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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
S809 Mini-Review
18FDG PET inOncology
Daen de Leon M3852083August 30th 2003
14 oktober 2010
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
1 INTRODUCTION...........................................................................................................................................1
2 A BRIEF HISTORY OF PET RELATING TO 18FDG ONCOLOGY IMAGING............................................2
3 HOW PET WORKS.......................................................................................................................................5
4 ABOUT 18FDG.............................................................................................................................................6
4.1 HISTORY...............................................................................................................................................6
4.2 PRODUCTION..........................................................................................................................................7
4.3 MECHANISM OF ACTION............................................................................................................................7
5 CURRENT CLINICAL USE IN ONCOLOGY................................................................................................8
5.1 GENERAL INFORMATION AND NORMAL DISTRIBUTION........................................................................................8
5.2 INDICATIONS...........................................................................................................................................9
5.2.1 Screening.......................................................................................................................................9
5.2.2 Diagnosis of Malignancy With a Primitive Tumour..........................................................................9
5.2.3 Localisation of a Primitive Tumour When Metastasis is Discovered...............................................9
5.2.4 Initial Staging of a Known Malignant Tumour................................................................................10
5.2.5 Evaluation of Treatment Response...............................................................................................10
5.2.6 Detection of Recurrence...............................................................................................................10
5.2.7 Differentiation Between Recurrence and Scarring Post-Treatment..............................................10
5.3 USE IN IMAGING DIFFERENT CANCER TYPES...............................................................................................11
5.3.1 Breast Cancer...............................................................................................................................11
5.3.2 Colorectal Cancer.........................................................................................................................13
5.3.3 Head and Neck Cancer.................................................................................................................14
5.3.4 Lung Cancer.................................................................................................................................15
5.3.5 Lymphoma....................................................................................................................................16
5.3.6 Melanoma.....................................................................................................................................17
5.3.7 Esophageal Cancer......................................................................................................................18
5.3.8 Testicular Cancer..........................................................................................................................19
5.3.9 Other Cancer Types.....................................................................................................................19
6 ADVANTAGES AND DISADVANTAGES..................................................................................................20
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
6.1 ADVANTAGES.......................................................................................................................................20
6.1.1 Long Half-Life Compared to Other Biologically Available Radioisotopes......................................20
6.1.2 Low Toxicity..................................................................................................................................20
6.1.3 No Side Effects.............................................................................................................................20
6.1.4 High Sensitivity.............................................................................................................................20
6.1.5 Shorter Post-Examination Irradiation Period.................................................................................20
6.1.6 No Significant Sterical Changes....................................................................................................21
6.1.7 18F is Lowest Energy First-Row Positron Emitting Element.........................................................21
6.2 DISADVANTAGES...................................................................................................................................22
6.2.1 Half Life.........................................................................................................................................22
6.2.2 Radioactivity..................................................................................................................................22
6.2.3 Low Specificity..............................................................................................................................22
6.2.4 Cost & Convenience.....................................................................................................................22
6.2.5 Lowered Sensitivity in Diabetics....................................................................................................22
7 COMPLEMENTARY TECHNIQUES...........................................................................................................23
7.1 COMBINED / CO-REGISTERED PET/CT......................................................................................................24
7.2 CO-REGISTERED PET/MRI....................................................................................................................25
7.3 11C METHIONINE.................................................................................................................................25
8 ALTERNATIVES.........................................................................................................................................26
8.1 ALTERNATIVE IMAGING MODALITIES............................................................................................................27
8.1.1 CT.................................................................................................................................................27
8.1.2 MRI...............................................................................................................................................28
8.1.3 SPECT..........................................................................................................................................28
8.1.4 Mammography/scintimammography.............................................................................................29
8.2 ALTERNATIVE RADIOTRACERS...................................................................................................................30
8.2.1 Non 18F-labeled Radiotraces.......................................................................................................30
8.2.1.1 Tc99m tetrofosmin...................................................................................................................................30
8.2.1.2 11C methionine, 11C thymidine, 11C tyrosine........................................................................................30
8.2.2 18F-labelled Radiotracers.............................................................................................................31
8.2.2.1 18F fluorinated thymidine (FLT)...............................................................................................................31
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
8.2.2.2 3-O-methyl-6-[18F]fluoro-L-DOPA...........................................................................................................31
8.2.2.3 O-(3-[18F]fluoropropyl)-L-tyrosine (18FPT).............................................................................................31
8.2.2.4 5-[18F]fluorouracil....................................................................................................................................32
8.2.2.5 Other 18F Labeled Radiotracers.............................................................................................................33
9 FUTURE DEVELOPMENTS.......................................................................................................................34
10 CONCLUSION..........................................................................................................................................35
A. FIGURE AND TABLE LIST.......................................................................................................................36
B. REFERENCES..........................................................................................................................................37
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
2 A Brief History of PET Relating To 18FDG Oncology Imaging
Date Event
1859 Roentgen accidentally discovers X-rays
1896 Becquerel discovers natural radiation of uranium
1911 Hevesey uses radioactive lead as a radiotracer in foodstuff
1923 Hevesey shows the distribution of radioactive lead in growing bean plants
1924 Warburg wonders how to differentiate tumour cells from healthy cells, and
subsequently finds the answer lies with glucose and glycolysis
1931 Lawrence invents the cyclotron
1934 The Joliot-Curies produce the first artificial radioisotopes
1935 Lawrence produces radioactive isotopes of sodium and over the next few years
produces another 17 biologically useful radioisotopes
1939 Hamilton uses 131I for diagnostic purposes in patients
1942 First nuclear reactor constructed and operated at Oak Ridge Nuclear Lab(ORNL)
1946 Radioisotopes produced from reactor at ORNL become available for research
1951 Cassen at UCLA invents scintiscanner for measuring radioiodine in the body.
In the same year, Brownell and Sweet at Massachusetts General Hospital(MGH) develop a brain scanner for detecting brain tumours
1958 Anger invents the eponymous camera which permits visualisation of radiotracer distribution in biological systems
1960s Kuhl and Edwards develop image reconstruction techniques for single photontomography
1973-75 Phelps and Hoffman develop Positron Emission [Transaxial] Tomography(PE[T]T)
1976-80 18FDG synthesised by Wolf and Fowler at Brookhaven National Laboratory (BNL)
1977-78 BGO scintillator developed (investigated by Cho and Farukhi, and Derenzo –
tomography using BGO made by Thompson at Montreal Neurological Institute)
1980s Several researchers study tumour uptake of
18
FDG (eg Di Chiro)1984-86 First PET medical cyclotron and automated chemistry – commercial production
of 18FDG
1984-85 Development of “Block” scintillation detector
1990-2001 Development of LSO for use in scintillators
1991 18FDG PET in whole body oncology imaging by Dahlbohm, Hoffman and Phelps
1997-1998 18FDG approved as radiopharmaceutical by Food and Drug Administration (FDA)
Table 1 : Significant events in the history of 18FDG PET
(from Warburg 1924, Toyokuni 1998, Brownell 1999, Nutt 1999)
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The first clinical positron imaging device from the 1950s, although clinically useful, suffered from
very low resolution (Brownell 1999), see Figure 1.
Figure 1 : Coincidence and ”unbalance” scans from the first clinical positronimaging detector (from Brownell and Sweet 1953)
The technology of positron detectors improved rapidly, producing a string of viable devices. The
first computed tomographic imaging device (PC I) was developed between 1968 and 1971.
Filtered back projection algorithms were developed between 1970 and 1972, and the images thus
produced were first called ”PET” at that time. In1976 the first commercial PET scanner, the ECAT
II, designed by EC&G ORTEC, was in operation at UCLA (Nutt 1999).
Figure 2 : The first commercial PET scanner at UCLA in 1976 (From Nutt 1999 figure 9)
Development of ring and cylinder detectors and associated advances in PET detector electronics
and computer assisted image acquisition and interpretation have continued over the last 25 years.
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
Todays detector assemblies contain tens of thousands of detector elements of high sensitivity LSO,
controlled by multi gigahertz processor technologies.
Figure 3 : A modern LSO-based detector PET scanner : Siemens ECAT ACCEL PET system(from Siemens website)
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3 How PET Works
PET relies on Einstein’s famous equation e = mc
2
(Einstein 1905) where a positron (an anti-electron, see Anderson 1932) and an electron totally annihilate each other to produce two
coincident 511 keV gamma rays (see Figure 4).
Figure 4 : The basic principle of PET. The unstable nucleus decays by emission of a positron (a positivelycharged electron, β+) which interacts with an adjacent electron (β-) to emit two orthogonal gamma rays (γ) at
511 keV. It is these coincident gamma rays that are detected by the PET camera (from Price 2001, fig 2)
The precise energy and coincident nature of these two gamma rays means their origin can be
computed when they are detected by a ring of detectors. The small difference between their arrival
times used to calculate the offset within the enclosed slice of the detector array (see Figure 5).
Figure 5 : Detection of annihilation radiation. 18FDG is injected into the patient, where it decays by positronemission, which produce two gamma rays at 180 o to each other. These are detected by a ring of detectors
placed around the part of the body to be observed. By measuring the time of detection of the gamma rays, theposition of the annihilation event and hence location in the body slice can be computed (from Price 2001, fig 3)
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
4 About 18FDG
Original PET images were obtained using
11
C-glucose,
15
O water and
13
N ammonia, but withhalflives of less than 20 minutes, these radioisotopes must be produced and used very quickly.
18FDG was suggested as a viable radiotracer after the success of 14C-deoxyglucose studies. Here its
history is briefly described along with how it is produced.
4.1 History
Figure 6 : The structure of 18F-2-Deoxy-2-fluoro-D-glucose (or fluorodeoxyglucose, or 18FDG)
18FDG was originally developed in the1970’s by Brookhaven National Laboratory (BNL), the
University of Pennsylvania and the National Institutes of Health as a radiotracer for imaging brain
function in the living human being, made possible due to the great glucose requirement of active
brain cells (Ido et al 1977, Gallagher 1977). Other researchers at BNL, bearing in mind Warburg’s
1924 findings, investigated18
FDG uptake in tumour cells in the 1980s and found a tumour-to-
normal tissue ratio of 2.10 – 9.5 of 18FDG (Som et al 1980).
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
4.2 Production
The radioactive 18F is produced in a cyclotron and is converted into an aqueous medium. Mannose
triflate, a glucose precursor, is used to carry out a nucleophilic substitution with the radioactive
fluoride and after purification steps 18FDG is obtained in an isotonic medium, in injectable form
(Bomanji et al 2001). It has a halflife of 110 minutes so in practice, this is just long enough for it
to be shipped from a hospital-based cyclotron facility to the imaging facility.
4.3 Mechanism of Action
Figure 7 : Pharmacokinetics of 18FDG in vivo : K 1, k 2, k 3 and k 4 are rate constants.(From Young 1999 figure 1)
18FDG, being a glucose analogue, is taken into tissues from the bloodstream by the same
mechanism as glucose. 18FDG is transported and fixed as 18F-FDG-6-phosphate by hexokinase,
and, as this product is not a substrate for the same enzymatically driven pathways as glucose and
the uncatalysed dephosphorylation rate is low, it is effectively “trapped” (Young 1999). These high
concentrations of bound radioactive fluorine will lead to a high emission of gamma rays as it
decays, which can be detected as “hotspots” by a PET scanner.
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
5 Current Clinical Use in Oncology
18
FDG has found many uses in oncology imaging. This section begins by briefly describing patient preparation, and the normal distribution of 18FDG throughout a healthy body before looking at
18FDG in oncology imaging, both in terms of techniques, types of cancer and in oncology staging,
investigation, assessment and other indications.
5.1 General Information and Normal Distribution
In clinical oncology usage, the patient is required to fast for a few hours in order to lower serum
glucose levels so that 18FDG uptake can be measured once injected. Imaging begins after 60-90
minutes, although the exact choice of post-injection imaging varies widely and it is conceded that
true optimisation remains a complex issue (Thie 2002).
Figure 8 : Coronal whole-body tomograms showing normal distribution of 18FDG in the body. Intense uptakein the brain and myocardium, normal activity in liver, spleen and bone marrow, and excretion of tracer in
urinogenitary system. From Bomanji (2001) figure 2.
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
5.2 Indications
18FDG PET has many indications in clinical oncology, although there are some for which it is not
suitable.
5.2.1 Screening
18FDG PET is not so useful for systematic oncology screening due to cost and time considerations.
(Talbot et al 2003, Jerusalem et al 2003).
5.2.2 Diagnosis of Malignancy With a Primitive Tumour
18FDG PET is potentially useful in detecting malignancy in primitive tumours, but currently
restricted to high prevalence cancers with otherwise unsatisfactory diagnostic techniques such as
isolated pulmonary nodules (Comber et al 2003) and pancreatic cancers. It can also indicate
whether a tumour which appears necrotic with anatomical imaging modalities is, in fact,
metabolically active. (Talbot et al 2003). It appears not to work well in evaluating pancreatic
masses (Jerusalem et al 2003).
5.2.3 Localisation of a Primitive Tumour When Metastasis is Discovered
18FDG PET can highlight tumour sites (including unknown primary tumour sites in a significant
proportion of patients – see Lonneux and Reffad 2000 and Lassen et al 1999), but cannot
differentiate between primitive and metastatic tissue.
Some tumours, poorly differentiated or aggressive ones, take up more glucose than better
differentiated ones, such as differentiated thyroid neoplasms or neuroendocrine tumours, or
tumours with a low growth rate, such as cancer of the prostrate or kidney. These are often missed
by 18FDG PET. (Talbot et al 2003)
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
5.2.4 Initial Staging of a Known Malignant Tumour
This is a major indication of 18FDG PET, especially in non-small cell lung cancer (NSLC)
(Jerusalem et al 2003). Many surgeons do not operate for malignant pulmonary masses without
first having a PET scan performed. PET has been repeatedly shown to outperform CT in the
detection of regional metastases, and it is also very efficient at detecting remote metastatic sites
through the use of whole-body imaging (Lassen etc al 1999). It has been shown that PET provides
information of similar accuracy as a whole body technique than a whole battery of other invasive
and non-invasive tests together (Czernin 2002).
5.2.5 Evaluation of Treatment Response
18FDG uptake by malignant tissue decreases or disappears after a few cycles of treatment, even
before a reduction in tumour size can be measured. Conversely, continuing 18FDG uptake is
symptomatic of the failure of a tumour to respond to therapy. (Talbot et al 2003)
5.2.6 Detection of Recurrence
18FDG PET is often used to detect recurrence. If recurrence is found, then 18FDG PET also
provides information as to which part of the mass is metabolically active. (Talbot et al 2003)
5.2.7 Differentiation Between Recurrence and Scarring Post-Treatment
18FDG has been used for this purpose in lymphomas, head and neck cancers, lung cancer, colorectal
cancers and sarcomas. (Talbot et al 2003)
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
5.3 Use in Imaging Different Cancer Types
5.3.1 Breast Cancer
18FDG PET has been used in breast cancer for many years in investigating recurrence and
metastatic sites (Bomanji et al 2001). Indeed, 18FDG is the only approved PET radiotracer right
now (Zheng et al 2003). It has also been used to resolve unknown primary tumours and is well
suited to imaging dense breasts (Czernin 2001).
Figure 9 : Whole-body 18FDG PET identified a primary tumour (marked with an arrow).(from Czernin 2001figure 2)
Czernin (2001) and Eary (1999) indicate that it is good at determining axillary lymph node staging,
wheras Bomanji et al (2001) dispute this.
Figure 10 : 18FDG uptake in right-sided ductal carcinoma (marked with an arrow) with no axillary lymph nodeinvolvement (from Czernin 2001 figure 1)
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
Czernin further indiates 18FDG PET for addressing internal mammary node involvement. Czernin
(2001) also reports that 18FDG PET in detecting metastatic sites in breast cancer has been measured
as having sensitivity and specificity of 93% and 78% respectively, and has had reports of 100%
accuracy, superior to all other imaging modalities combined. However, PET’s resolution is limited
to detecting lesions above 8-10mm and sentinel lymph node biopsy remains superior in this regard
(Jerusalem et al 2003).
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5.3.2 Colorectal Cancer
18FDG PET has been used to differentiate recurrent tumours from scar tissue (Jerusalem et al 2003).
18FDG PET wins over CT in that CT is often not able to distinguish between soft tissue and tumour,
in recurrence scans. One study put 18FDG PET’s sensitivity, specificity and accuracy at 95, 90 and
96% over 192 patients (Coleman 1998).
Figure 11 : 18FDG PET image of liver metastasis in patient with history of colon cancer, previously missed byspiral CT but indicated by ultrasound (from Jerusalem et al 2003 figure 2)
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Daen de Leon S809 Mini-Review :18 FDG PET in Oncology M3852083
5.3.3 Head and Neck Cancer
It can be seen from Figure 12 that PET has better sensitivity and specificity for detecting recurrent
or residual head and neck tumours after chemo- or radiotherapy. (Klabbers et al 2003).
Figure 12 : Sensitivity vs specificity for CT/MRI vs PET in head and neck cancer response treatment (fromKlabbers et al 2003 figure 1)
FDG PET has also been shown to be more sensitive in detecting primary head and neck or involved
lymph nodes than CT or MRI. (Coleman 1998)
Figure 13 : Coronal (left) and sagittal (right) images of patient with primary tumour at base of tongue (markedby crosshairs) (from Lassen et al 1999 figure 2b)
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5.3.4 Lung Cancer
18FDG PET has some value in NSCLC, but that it cannot replace preoperative (invasive) surgical
staging due to its inability to detect microscopic structures (Jerusalem et al 2003).
Figure 14 : Squamous cell carcinoma of right lobe and right paratracheal adenopathy(from Vansteenkiste 2003 figure 4)
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5.3.5 Lymphoma
18FDG PET is the best end-of-treatment evaluation procedure for lymphoma patients, with better
results in both positive (100% vs 42%) and comparable negative (83% vs 87%) predictive values
against CT (Jerusalem et al 2003). A negative result from a 18FDG PET scan may well negate the
need for further chemo- and radiotherapy treatments (Maisey et al 2000)
Figure 15 : Transaxial 18FDG image showing increased pancreatic uptake consistent with lymphomatousinvolvement (from Delbeke et al 2002 figure 2)
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5.3.6 Melanoma
18FDG PET is very sensitive at detecting metastatic disease in melanoma patients (Jerusalem et al
2003). Sensitivity has been reported as 92% and specificity as 77% without clinical information,
rising to 100% with clinical information (eg biopsy site locations) (Coleman 1998).
Figure 16 : High risk melanoma patient suffering from lung metastasis (coronal left and transaxial right)(From Jerusalem et al 2003 figure 3)
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5.3.7 Esophageal Cancer
FDG PET has been shown to be of value in staging esophageal cancer, in that it improves the
ability to classify patients as having either resectable or unresectable disease, thus determing
selection of patients for operation. It also identifies metastases missed by CT, or those which are
more amenable to biopsy than those shown by CT. (Block et al 1997)
Figure 17 : Primary tumour and myocardial (large arrows) and metastatic (small arrows) uptake of 18FDG in
esophageal cancer patient (from Block et al 1997 figure 1)
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5.3.8 Testicular Cancer
FDG PET has been shown to improve the staging of testicular cancer (Cremerius et al 1999) but
with some reservations on the limiting resolution, as with CT.
Figure 18 : Coronal scans of a patient with suspected testicular cancer showing increased uptake in multiplelymph nodes and testis (from Cremerius et al 1999 figure 1)
5.3.9 Other Cancer Types
Musculoskeletal, ovarian, pancreatic and thyroid cancers have all been imaged with varying
degrees of clinical usefulness by FDG PET. (Conti et al 1996, Coleman 1998)
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6 Advantages and Disadvantages
In considering advantages, I consider those which are specific to
18
FDG (although some pertainother 18F radiotracers) and not to PET in general.
6.1 Advantages
6.1.1 Long Half-Life Compared to Other Biologically Available Radioisotopes
Witth a half-life of 110 minutes, compare dto 11C of 20 minutes and 15O of 2 minutes, 18F
compounds offer far more practical usage in PET. (Varognolo et al 2000)
6.1.2 Low Toxicity
18FDG has low toxicity with toxicity studies showing no adverse affects in animals at 3,000 the
human dose (Som et al 1980).
6.1.3 No Side Effects
No side effects are known. 18FDG does not cause drowsiness, and patients may drive a car after
examinations (assuming they could drive one beforehand) (Talbot et al 2003).
6.1.4 High Sensitivity
The tumour-to-normal tissue ratio of 18FDG has been measured as 2.10 – 9.5 (Som et al 1980)
6.1.5 Shorter Post-Examination Irradiation Period
Patients remain slightly radioactive after examination, but this is for a shorter period than with, for
example, a classical bone scintigraphy. (Talbot et al 2003)
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6.1.6 No Significant Sterical Changes
Introducing a fluorine atom for a hydrogen (H) or alcohol (OH) in metabolic substrates causes no
significant sterical changes, although it may cause changes in biological behaviour due to
differences in physiochemical properties (Varognolo et al 2000). Indeed, this is what we see with
18FDG – it’s uptake is more or less through the same pathways as glucose, but once phosphorylated
by hexokinase, it is not a substrate for the phosphoglucose isomerase enzyme driven glycolysis
pathway (McMurry 1998).
6.1.7 18F is Lowest Energy First-Row Positron Emitting Element
This means that, potentially, imaging can be performed at high resolutions. (Varognolo et al 2000)
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6.2 Disadvantages
6.2.1 Half Life
The 110 minute half life of 18F means that preparation, preparation and imaging must be done
swiftly.
6.2.2 Radioactivity
18F is a radioactive substance, and hence is subject to regulated usage, although studies suggest that
18FDG PET does not present a greater risk than conventional imaging modalities. (White et al 2000)
6.2.3 Low Specificity
Glycolysis is a universal process throughout the body, especially in the brain, tumours and areas of
inflammation which means that 18FDG PET is susceptible to false positives results. (Talbot et al
2003)
6.2.4 Cost & Convenience
The cyclotron facilities required for 18FDG PET are expensive, and not all medical facilities can
afford them. Those that do not possess a cyclotron need to be located near such a facility so that
the 18FDG has not travelled too long and hence “decayed” too much before it is used. Some effort
has been invested in the USA into tackling the logistics of this by arranging the building of
cyclotron facilities at near equidistant points from PET imaging clinics (Varognolo et al 2000)
6.2.5 Lowered Sensitivity in Diabetics
Diabetics have a reduced sensitivity to 18FDG. (Talbot 2003)
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7 Complementary Techniques
One of the most interesting recent developments in
18
FDG imaging is the ability to generate co-registered images with CT. This allows anatomic and metabolic information to be superimposed,
allowing the images of gross anatomic structure of CT to guide the radiologist to sites of metabolic,
molceular pathway or molecular target/receptor interest.
Figure 19 : The spectrum of medical imaging (from Price 2001 figure 1)
Another complementary technique is the use of 11C methionine, a radiocarbon labeled amino acid.
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7.1 Combined / Co-registered PET/CT
This technique has progressed rapidly in the last few years with combined PET/CT scanners now
being commercially available from companies such as Siemens.
Figure 20 : Siemens biograph combined PET/CT scanner (from Siemens 2003)
The advantage of combined CT and 18FDG PET images is the ability to take the high resolution
anatomically detailed images of CT and use the metabolically useful images of 18FDG PET to
resolve questions about malignancy, determine primary tumour sites or indicate the metabolic state
of a post-operative mass. Co-registered PET/CT images were generated for some time by separate
imaging procedures, but scanners such as Siemens’ biograph allow both procedures to take place in
one session, which provides a much more accurate image set. Co-registered images are shown to
have higher diagnostic value than either imaging modality alone (Kluetz et al 2000, Wahl 2003).
Figure 21 : CT (left), 18FDG PET (middle) and co-registered images (right) (from Siemens biograph brochure)
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7.2 Co-registered PET/MRI
Although this technique seems to be less common, I found mention of it in Coleman (1998) in
reference to image interpretation of 18FDG PET scans.
7.3 11C Methionine
11C methionine is often used instead of 18FDG (see Section 8.2.1.2 for full details). However, their
diagnostic imaging characteristics are complementary (Vu and Fischman 2000).
Figure 22 : 18FDG (top), 11C methionine (middle) and fused (bottom) PET images of a cerebral tumour. Thelower uptake of 11C methionine in gray and white matter leads to a clearer indication of metabolic activity in
the middle set of images (from Vu and Fischmann 2000)
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8 Alternatives
A number of alternatives exists to
18
FDG PET, including CT, MRI, PET using other radiotracersand 18FDG SPECT. Many other 18F labeled radiotracers are being investigated, with a twofold
purpose : 1) to find a radiotracer that is not taken up so readily as 18FDG is by other tissues with
high glucose requirements such as gray and white matter, myocardial tissue and inflammation ; and
2) to find a radiotracer with a higher preferential uptake by tumour cells. In this section I review
these alternatives to 18FDG PET from a variety of extant literature.
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8.1 Alternative Imaging Modalities
With PET being a relatively new imaging modality in general, and 18FDG PET being especially
new in particular, a number of more established imaging modalities are often used to generate
images in all aspects of cancer management.
8.1.1 CT
CT has for many years been used in all aspects of cancer management. However, 18FDG PET
seems to be challenging CT in many areas. It has been shown that 18FDG PET’s ability to separate
high and low grade brain tumours by their glucose utilization led to more accurate grading than
with CT. Likewise, 18FDG PET can distinguish benign from malignant abnormalities in the lung,
head and neck. 18FDG PET scores over CT in that it can be useful in staging and evaluating
response to therapy bronchogenic carcinoma, in distinguishing tumour from other soft tissue in the
colon and rectum and in detecting lesions in lymph nodes. (Coleman 1998).
Similar conclusions have been made from studies of esophageal cancer (Block et al 1997) and, with
certain caveats on limits of resolution, in testicular cancer (Cremerius et al 1999). Techniques such
as Quantitative Contrast-enhanced CT (QECT) may have some benefits in assessing solitary
pulmonary nodules, but this is dependent upon local prevalence of malignancy and FDG-
PET/surgery costs (Comber et al 2003)
Most authors conclude that 18FDG PET will increasingly be used with CT rather than instead of it,
for the reasons mentioned in Section 7.1.
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8.1.2 MRI
MRI is often used in preference to CT due to its superior soft tissue contrast which can improve
tumour localisation and nodal staging. However, compared to 18FDG PET, it suffers from many of
the same issues as does CT. Many post surgical gross anatomical changes induce contrast
enhancement which cannot be distinguished from tumour persistence. Only metabolic images can
determine whether post-operatives masses are tumour remnants or scar tissue, and if they are
tumour remnants, which parts are still metabolically active. It seems that co-registration of 18FDG
PET and MRI images is a relatively common diagnostic imaging procedure (eg Coleman 1998,
Lawson et al 2000), but for some reason there do not seem to be much movement towards
combined PET/MRI scanners as there has been for PET/CT. SPECT and MRI co-registered
images seem to be more common co-imaging techniques (Maria et al 1998).
8.1.3 SPECT
18FDG SPECT has been investigated for use in breast cancer imaging for tumours > 2cm.
(Ivancevic et al 2000). However, studies of childhood brain tumours of 18FDG vs 201thallium
chloride SPECT indicate that 18FDG SPECT images couldn’t beinterpreted without MRI co-
registered images to assist (Maria et al 1998) as SPECT does not offer full tomographic images,
being a planar technique. 18FDG SPECT does have the advantage of being able to use existing
gamma cameras with some modifications (eg addition of a collimator). There is a reduction in
sensitivity also, as gamma camera detectors are typically optimised to scintillate to lower energy
photons than gamma rays, and there are a smaller number of them compared to a PET ring
detector. (Lamonica et al 1999)
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8.1.4 Mammography/scintimammography
These techniques are conventionally used in detection of breast tumours. Conventional
mammography presents sub-mm resolution and excellent contrast, and is used in screening,
whereas scintimammography is typically used in staging and detection of primary and recurrent
tumours. However, techniques are being developed for both SPECT and PET to minimise the
distance between the camera detector and the tumour in the breast, as has been done in
mammography. (Palmedo et al 2002).
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8.2 Alternative Radiotracers
There has been much recent research into investigating other viable radiotracers, especially to
overcome 18FDG’s lack of specificity.
8.2.1 Non 18F-labeled Radiotraces
Several non 18F radiotracers are known.
8.2.1.1 Tc99m tetrofosmin
This is a relatively new radiotracer used in SPECT imaging of breast, lung and thyroid cancer
(Ivancevic et al 2000). It is a liphophilic cationic compound which is passively moved across cell
membranes. However, in tumour cells with overexpression of multi-drug resistance protein (MDR)
its uptake is limited, in much the same was a cisplatin is actively restricted from entering the same
types of cell.
8.2.1.2 11C methionine, 11C thymidine, 11C tyrosine
11C methionine (MET) offers a more specific radiotracer than 18FDG for amino acid metabolism in
brain tumours and is less influenced by inflammation, but is unfortunately limited by the 20 minute
half life of 11C (Jerusalem et al 2003). MET can also be used to determine tumour response to
treatment (Eary 1999). MET uptake has been found to correlate with tumour proliferation and
response to radiotherapy (although the latter only with limited relevance) (Klabbers et al 2003).11C thymidine (THY) and 11C tyrosine (TYR) are being investigated in ongoing studies of tumour
expression (Bomanji et al). They can also be used for tumour grading, and also for measuring
response to treatment (Eary 1999). However, Klabbers et al (2003) reports that there was no
relationship between TYR and tumour proliferation. For THY, results indicate that uptake may
decline more rapidly that 18FDG retention after successful therapy although the fast metabolism and
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plasma clearance, coupled with formation of metabolites such as 11CO2 make it difficult to monitor
the signal (Klabbers et al 2003).
8.2.2 18F-labelled Radiotracers
A number of promising 18F labeled radiotracers are being developed which are proving to be more
specific for tumour uptake than 18FDG.
8.2.2.1 18F fluorinated thymidine (FLT)
Attempts to create this 18F labeled analogue of thymidine appear to be more successful than the
11C labeled version due to more favourable metabolite patterns. Phosphorylated FLT seems to
accumulate instead of being incorporated into DNA as thymidine monophosphate is (Klabbers et al
2003).
8.2.2.2 3-O-methyl-6-[18F]fluoro-L-DOPA
Recent investigation (Bergmann et al 2003) has found this to be an effective tracer for tumour
tissue.
8.2.2.3 O-(3-[18F]fluoropropyl)-L-tyrosine (18FPT)
Figure 23 : The structure of 18FPT (from Tang et al 2003 figure 1)
Tang et al (2003) have found this amino acid tracer to be more selective for tumour tissue than
18FDG – almost the same tumour-to-muscle ratio as 18FDG in tumour bearing mice, but a seven-
fold lower ratio of infected tissue-to-blood in mice with infected tissue. However, there was a
twofold lower ratio of tumour-to-blood takeup in 18FPT injected mice than those injected with
18FDG, so overall specificity seems to have been improved at the expense of sensitivity.
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8.2.2.4 5-[18F]fluorouracil
Figure 24 : The structure of [18F]fluorouracil (from Varagnolo et al 2000 figure 10)
5-[18F]fluorouracil is a chemically identical form of 5-fluorouracil, which is a conventional
chemotherapeutic treatment for liver metastases in colorectal cancer treatment. (Varagnolo 2000)
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8.2.2.5 Other 18F Labeled Radiotracers
Figure 25 : The structure of [18F]α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol(from Varagnolo et al 2000 figure 1)
Varognolo et al (2000) have reported on a large number of 18F labeled radiopharmaceuticals
including:
• proteins and peptides – eg N-succinimydyl 4-([18F]fluoromethyl)-benzene
• σ receptor binders – eg [18F]α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-
piperazine-butanol. σ receptors are present in larger numbers on certain tumours of the
colon, lung, brain, breast and kidney, and on malignant melanoma cells.
• hypoxic cell binding agents – eg [18F]fluoromisonidazole (also reported in Eary 1999)
• tissue-specific tumour imaging agents – eg 3’-deoxy-3’-[18F]fluorothymidine (18FLT),
which is incorporated into newly synthesized DNA
• radiolabelled monoclonal antibodies for use in melanoma imaging
• radiolabelled amino acids for imaging brain tumours – eg L-[2-
18F]fluorophenylalanine and L-[3-18F]α-methyltyrosine (18FMT)
• radiolabelled estrogen and progesterone for imaging breast cancer – eg [18F]fluoro-17β-
estradiol
• radiolabelled androgens for imaging prostate cancer – eg 11β-[18F]fluoro-5α-
dihydrotestosterone (18F-DHT)
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9 Future Developments
There are many possible future uses for 18FDG PET. Some of these include:• Phase I/II assays for selecting new anti-cancer drugs (Talbot 2001, Gupta et al 2002)
• Expanded use in tumour biology (Eary 1999)
• In vivoimaging of pharmacodynamic endpoints (Price 2001)
• In vivoimaging of pharmacokinetics of drugs (Price 2001).
• In vivo determination of mechanism of action (Price 2001).
• In vivo imaging of molecular pathways and mechanisms (Price 2001).
• In vivoimaging of gene expression and gene therapy (Price 2001).
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A. Figure and Table List
Cover From Brookhaven National Laboratory website (http://www.bnl.gov/pet/FDG.htm)Figure 1 From Brownell (1999), figure 2Figure 2 From Nutt (1999), figure 9.Figure 3 From Siemens’ website (www.siemens.com)Figure 4 From Price (2001), figure 2Figure 5 From Price (2001), figure 3Figure 6 From Crump InstituteWebsite, UCLA (http://www.crump.ucla.edu:8801/NM-
Mediabook/tracers/fdg.html)Figure 7 From Young (1999) figure 1Figure 8 From Bomanji et al (2001) figure 2Figure 9 From Czernin (2001) figure 2
Figure 10 From Czernin (2001) figure 1Figure 11 From Jerusalem et al (2003) figure 2Figure 12 From Klabbers et al (2003) figure 1Figure 13 From Lassen et al (1999) figure 2bFigure 14 From Vansteenkiste (2003) figure 4Figure 15 From Delbeke et al (2002) figure 2Figure 16 From Jerusalem et al (2003) figure 3Figure 17 From Block et al (1997) figure 1Figure 18 From Cremerius et al (1999) figure 1Figure 19 From Price (2001) figure 1Figure 20 From Siemens’ website (www.siemens.com)Figure 21 From Siemens’ website (www.siemens.com)Figure 22 From Vu and Fischmann (2000)Figure 23 From Tang et al(2003) figure 1Figure 24 From Varagnolo et al (2000) figure 10Figure 25 From Varagnolo et al (2000) figure 1
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Thanks to Johanne (again!) for her patience and support during the last 8 months – Love Daen