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Current Medicinal Chemistry, 2018, 25, 1-13 1
REVIEW ARTICLE
0929-8673/18 $58.00+.00 © 2018 Bentham Science Publishers
Recent Developments of 18F-FET PET in Neuro-oncology
Barbara Muoio, Luca Giovanella and Giorgio Treglia*
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
A R T I C L E H I S T O R Y
Received: November 14, 2016
Revised: September 19, 2017
Accepted: November 07, 2017
DOI:
10.2174/0929867325666171123202644
Abstract: Background: From the past decade to date, several studies related to O-(2-
[18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tu-
mours have been published in the literature.
Objective: The aim of this narrative review is to summarize the recent developments and
the current role of 18F-FET PET in brain tumours according to recent literature data.
Methods: Main findings from selected recently published and relevant articles on the role
of 18F-FET PET in neuro-oncology are described.
Results: 18F-FET PET may be useful in the differential diagnosis between brain tumours
and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of
18F-FET PET into surgical planning allows better delineation of the extent of resection
beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particu-
larly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET
PET may improve the radiation therapy planning in patients with gliomas. This metabolic
imaging method may be useful to evaluate treatment response in patients with gliomas
and it improves the differential diagnosis between brain tumours recurrence and post-
treatment changes. 18F-FET PET may provide useful prognostic information in high-grade
gliomas.
Conclusion: Based on recent literature data 18F-FET PET may provide additional diag-
nostic information compared to standard MRI in neuro-oncology.
Keywords: PET, O-(2-[18F]fluoroethyl)-L-tyrosine, FET, neuro-oncology, neuroimaging, glioma, brain tumours,
glioblastoma.
1. INTRODUCTION
Magnetic resonance imaging (MRI) is the standard
neuroimaging method to diagnose neoplastic brain le-
sions, as well as to perform stereotactic biopsy and sur-
gical planning in neuro-oncology. MRI has the advan-
tage of providing structural anatomical details with
high sensitivity, though histological specificity is lim-
ited. Metabolic imaging by using radiolabelled amino
acids may be helpful in the diagnostic evaluation of
brain lesions providing significant information com-
pared to conventional morphological imaging tech-
niques such as computed tomography (CT) or MRI [1].
*Address correspondence to this author at the Department of Nu-
clear Medicine and PET/CT Centre, Oncology Institute of Southern
Switzerland, Via Ospedale 12, zip code: 6500, Bellinzona,
Switzerland; Tel: 0041 918118919; Fax: 0041918118250;
E-mail: giorgio.treglia@eoc.ch
Several factors influence the increased amino acid up-
take in brain tumour cells including the overexpression
of the amino acid transport systems in tumour cells,
alterations in the tumour vasculature and tumour cell
proliferation [1].
O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) is a ra-
diolabelled amino acid, tyrosine analogue, which can
be used to visualize brain tumours by using positron
emission tomography (PET). The results of the first
human study using 18F-FET PET in a patient with brain
tumour have been reported in 1999 [2]. Characteristics
of this amino acid radiopharmaceutical are the high in
vivo stability, the fast brain and tumour uptake kinetics,
the usually low accumulation in non-tumour tissue and
its ease of synthesis [2]. 18F-FET penetrates the blood-
brain barrier by a specific amino acid transport system
and it is not incorporated into proteins [2]. Its uptake
2 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Muoio et al.
mechanism in tumour cells is mediated by the L-type
amino acid transport system [3].
Contraindications for 18F-FET PET are only preg-
nancy and lack of patient cooperation [4].
About the 18F-FET PET imaging procedure [4] pa-
tients should be fasting for more than four hours before
the radiopharmaceutical injection. A mean dose of 200-
250 MBq is intravenously injected in adult patients.
Hybrid PET/CT or PET/MRI is used for image acquisi-
tion. In some centers a 40 minutes dynamic acquisition
just after the radiopharmaceutical injection is per-
formed. In other centers static PET image acquisition
from 20 to 40 minutes post-injection is carried out [4].
18F-FET PET image interpretation is usually performed
by using visual (qualitative) and semi-quantitative cri-
teria such as lesion-to-background uptake ratios
(LBRs) [4].
About dosimetry of 18F-FET PET, the highest ab-
sorbed dose was found for the bladder. The effective
dose is 16.5 microSv/MBq for adults, which would
lead to an effective dose of 6.1 mSv in a PET study
using 370 MBq [5]. The potential radiation risks asso-
ciated with this metabolic imaging method are well
within accepted limits [6].
From the past decade to date, several studies related
to 18F-FET PET in brain tumours have been published
in the literature. The aim of this narrative review is to
summarize the recent developments and the current
role of 18F-FET PET in neuro-oncology according to
selected recently published and relevant articles on this
topic.
2. 18
F-FET PET IN THE INITIAL ASSESSMENT
OF PATIENTS WITH NEWLY DIAGNOSED
BRAIN LESIONS
Recent literature data show the additional high di-
agnostic value of 18F-FET PET in patients with newly
diagnosed brain lesions at MRI [7-24].
2.1. Static Measures
A meta-analysis published in 2012 including 13
studies (462 patients with brain lesions) demonstrated
that 18F-FET PET is an accurate method for the diagno-
sis of primary brain tumour, showing a pooled sensitiv-
ity of 82% and a pooled specificity of 76% [7]. Re-
ceiver-operating-characteristic (ROC) analysis indi-
cated that a mean LBR threshold of at least 1.6 and a
maximum LBR of at least 2.1 had the best diagnostic
value for differentiating primary brain tumours from
non-neoplastic lesions [7]. Furthermore, mean LBR
and maximum LBR were significantly higher in high-
grade gliomas than in low-grade gliomas (mean LBR:
1.7 ± 0.7 vs. 2.6 ± 1.0, respectively; p < 0.001; maxi-
mum LBR: 2.2 ± 0.9 vs. 3.1 ± 1.1, respectively; p <
0.001) [7].
In a recent retrospective study on 174 patients with
newly diagnosed brain lesions on MRI, 18F-FET PET
provided valuable additional information for the differ-
entiation of cerebral lesions and the grading of gliomas.
Neoplastic lesions showed significantly higher 18F-FET
uptake than non-neoplastic lesions (maximum LBR:
3.0 ± 1.3 vs. 1.8 ± 0.5, respectively; p < 0.001). ROC
analysis yielded an optimal cut-off of 2.5 for maximal
LBR to differentiate between neoplastic lesions and
non-neoplastic lesions (sensitivity 57%, specificity
92%, accuracy 62%, positive predictive value 98%, and
negative predictive value 27%). High-grade gliomas
showed significantly higher 18F-FET uptake than low-
grade gliomas (maximal LBR: 3.6 ± 1.4 vs. 2.4 ± 1.0,
respectively; p < 0.001). ROC analysis for differentia-
tion between high-grade and low-grade gliomas yielded
an optimal cut-off of 2.5 for maximum LBR (sensitiv-
ity 80%, specificity 65%, accuracy 72%, positive pre-
dictive value 66%, and negative predictive value 79%).
The results for mean LBR were similar with a cut-off
of 1.9 [10].
Another recent retrospective study on 393 patients
with brain lesions at MRI demonstrated that 18F-FET
PET has a high sensitivity for the detection of high-
grade brain tumours. Its specificity, however, is limited
by passive tracer influx through a disrupted blood-brain
barrier. Sensitivity and specificity of 18F-FET PET for
the detection of brain tumour were 87% and 68%, re-
spectively. Significant differences in maximum LBR
were detected between high-grade brain tumours and
low-grade brain tumours (maximum LBR: 2.04 ± 0.72
and 1.52 ± 0.70, respectively; p < 0.001), as well as
among inflammatory and other non-neoplastic brain
lesions (maximum LBR: 1.66 ± 0.33 and 1.10 ± 0.37,
respectively; p < 0.0001). Gliomas showed 8F-FET up-
take in 80% of World Health Organization (WHO)
grade I, 79% of grade II, 92% of grade III, and 100%
of grade IV tumours. Low-grade oligodendrogliomas
WHO grade II had significantly higher tracer uptakes
than astrocytomas grades II and III (p = 0.018 and p =
0.015, respectively). Furthermore 18F-FET uptake
showed a strong association with contrast enhancement
on MRI (p < 0.001) and was also positive in 52% of
nonglial brain tumours and non-neoplastic brain le-
sions. Nevertheless gliomas showed radiopharmaceuti-
cal uptake in the absence of contrast enhancement on
Recent Developments of 18F-FET PET in Neuro-oncology Current Medicinal Chemistry, 2018, Vol. 25, No. 00 3
MRI, which most likely reflects biologically active tu-
mour [11].
2.2. Kinetic Analysis and Correlation between 18F-
FET PET and MRI-based Parameters
Jansen et al. investigated the discriminative value of
additional dynamic 18F-FET PET in 127 patients with
MRI-suspected low-grade gliomas. Maximum and
mean LBR did not differ significantly between high-
grade and low-grade gliomas but kinetic analysis relia-
bly identified high-grade gliomas (sensitivity 95% and
specificity 72%) [8]. The same group of researchers
demonstrated that 18F-FET uptake was significantly
higher in gliomas with oligodendrial components,
compared with astrocytomas [9].
Zhang et al. explored the relationship between re-
gional cerebral blood flow (rCBF) as measured by arte-
rial spin labelling MRI and the kinetic behaviour of
18F-FET PET in 20 patients with gliomas demonstrat-
ing that there is a relationship between rCBF and 18F-
FET uptake in gliomas in the initial uptake phase, but
the kinetic behaviour of 18F-FET uptake in the late
phase is not significantly influenced by rCBF. Thus,
the differential kinetic pattern of 18F-FET uptake in
high-grade and low-grade gliomas appears to be deter-
mined by factors other than rCBF [12].
The research of Fills et al. by using PET/MRI con-
firmed that in patients with gliomas 18F-FET PET and
regional cerebral blood volume (rCBV) assessed by
perfusion-weighted MR imaging (PWI) yielded differ-
ent information. 18F-FET PET showed considerably
higher maximum LBR and larger tumour volumes than
rCBV maps. The spatial congruence of both parameters
was poor. The locations of the local hot spots differed
considerably. Therefore metabolic active brain tumour
tissue as depicted by 18F-FET PET is not reflected by
rCBV as measured with PWI [13].
The findings from the recent study of Göttler et al.
on 30 untreated glioma patients evaluated with simul-
taneous PET/MRI indicated that 18F-FET PET and
MRI-based rCBV may provide both congruent and
complimentary information on glioma biology [14].
Furthermore as recently published there is no con-
gruency between 18F-FET uptake and diffusivity at dif-
fusion-weighted MRI in nonenhancing low-grade
gliomas. Diffusion restriction in these tumours most
likely represents changes in brain and tumour cell den-
sities as well as alteration of water distribution and is
probably not directly correlated with the density of tu-
mour cells [15].
Combination of dynamic 18F-FET PET and diffu-
sion MRI reached good performance for gliomas grad-
ing. In fact, combination of time-activity curves
(TACs) at dynamic 8F-FET PET and apparent diffusion
coefficient (ADC) histogram analysis at diffusion MRI
improved the sensitivity from 67% to 86% and the
specificity from 63-67% to 100% about the differential
diagnosis between high-grade and low-grade gliomas
[16].
2.3. Dual-time-point PET Imaging
As dynamic 18F-FET PET could be time consuming
compared to static 18F-FET PET, some researchers
demonstrated that dual-time-point 18F-FET PET imag-
ing could be equivalent to dynamic 18F-FET PET for
grading of gliomas [17,18]. Reduced imaging time in-
creases patient comfort and sedation might be avoided.
Furthermore quicker image interpretation with dual-
time-point PET is possible, as no curve evaluation is
needed [17]. As recently demonstrated, early maximum
LBR at 18F-FET PET (with early images performed at
5-15 minutes after radiopharmaceutical injection)
seems to be more accurate for the differentiation be-
tween low-grade and high-grade gliomas than the stan-
dard static PET scan (performed between 20 and 40
minutes after radiopharmaceutical injection) mainly
caused by the characteristic high 18F-FET uptake of
high-grade gliomas in the initial phase. Therefore,
when dynamic 18F-FET PET cannot be performed,
early maximum LBR assessment can be considered as
an alternative for grading of gliomas [19].
2.4. Textural Analysis
Determination of 18F-FET uptake heterogeneity us-
ing textural features recently proved valuable for the
subgrading of high-grade gliomas. In the study by Pyka
et al. on 113 patients with high-grade gliomas all 18F-
FET-PET textural parameters showed the ability to dif-
ferentiate between WHO grade III and IV tumours (ac-
curacy: 77.5%; p < 0.001). Further improvement in
discriminatory power was possible through a combina-
tion of texture and metabolic tumour volume, classify-
ing 85% of tumours correctly [20].
2.5. Evaluation of other Brain Tumours Beyond Su-
pratenturial Gliomas in Adult Patients
Beyond gliomas 18F-FET PET may provide addi-
tional information for noninvasive grading of men-
ingiomas as demonstrated by the preliminary study of
Cornelius et al. The difference in maximum LBR be-
tween low-grade and high-grade meningiomas was sig-
4 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Muoio et al.
nificant in the late phase of 18F-FET uptake (2.1 ± 0.2
vs. 2.5 ± 0.2, respectively; p = 0.003) while there
was no significant difference in the early phase. A
maximal LBR cut-off of 2.3 at 18F-FET PET in the late
phase was accurate in differentiating low-grade from
high-grade meningiomas (sensitivity 83%, specificity
83%). Combination of maximum LBR and TAC pat-
tern at dynamic imaging slightly improved the differen-
tiation of high-grade from low-grade meningiomas (ac-
curacy 92%) [21].
Untreated metastases predominantly show increased
18F-FET-uptake. As recently described by Unterrainer
et al. only a third of metastases <1.0 cm was negative
at 18F-FET-PET, most likely due to scanner resolution
and partial volume effects. In metastases >1.0 cm, 18F-
FET-uptake intensity is highly variable and independ-
ent of tumour size. 18F-FET PET might provide addi-
tional information beyond the tumour extent by reflect-
ing molecular features of a metastasis and might be a
useful tool for future clinical applications, e.g. response
assessment [22].
In paediatric patients with newly diagnosed cerebral
lesions, 18F-FET PET may provide useful information
as recently described by Dunkl et al. The highest accu-
racy to detect neoplastic tissue was obtained when the
maximum LBR was 1.7 or greater (sensitivity 79%,
specificity 71%, accuracy 77%) [23].
Finally preliminary data suggest that 18F-FET PET
may add valuable diagnostic information in brainstem
and spinal cord gliomas, particularly when the diagnos-
tic information derived from MRI is equivocal [24].
3. 18F-FET PET FOR GUIDING BIOPSY OF
BRAIN LESIONS AND RESECTION PLANNING
Several recent studies have demonstrated the value
of 18F-FET PET in guiding biopsy and resection plan-
ning in patients with brain lesions at MRI [25-31].
As showed by Floeth et al. 18F-FET PET was more
sensitive to detect glioma tissue than 5-aminolevulinic
acid (5-ALA) fluorescence and should be considered as
an additional tool in resection planning. In fact there
was significant differences between 18F-FET and 5-
ALA uptake in 30 patients with brain lesions sugges-
tive of diffuse WHO grade II or III gliomas on MRI
owing to a limited sensitivity of 5-ALA to detect tu-
mour tissue especially in low-grade gliomas. In biop-
sies corresponding to high-grade gliomas 18F-FET PET
was positive in 86% of cases, but 5-ALA and Gd-
diethylenetriaminepentaacetic acid enhancement on
MRI (Gd) in only 57% of cases. In biopsies corre-
sponding to low-grade gliomas 18F-FET PET was posi-
tive in 41% of cases, while 5-ALA and Gd were nega-
tive in all but one instance. All tumour areas with 5-
ALA fluorescence were positive on 18F-FET PET [25].
A recent cost-effectiveness study demonstrated that
the combined use of 18 F-FET PET and MRI resulted in
an increase of 18.5% in the likelihood of a correct di-
agnosis and that the use 18F-FET PET is cost-effective
for biopsy targeting in patients with glioma [26].
The use of an automated hotspot detection system
through 18F-FET PET uptake data may also be able to
provide more precise information for stereotactic bi-
opsy trajectories compared to MRI-guided plans. The
use of specially designed computational tools may re-
fine surgical planning by improving biopsy targeting
[27].
A combined PET/MRI multimodal imaging ap-
proach may provide potential benefits in detecting
glioma heterogeneity. In fact, based on recent findings,
multimodal imaging-guided stereotactic biopsy corre-
lated more with histological malignancy indices than
targets that were based solely on the highest 18F-FET
uptake or contrast enhancement on MRI [28].
18F-FET PET may be helpful for target selection and
can be integrated in surgical guidance in paediatric pa-
tients with brain tumours. In fact as reported by Misch
et al. 18F-FET-PET image-guided surgical targeting
yielded histological diagnosis with good diagnostic
accuracy in paediatric patients with brain tumours [29].
Finally, it has recently been demonstrated that in pa-
tients with brain metastases surgical treatment planning
based on MRI or 18F-FET PET only might have a sub-
stantial risk of undertreatment at the tumour margins
[31].
4. 18F-FET PET FOR RADIOTHERAPY PLAN-
NING
Several clinical trials have demonstrated the signifi-
cant differences between 18F-FET PET and standard
MRI concerning the definition of tumour volumes for
radiotherapy planning in glioma patients but it remains
open whether 18F-FET PET-based target definition has
a relevant clinical impact for treatment planning [32-
37].
Comparing for radiotherapy planning of glioblas-
toma MRI-based morphological gross tumour volumes
(GTVs) to biological tumour volumes (BTVs) defined
by the abnormal 18F-FET uptake, Niyazi et al. found
that with 18F-FET PET planning the size and geometri-
cal location of GTVs/BTVs differed in the majority of
patients [32].
Recent Developments of 18F-FET PET in Neuro-oncology Current Medicinal Chemistry, 2018, Vol. 25, No. 00 5
Recently Danish researchers assess the impact of
18F-FET PET on the volumetric target definition for
radiation therapy of high-grade gliomas versus the cur-
rent standard using MRI alone. They found that by in-
cluding 18F-FET PET for GTV the clinical target vol-
ume (CTV) increased moderately for most patients, and
quite substantially for a minority of patients. Patients
with glioblastoma were found to be the primary candi-
dates for 18F-FET PET-guided radiation therapy plan-
ning [33].
In a prospective phase II study, 22 patients with
glioblastoma received post-surgical radiochemother-
apy. The radiotherapy was performed as an MRI and
18F-FET PET-based integrated-boost intensity-
modulated radiotherapy (IMRT). The dose escalation
concept with a total dose of 72 Gy, based on 18F-FET-
PET, did not lead to a survival benefit [34].
Rieken et al. investigated the impact of 18F-FET
PET on target volume definition in low- and high-grade
glioma patients undergoing either first or re-irradiation
with particles. Integrating 18F-FET-uptake into the de-
lineation of GTVs yielded larger volumes. Combined
PET- and MRI-derived planning target volumes
(PTVs) were significantly enlarged in high-grade glio-
mas and in case of primary radiation therapy [35].
18F-FET PET may also be useful for guiding re-
irradiation in patients with recurrent high-grade glio-
mas [36].
5. 18F-FET PET FOR DETECTING RESID-
UAL/RECURRENT BRAIN TUMOURS AFTER
TREATMENT
5.1. Detection of Residual Brain Tumours After
Surgery
Recent studies evaluated the usefulness of 18F-FET
PET in detecting residual brain tumour after surgery
[38-40].
Comparing 5-ALA fluorescence and 18F-FET PET
in detecting residual tumour after surgery, Roessler et
al. showed that residual faint 5-ALA uptake was
documented in large areas at the end of glioblastoma
resection and corresponded to tumour infiltration.
These 5-ALA positive resection plans exceeded the
18F-FET uptake areas in postoperative PET scans.
Thus, intraoperative 5-ALA residual fluorescence
seems to be a more sensitive marker than 18F-FET PET
for residual glioblastoma [38].
Otherwise Kläsner et al. demonstrated that early as-
sessment of the resection status in high-grade gliomas
with 18F-FET-PET seems to be feasible. 18F-FET PET
findings were concordant with intra-operative assess-
ment by using 5-ALA and MRI in detecting or exclud-
ing residual high-grade glioma after surgery in 72%
patients, whereas 18F-FET PET revealed discordant
findings in 28% of patients [39].
In a series of 62 patients with high-grade gliomas
postoperative 18F-FET-PET revealed residual tumour
with higher sensitivity than MRI and showed larger
tumour volumes. Performing PET >72 hours after re-
section did not influence PET results. Based on these
finding 18F-FET PET seems a helpful adjunct in addi-
tion to MRI for postoperative assessment of residual
brain tumour [40].
5.2. Differential Diagnosis Between Glioma Recur-
rence and Post-treatment Changes
Several recent studies have underlined the role of
18F-FET PET in differentiating glioma recurrence and
non-neoplastic post-treatment changes [41-46].
In a retrospective study on 124 glioma patients
compared with the diagnostic accuracy of conventional
MRI to diagnose tumour progression or recurrence
(85%), a higher diagnostic accuracy (93%) was
achieved by 18F-FET PET when a mean LBR ≥ 2.0 or
time to peak < 45 minutes was present at dynamic PET
imaging (sensitivity 93%, specificity 100%) [41].
18F-FET PET may facilitate the differential diagno-
sis between early tumour progression and pseudopro-
gression following radiochemotherapy of glioblastoma
as demonstrated by Galldiks et al. In patients with
pseudoprogression 18F-FET uptake was significantly
lower than in patients with tumour progression (maxi-
mum LBR: 1.9 ± 0.4 vs. 2.8 ± 0.5, respectively;
mean LBR: 1.8 ± 0.2 vs. 2.3 ± 0.3, respectively;
both p < 0.001). A maximum LBR cut-off value of
2.3 had 96% of accuracy in differentiating pseudopro-
gression from tumour progression [42].
18F-FET PET may also provide valuable informa-
tion in differential diagnosis between late pseudopro-
gression and true tumour progression in patients with
glioblastoma. In the study of Kebir et al. maximum
LBR and mean LBR were significantly higher in pa-
tients with tumour progression than in patients with late
pseudoprogression (maximum LBR: 2.4 ± 0.1 vs. 1.5 ±
0.2, respectively; p = 0.003; mean LBR: 2.1 ± 0.1 vs.
1.5 ± 0.2, respectively; p = 0.012). ROC analysis
yielded an optimal cut-off value of 1.9 for maximum
LBR to differentiate between true progression and late
pseudoprogression (sensitivity 84%, specificity 86%,
accuracy 85%) [43].
6 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Muoio et al.
Furthermore recently it has been demonstrated that
clustering based on textural 18F-FET PET features may
provide valuable information in assessing pseudopro-
gression in high-grade gliomas [44].
Hybrid simultaneous multiparametric 18F-FET
PET/MRI might play a significant role in the evalua-
tion of patients with suspected glioma recurrence as
described by Jena et al. Individually, maximal LBR,
mean LBR, mean apparent diffusion coefficient (AD-
Cmean), and choline-to-creatine (Cho/Cr) ratios as well
as normalized mean relative cerebral blood volume
(rCBVmean) was significant in differentiating recur-
rence from radiation necrosis, with an accuracy of
93.8% for maximum LBR, 87.5% for mean LBR,
81.3% for ADCmean, 96.9% for Cho/Cr ratio, and
90.6% for normalized rCBVmean. Furthermore, the
combination of 18F-FET PET and MRI parameters pro-
vided very high diagnostic accuracy in this setting [45].
5.3. Differential Diagnosis Between Brain Metasta-
ses Recurrence and Post-treatment Changes
18F-FET-PET is also an accurate method in differen-
tiating recurrent brain metastases from radiation necro-
sis as recently demonstrated in several studies [47-50].
In the preliminary study by Galldiks et al. both
maximum LBR and mean LBR were significantly
higher in patients with recurrent metastasis than in pa-
tients with radiation necrosis (maximum LBR: 3.2 ±
0.9 vs. 2.3 ± 0.5, respectively; p < 0.001; mean LBR:
2.1 ± 0.4 vs. 1.8 ± 0.2, respectively; p < 0.001). The
diagnostic accuracy of 18F-FET PET for the correct
identification of recurrent brain metastases reached
78% using maximum LBR with a cut-off of 2.55 (sen-
sitivity 79%, specificity 76%) and 83% using mean
LBR cut-off of 1.95 (sensitivity 74%, specificity 90%).
Diagnostic accuracy increased to 92% by using dy-
namic 18F-FET PET parameters [47].
In a second study including 62 patients LBRs were
significantly higher in recurrent metastases than in ra-
diation injuries (maximum LBR: 3.3 ± 1.0 vs. 2.2 ±
0.4, respectively; p < 0.001; mean LBR: 2.2 ± 0.4 vs.
1.7 ± 0.3, respectively; p < 0.001). The highest accu-
racy (88%) for diagnosing recurrent metastasis could
be obtained with LBRs in combination with dynamic
PET parameters [48].
Another recent study on 50 patients confirmed that
18F-FET uptake was higher in recurrent metastases
compared to radiation-induced changes (maximum
LBR: 2.9 vs. 2.0, respectively; p < 0.001; mean LBR:
2.2 vs. 1.7, respectively; p < 0.001). Optimal cut-off
values of 2.15 for maximum LBR and 1.95 for mean
LBR gave good diagnostic accuracy (sensitivity 86%,
specificity 79%). Combining LBRs and dynamic PET
parameters, sensitivity and specificity increased to 93%
and 84%, respectively [49].
Lastly, textural feature analysis at 18F-FET PET in
combination with LBRs may have the potential to in-
crease diagnostic accuracy for discrimination between
brain metastases recurrence and radiation injury, with-
out the need for dynamic 18F-FET PET scans, as re-
cently demonstrated by Lohmann et al. [50].
6. 18F-FET PET FOR DETECTING TUMOUR
PROGRESSION AND FOR TREATMENT
MONITORING AND RESPONSE ASSESSMENT
18F-FET PET using both LBRs and kinetic parame-
ters at dynamic imaging may provide valuable diagnos-
tic information for the non-invasive detection of malig-
nant progression of low-grade gliomas with higher di-
agnostic accuracy than changes of contrast enhance-
ment at MRI. Thus, repeated 18F-FET PET may be
helpful for further treatment decisions [51,52].
Treatment monitoring and response assessment in
patients with glioblastoma is difficult by using MRI
because unspecific alterations with contrast enhance-
ment can mimic tumour progression [53].
As demonstrated by the prospective study of
Galldiks et al., in contrast to gadolinium contrast-
enhancement volumes on MRI, changes in 18F-FET
uptake may be a valuable parameter to assess treatment
response in glioblastoma [54].
In recurrent high-grade glioma patients undergoing
antiangiogenic treatment, 18F-FET PET seems to be
useful to predict treatment failure and to provide im-
portant information to response assessment based
solely on MRI [55].
18F-FET PET may also be useful for therapy moni-
toring of glioma after stereotactic iodine-125
brachytherapy; in this setting post-treatment changes
can mimic tumor progression at MRI, whereas 18F-FET
PET performed 6 months after stereotactic brachyther-
apy may differentiate accurately between therapeutic
effects and local tumour progression [56].
18F-FET PET parameters seem to predict bevacizu-
mab-irinotecan treatment failure in patients with recur-
rent high-grade gliomas providing additional informa-
tion for clinical management over and above the infor-
mation obtained by MRI response assessment [57]. The
additional use of 18F-FET PET in the management of
patients with recurrent high-grade gliomas treated with
bevacizumab-irinotecan may be cost-effective. Integra-
Recent Developments of 18F-FET PET in Neuro-oncology Current Medicinal Chemistry, 2018, Vol. 25, No. 00 7
tion of 18F-FET PET has the potential to avoid over-
treatment and corresponding costs, as well as unneces-
sary side effects to the patient [58].
7. PROGNOSTIC ROLE OF 18F-FET PET IN
BRAIN TUMOURS
18F-FET PET can predict prognosis and survival in
patients with gliomas and serves as a valuable tool to
supplement the established clinical and histopathologi-
cal parameters [59].
Absence of 18F-FET uptake in newly diagnosed as-
trocytic low-grade gliomas does not generally indicate
an indolent disease course. Among the 18F-FET-
positive gliomas, decreasing TACs at dynamic 18F-FET
PET may constitute an unfavourable prognostic factor
in astrocytic low-grade gliomas [60]. Another recent
study demonstrated that dynamic 18F-FET PET might
be an important and independent prognostic marker for
patients with grade II glioma [61], whereas no correla-
tion of survival to 18F-FET uptake was observed in
low-grade gliomas in a recent study by Bette et al. [62].
Early time-to-peak at dynamic 18F-FET PET was as-
sociated with worse outcome in patients with newly
diagnosed astrocytic high-grade gliomas [63].
Static 18F-FET PET provided significant and addi-
tional prognostic information in grade III gliomas,
compared to MRI, supporting the use of both modali-
ties preoperatively to assess individual risks and esti-
mate prognosis [64].
A correlation of 18F-FET PET texture but not LBR
was shown with survival of high-grade glioma patients
[20].
Postoperative tumour volume in 18F-FET PET had a
significant independent influence on survival in pa-
tients with glioblastoma [65]. A recent prospective
study demonstrated that 18F-FET PET-derived volumes
before radiochemotherapy and TACs at dynamic 18F-
FET PET represent important prognostic markers in
glioblastoma. 18F-FET PET-derived volume before ra-
diochemotherapy is a strong prognostic factor for sur-
vival independent of the mode of surgery [66].
18F-FET uptake was described as an independent
prognostic determinant in patients with glioma referred
for radiation therapy. Higher 18F-FET uptake appears to
be associated with a worse tumour-related mortality
and a shorter duration of the disease-free interval [67].
Large BTV on 18F-FET PET was shown as independent
prognostic factor of survival in glioblastoma patients
[68].
18F-FET PET was described as a sensitive tool to
predict treatment response in patients with glioblas-
toma at an early stage after radiochemiotherapy. Early
PET responders had a significantly longer median sur-
vival [69]. In contrast to gadolinium contrast enhance-
ment volumes on MRI, changes in 18F-FET PET may
be a valuable parameter to predict survival time [54].
Furthermore 18F-FET PET uptake before re-
irradiation was revealed as independent significant pre-
dictor for survival after re-irradiation of high-grade
gliomas [70-72].
8. COMPARISON OF 18F-FET WITH OTHER
PET RADIOPHARMACEUTICALS FOR BRAIN
TUMOUR IMAGING
Several PET radiopharmaceuticals may be used in
neuro-oncology and some of them have recently been
compared with 18F-FET.
PET using 11C-methionine, a radiolabelled amino
acid tracer, has high sensitivity and specificity for im-
aging of gliomas and brain metastases. The short half-
life of 11C (20 minutes) limits the use of 11C-
methionine PET to institutions with onsite cyclotron.
18F-FET is labelled with 18F (half-life: 120 minutes)
and could be used much more broadly. Based on litera-
ture data 18F-FET PET and 11C-methionine PET pro-
vided comparable diagnostic information on gliomas
and brain metastases [73].
For brain tumour diagnosis radiolabelled choline
PET was not found superior to 18F-FET PET, in par-
ticular in nongadolinium-enhancing low-grade gliomas
[74].
18F-FET PET has shown higher sensitivity in detec-
tion of gliomas than proliferation imaging with 18F-
fluorothymidine (18F-FLT) PET [75]. In high-grade
gliomas 18F-FET PET but not 18F-FLT PET was able to
detect metabolic active tumour tissue beyond contrast
enhancing tumour on MRI. In contrast to 18F-FET,
blood-brain barrier breakdown seems to be a prerequi-
site for 18F-FLT uptake [76].
In evaluating brain tumours PET using another
amino acid tracer, 18F-fluorodihydroxyphenylalanine
(18F-FDOPA), demonstrated superior contrast ratios for
lesions outside the striatum compared to 18F-FET PET,
but 18F-FDOPA uptake values did not correlate with
grading. Compared to 18F-FDOPA, 18F-FET-PET can
provide additional information on tumour grading and
benefits from lower striatal uptake [77]. Whereas visual
analysis revealed no significant differences in uptake
pattern for 18F-FET and 18F-DOPA in patients with
8 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Muoio et al.
Fig. (1). Axial MRI (a) and 18F-FET PET (b) images in a 54 y.o. female patient with a suspicious right temporal glioma (ar-
row). 18F-FET PET shows an area of increased radiopharmaceutical uptake corresponding to the anterior portion of the cerebral
lesion and suggesting the presence of a component of high-grade glioma, as confirmed by 18F-FET PET-guided biopsy.
primary or recurrent high-grade gliomas both maxi-
mum LBR and mean LBR were significantly higher for
18F-FET PET. However, regarding tumour delineation,
both tracers performed equally well and seem equally
feasible for imaging of primary and recurrent high-
grade gliomas [78].
A recent meta-analysis demonstrated that for brain
tumour diagnosis, 18F-FET PET performed much better
than PET using the glucose analogue 18F-
fluorodeoxyglucose (18F-FDG) and 18F-FET PET
should be preferred when assessing a new isolated
brain tumour. For glioma grading, however, both trac-
ers showed similar performances [79].
GENERAL REMARKS AND CONCLUSIONS
Recommendations for the clinical use of PET in
neuro-oncology have recently been published from the
Response Assessment in Neuro-Oncology (RANO)
working group and the European Association for
Neuro-Oncology (EANO) [80].
Based on evidence-based data 18F-FET PET is an
accurate method in diagnosing brain tumours with
higher accuracy than 18F-FDG PET in this setting [81].
As stated by RANO-EANO recommendations, 18F-FET
PET provides additional diagnostic information for the
management of patients with glioma compared to stan-
dard MRI. In particular, 18F-FET PET improves the
differential diagnosis among brain tumours and and
non-neoplastic lesions and it is useful for glioma grad-
ing [80] (Fig. 1). Although 18F-FET uptake is usually
higher in high-grade compared to low-grade gliomas, a
significant overlap in uptake values may be observed
using static PET measures (maximum and mean LBR).
Kinetic analysis using dynamic 18F-FET PET signifi-
cantly improves the differential diagnosis between low-
grade and high-grade gliomas [80].
Delineation of tumour borders by using 18F-FET
PET is superior compared to standard MRI. Therefore,
it is suggested to integrate 18F-FET PET data for surgi-
cal planning to allow a better delineation of the extent
of resection. As 18F-FET PET may identify malignant
foci within non-contrast-enhancing gliomas, this
method can be used for biopsy planning of gliomas
[80]. 18F-FET PET may also improve the delineation of
a BTV beyond conventional MRI and radiation therapy
planning using 18F-FET PET appears to be feasible
[80].
18F-FET PET may be useful in evaluating treatment
response in patients with high-grade gliomas because a
decrease in 18F-FET uptake and/or volume is associated
with treatment response. Furthermore, 18F-FET PET
may improve the differential diagnosis between brain
tumours recurrence and post-treatment changes com-
pared to standard MRI (Figs. 2 and 3) [80].
About prognosis, 18F-FET uptake is associated with
outcome in high-grade gliomas both in a pretreatment
setting and following therapy [80].
Recent Developments of 18F-FET PET in Neuro-oncology Current Medicinal Chemistry, 2018, Vol. 25, No. 00 9
Fig. (2). Axial MRI (a) and 18F-FET PET (b) images in a 64 y.o. female patient treated with surgery and radiochemotherapy for
a right temporal-occipital high-grade glioma and with a contrast-enhanced area suspicious for disease relapse or radionecrosis
at MRI (arrow). 18F-FET PET shows increased radiopharmaceutical uptake corresponding to the MRI abnormality, suggesting a
disease relapse as confirmed by histology.
Fig. (3). Axial MRI (a, c) and 18F-FET PET (b, d) images in a 58 male patient with a recurrent left temporal high-grade glioma
post-radiochemotherapy, before (a-c) and after (d-f) antiangiogenic therapy. 18F-FET PET after antiangiogenic therapy shows a
new area of increasing radiopharmaceutical uptake in the left temporal lobe (arrows) compared to the pretratment PET scan,
suggesting disease progression.
10 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Muoio et al.
Unfortunately, to date, the widespread use of 18F-
FET PET is hampered by the limited availability of this
radiopharmaceutical to some countries.
Future perspectives are represented by the stan-
dardization of PET acquisition protocols and the more
widely diffusion of hybrid PET/MRI imaging tech-
nique [82,83].
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
or otherwise.
ACKNOWLEDGEMENTS
Declared none.
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