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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




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

Page i of iii 14 oktober 2010




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

Page ii of iii 14 oktober 2010




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

Page iii of iii 14 oktober 2010




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)

Page 2 of 40 14 oktober 2010




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.





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)





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)





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).





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.





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.





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)





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)





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)





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).





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)





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)





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)





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)





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)





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)





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)





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)





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)





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)





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.





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)





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)





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.





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.





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)





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).





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





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.





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)





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)





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).





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


http://www.bnl.gov/pet/FDG.htm

http://www.siemens.com/

http://www.crump.ucla.edu:8801/NM-Mediabook/tracers/fdg.html




http://www.bnl.gov/pet/FDG.htm









B.References

Anderson, Carl D. "The Apparent Existence of Easily Deflectable Positives." Science 76, 238(September 9, 1932).

Mark I. Block, G. Alexander Patterson, R. Sudhir Sundaresan, Marci S. Bailey, Fidelma L.Flanagan, Farrokh Dehdashti, Barry A. Siegel, and Joel D. Cooper, Improvement in Staging of Esophageal Cancer With the Addition of Positron Emission Tomography, Ann Thorac Surg1997;64:770 –7

Bomanji JB, Costa DC, Ell, ”Clinical role of positron emission tomography in oncology”, TheLancet Oncology March 2001, 2:157-164

Brownell, G.L., W.H. Sweet, ”Localization of brain tumors with positron emitters", Nucleonics1953, 11:40-45.

Brownell G.L. ”A History of Positron Imaging”, Presentation to Massachusetts General Hospital onauthor’s 50th anniversary, October 15th 1999

Coleman RE, Clinical PET in Oncology, Clinical Positron Imaging Vol. 1, No. 1, 15–30. 1998

Comber LA, Keith CJ,Griffiths M, Miles KA, Solitary Pulmonary Nodules: Impact of QuantitativeContrast-enhanced CT on the Cost-effectiveness of FDG-PET, Clinical Radiology (2003) 58: 706– 711

Peter S. Conti, David L. Lilien, Kimberly Hawley, Jennifer Keppler, Scott T. Grafton and James R.Bading, PET and [18F]-FDG in Oncology: A Clinical Update, Nuclear Medicine and Biology,Volume 23, Issue 6, August 1996, Pages 717-735

Cremerius U,Wildberger JE, Borchers H, Zimny M, Jakse G, Günther RW and Buell U, Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer? Results of a study in 50 patients. Urology. 1999;54:900-904.

Czernin J, FDG-PET in Breast Cancer: A Different View of its Clinical Usefulness, Molecular Imaging and Biology Vol. 4, No. 1, 35–45. 2002

Dominique Delbeke,William H. Martin, David S. Morgan, Marsha C. Kinney, Irene Feurer, EricKovalsky, Ted Arrowsmith, John P. Greer, 2-Deoxy-2-[F-18]Fluoro-D-Glucose Imaging withPositron Emission Tomography for Initial Staging of Hodgkin’s Disease and Lymphoma,Molecular Imaging and Biology Vol. 4, No. 1, 105–114. 2002

Janet F Eary, Nuclear medicine in cancer diagnosis, Lancet 1999; 354: 853-57

Einstein A, On Electrodynamics of moving bodies or Zur Electrodynamik bewegter Korper,Annalen der Physik, 17, 891-921 1905

BM Gallagher, A Ansari, H Atkins, V Casella, DR Christman, JS Fowler, T Ido, RR MacGregor, PSom, C-N Wan, AP Wolf, DE Kuhl, M Reivich (1977). Radiopharmaceuticals XXVII: 18F-labeled 2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring regional myocardial





glucose metabolism in vivo: tissue distribution and imaging studies in animals. J Nucl Med 18:990-996, 1977.

N. Gupta, P.M. Price, E.O. Aboagye, PET for in vivo pharmacokinetic and pharmacodynamic

measurements, European Journal of Cancer 38 (2002) 2094–2107

T Ido, C-N Wan, V Casella, JS Fowler, AP Wolf, M Reivich and D Kuhl (1978). Labeled 2-deoxy-D-glucose analogs. F-18 labeled 2-deoxy-2-fluoro-D-glucose, 2-deoxy-2-fluoro-D-mannose and C-14 2-deoxy-2-fluoro-D-glucose. J Labeled Compounds and Radiopharm. 14: 175-184, 1978.

Velimir Ivancevic, Andreas Wolter, Klaus-Jürgen Winzer, Hans-Ulrich Aldinger, Joachim M.Müller, Dieter L. Munz, Intraindividual Comparison of F-18-Fluorodeoxyglucose and Tc-99m-Tetrofosmin in Planar Scintimammography and SPECT, Clinical Positron Imaging Vol. 3, No. 1,17–29. 2000

G. Jerusalem, R. Hustinx, Y. Beguin, G. Fillet, PET scan imaging in oncology, European Journalof Cancer 39 (2003) 1525–1534

Bianca M. Klabbers, Adriaan A. Lammertsma, Ben J. Slotman, The Value of Positron EmissionTomography for Monitoring Response to Radiotherapy in Head and Neck Cancer, Molecular Imaging and Biology Vol. 5, No. 4, 257–270. 2003

Kluetz PG, Meltzer CC, Villemagne VL, Kinahan PE, Chander S, Martinelli MA, Townsend DW.Combined PET/CT Imaging in Oncology. Impact on Patient Management. Clin Positron Imaging.2000 Nov;3(6):223-230.

Lamonica D, Grossman Z, Klippenstein D, Wang H, Vilani J, Nabi HA. A Comparative Study of 511 keV SPECT and PET Using Separate 370 MBq F-18-FDG Doses on Different Days. ClinPositron Imaging. 1999 Mar;2(2):81-91.

Larson SM, Erdi Y, Akhurst T, Mazumdar M, Macapinlac HA, Finn RD, Casilla C, Fazzari M,Srivastava N, Yeung HW, Humm JL, Guillem J, Downey R, Karpeh M, Cohen AE, Ginsberg R.Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor GlycolysisUsing PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis.Clin Positron Imaging. 1999 May;2(3):159-171.

U. Lassen, G. Daugaard, A. Eigtved, K. Damgaard and L. Friberg, 18F-FDG Whole Body Positron

Emission Tomography (PET) in Patients with Unknown Primary Tumours (UPT), EuropeanJournal of Cancer, Vol. 35, No. 7, pp. 1076-1082, 1999

Michael A. Lawson, Jerome H. Targovnik, Kewei Chen, Daniel J. Bandy, Sandra J. Goodwin,Leslie B. Mullen, Jennifer T. Frost, Udaya M. Kabadi, James V. Felicetta, Ifat A. Shah, ThreeCases of Primary Hyperparathyroidism (PHP) with Prior Failed Surgery Where Culprit LesionsWere Identified by 11C-Methionine Positron Emission Tomography (PET) and AccuratelyLocalized with PET-MRI Coregistration, Clinical Positron Imaging Vol. 3, No. 1, 31–36. 2000

Max Lonneux, , Abdel-Malek Reffad, Metastases from Unknown Primary Tumor: PET-FDG asInitial Diagnostic Procedure?, Clinical Positron Imaging Vol. 3, No. 4, 137–141. 2000





N.R. Maisey, M.E. Hill, A. Webb, D. Cunningham, G.D. Flux, A. Padhani, R.J. Ott, A. Norman, L.Bishop, Are 18Fluorodeoxyglucose positron emission tomography and magnetic resonance imaginguseful in the prediction of relapse in lymphoma residual masses? European Journal of Cancer 36(2000) 200-206

Bernard L. Maria, , Walter E. Drane, , Suzanne T. Mastin, and Luis A. Jimenez, ComparativeValue of Thallium and Glucose SPECT Imaging in Childhood Brain Tumors, Pediatr Neurol1998;19:351-357.

McMurry J, Fundamentals of Organic Chemistry 4th ed., Brooks/Cole Publishing, 1998

R Nutt, The History of Positron Emission Tomography, Molecular Imaging & Biology, Volume 4,Issue 1, January-February 2002, Pages 11-26

Holger Palmedo, Jenne Hensel, Michael Reinhardt, Dirk Von Mallek, Alexander Matthies, Hans-

Ju¨rgen Biersack, Breast cancer imaging with PET and SPECT agents: an in vivo comparison, Nuclear Medicine and Biology 29 (2002) 809–815

Price P, PET as a potential tool for imaging molecular mechanisms of oncology in man, TRENDS in Molecular Medicine, 7:10, October 2001, pp 442-446

S. B. Sobottka, R. Steinmeier, B. Beuthien-Baumann, D. Mucha and G. Schackert, Evaluation of automatic multimodality fusion technique of PET and MRI/CT images for computer assisted braintumor surgery, International Congress Series, Volume 1230, June 2001, Pages 261-267

P Som, HL Atkins, D Bandoypadhyay, JS.Fowler, RR MacGregor, KÊMatsui, ZH Oster, DF

Sacker, CY Shiue, H Turner, C-N Wan, A P Wolf and S Zabinski. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (18F): Nontoxic tracer for rapid tumor detection. J Nucl Med 21, 670-675 (1980).

J.N. Talbot, Y. Petegnief, K. Kerrou, F. Montravers, D. Grahek, N. Younsi, Positron emissiontomography with [18F]-FDG in oncology, Nuclear Instruments and Methods in Physics Research A504 (2003) 129–138

Ganghua Tang, Mingfang Wang, Xiaolan Tang, Lei Luo, Manquan Gan, Synthesis and evaluationof O-(3-[18F]fluoropropyl)-L-tyrosine as an oncologic PET tracer, Nuclear Medicine and Biology30 (2003) 733–739

Joseph A. Thie, Karl F. Hubner, Gary T. Smith, Optimizing Imaging Time for ImprovedPerformance in Oncology PET Studies, Molecular Imaging and Biology Vol. 4, No. 3, 238–244.2002

T Toyokuni 1998, Chemistry of Imaging Probes I, Pharmacology 248 : An Introduction toBiological Imaging (Winter 1998 presentation), UCLA Department of Molecular and MedicalPharmacology (http://laxmi.nuc.ucla.edu:8248/M248_98/synprob/part2/hist_rad.html)

Johan F. Vansteenkiste, PET scan in the staging of non-small cell lung cancer, Lung Cancer (2003)xxx, 1-11 (Article in press)


http://laxmi.nuc.ucla.edu:8248/M248_98/synprob/part2/hist_rad.html

http://laxmi.nuc.ucla.edu:8248/M248_98/synprob/part2/hist_rad.html




L. Varagnolo, M. P. M. Stokkel, U. Mazzi and E. K. J. Pauwels, 18F-labeled Radiopharmaceuticalsfor PET in Oncology, Excluding FDG, Nuclear Medicine & Biology, Vol. 27, pp. 103–112, 2000

Tung Vu, Alan J. Fischman, Combined F-18 FDG and C-11 Methionine PET for Cerebral Tumors,

Harvard Medical School, Joint Program in Nuclear Medicine web page, September 26 2000(http://www.med.harvard.edu/JPNM/TF00_01/Sept26/WriteUp.html) Accessed October 4/5th 2003

Richard L. Wahl, Anatomolecular Imaging with 2-Deoxy-2-[18F]Fluoro-D-Glucose: Bench toOutpatient Center, Molecular Imaging and Biology Vol. 5, No. 2, 49–56. 2003

Warburg, O.; Posener, K.; Negelein, E.; VIII. The metabolism of cancer cells. Biochem. Zeitschr.152:129–169; 1924.

Stephen White, David Binns, Val Johnston, Megan Fawcett, Occupational Exposure in Nuclear Medicine and PET, Clinical Positron Imaging Vol. 3, No. 3, 127–129. 2000

H. Young, R. Baum, U. Cremerius, K. Herholz, O. Hoekstra, A.A. Lammertsma, J. Pruim and P.Price, Measurement of Clinical and Subclinical Tumour Response Using [18F]-¯uorodeoxyglucoseand Positron Emission Tomography: Review and 1999 EORTC Recommendations, EuropeanJournal of Cancer, Vol. 35, No. 13, pp. 1773-1782, 1999

Qi-Huang Zheng, Xuan Liu, Xiangshu Fei, Ji-Quan Wang, David W. Ohannesian, Leonard C.Erickson, K. Lee Stone, Gary D. Hutchins, Synthesis and preliminary biological evaluation of radiolabeled benzylguanine derivatives, new potential PET imaging agents DNA repair protein O6-alkylguanine-DNA alkyltransferase breast cancer, Nuclear Medicine and Biology 30 (2003) 405– 415

Thanks to Johanne (again!) for her patience and support during the last 8 months – Love Daen

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