoclonal antibodies and peptides may potentially enable
a more specific assessment of molecular changes in
tumor tissue. For instance, glycosylated arginine–
glycine– aspartic acid peptide ([18F]Galacto-RGD)113
was demonstrated in glioblastoma to successfully
identify the expression of the integrin avb3,114 which
is associated with tumor-induced angiogenesis via
basic fibroblast growth factor and is also found in
small blood vessels, where it is thought to promote
extensive tumor progression.115 Such a concept has
become even more important, as avb3 integrin antagonists are promising new agents currently being
tested in clinical trials for supplemental therapy of
glioblastoma.116 Likewise, different antibodies and
peptides can be considered as worthwhile ligands
that might potentially be interesting for imaging in
glioma. Further development might lead to more selective radiotracers, which permit profound and more
selective insight into tumor biochemistry in vivo. As
an example, the development of antisense oligonucleotides for the visualization of specific mRNA and
protein expression would allow targeting of the
expression of almost any endogenous gene.117,118
However, further technological advancements are
needed in order to solve known problems, like low
accumulation in the target tissue, for which a more
widespread use of antisense imaging technique is currently avoided in favor of a reliable in vivo monitoring
of gene expression.119
Due to its remarkable sensitivity, molecular imaging
with PET allows the use of very low tracer doses in
physiological quantities that theoretically enable the
application of almost each substance with only a
minimal risk of adverse reaction, rather than bulk
tracer doses that are necessary for CT or MRI.
Therefore, PET appears to be one of the most interesting imaging modalities for further advancement in
molecular imaging. One might speculate whether
information gained by PET tracer development will
be transferrable for the elaboration of injectable targeted MR contrast agents that can cross the blood –
brain barrier.
Conclusion
The scientific data justify the use of PET in glioma,
especially when radiolabeled amino acids are used.
Although information assessed by MRI will remain
essential in glioma management, PET by means of
amino acids using dynamic PET data acquisition
together with assessment of the maximal or mean SUV
value was shown to be
† more specific for tumor delineation;
† beneficial for biopsy planning, in particular for
inhomogeneous gliomas without contrast enhancement on MRI;
† very helpful for the differentiation between remnant
tumor tissue and posttherapeutic changes, as well as
for assessment of early treatment response; and
† potentially useful for treatment planning of local
therapies.
With the introduction of PET radiopharmaceuticals
like [18F]FLT and [18F]FMISO, additional insight
into proliferation rate and oxygen metabolism of
gliomas can be obtained. Further prospective studies
are needed to evaluate their clinical impact.
Molecular imaging techniques might be promising
for the selection of patients who might better
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815
la Fougère et al.: PET in Glioma
respond to targeted therapies, as well as for the evaluation of treatment response, and therefore might
enable individualized patient management. PET can
therefore be regarded as a relevant tool for the accurate evaluation of new treatment strategies and
should be considered in upcoming prospective
studies. Early adjustment of patient care can also
avoid unnecessary treatment toxicity and reduce
treatment costs of ineffective therapies. However,
further randomized, prospective multicenter clinical
trials are needed to clearly demonstrate the additional
value of both PET combined with regular MR compared with regular MR alone.
Conflict of interest statement. None declared.
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