Positron Emission Tomography in oncology: Present and future of PET and PET/CT

Critical Reviews in Oncology/Hematology 72 (2009) 239–254

Positron Emission Tomography in oncology: Present and futureof PET and PET/CT

Dimitri Papathanassiou a,d,∗, Claire Bruna-Muraille a,d, Jean-Claude Liehn a,d,Tan Dat Nguyen b,d, Hervé Curé c,d

a Service de Médecine Nucléaire, Institut Jean Godinot, Reims, Franceb Département de Radiothérapie, Institut Jean Godinot, Reims, France

c Département d’Oncologie Médicale, Institut Jean Godinot, Reims, Franced Université de Reims Champagne Ardenne, UFR Médecine, Reims, France

Accepted 14 October 2008

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402. General PET principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.1. What is PET technique? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402.2. Why use radioactivity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412.3. What are the information provided by PET images? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412.4. What are the technical limitations of PET? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2422.5. Which tracers are used? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2422.6. The place of FDG-PET studies in oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2432.7. Why associate X-ray CT scanner with PET detector? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

3. Clinical applications in oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2433.1. The validated results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

3.1.1. Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.1.2. Lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.1.3. Head and neck cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.1.4. Digestive cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2463.1.5. Breast and gynecological cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2463.1.6. Genito-urinary tract cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.1.7. Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.1.8. Thyroid cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.1.9. Sarcomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.1.10. Unknown primary cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.1.11. Brain tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

3.2. The applications under validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473.2.1. Therapy monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2483.2.2. Full validation of PET/CT in clinical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2483.2.3. Other tracers than FDG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

3.3. What can we expect? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

∗ Corresponding author at: Service de Médecine Nucléaire, Institut Jean Godinot, 1 rue du Général Koenig, BP 171, 51056 Reims Cedex, France.Tel.: +33 3 26 50 43 16; fax: +33 3 26 50 43 39.

E-mail address: [email protected] (D. Papathanassiou).

1040-8428/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.critrevonc.2008.10.006

mailto:[email protected]

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40 D. Papathanassiou et al. / Critical Reviews in Oncology/Hematology 72 (2009) 239–254

. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2494.1. Background of the animal studies with PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2494.2. Micro-PET development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2494.3. Applications of micro-PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2494.4. Perspectives of micro-PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

bstract

PET is a crucial technique in molecular imaging, allowing in vivo assessment and localization of pathological processes, thanks to its abilityo detect very small amounts of radioactive molecules. This is of particular interest in oncology where abnormal metabolism or synthesis inumor cells but also various tumor characteristics can be studied using this nuclear medicine technique. FDG is currently the most widelysed tracer, nowadays essential in the management of various malignancies, with large applications in diagnosis, initial assessment, therapyonitoring, and recurrence detection. The combination of anatomical information provided by PET/CT further increased its interest. Beyond

ts spread use in daily practice, future applications of PET will involve other tracers than FDG and develop research applications in humanss well as in small animals.

2008 Elsevier Ireland Ltd. All rights reserved.

rwldta

dtypical duration of the imaging procedure in clinical practiceis nowadays about 30 min, but it is reduced down to 10 minusing the most recent PET scanners.

Fig. 1. Positron emission followed by the disintegration of a

eywords: PET; PET/CT; Imaging; Oncology

. Introduction

Positron Emission Tomography (PET) is one of the mostmportant steps among the recent advances in imaging tech-iques in oncology. Although PET technology is not new, itas moved during the last 10 years from research laboratorieso clinical environment in all of the developed countries. Theast years have also seen the rapid development and spreadingf devices which include both a PET and a X-ray Computer-zed Tomography (CT) scanner. This was the first time thatmultimodality imaging device has been commonly used inedical practice. Meanwhile, PET and PET/CT, and otherultimodality imagers have been developed for animal stud-

es in research laboratories. The purpose of this article iso review the basis and the interests of these techniques, toummarize the clinical indications already either validated ornder investigation, and to give an insight into animal studiesnd into what is expected for the future.

. General PET principles

.1. What is PET technique?

As in other nuclear medicine techniques, a radioactiveompound (the tracer) is administered to the subject. Theay emitted by the radionuclide which labels the tracerolecule is detected with a gamma-camera in “conventional”

i.e. excluding PET) nuclear medicine, where the radionu-
lides directly emit gamma rays. In the case of PET, themitted particle is a positron (the positive “brother” of thelectron—made of anti-matter), which rapidly meets an elec-ron and disappears while two high-energy (511 keV) gamma
porsd

ays are emitted (Fig. 1). Those two gamma rays are recordedith a special camera composed of rings (made with a

arge number of tiny crystals) [1]. Using information aboutetected rays, a computer calculates the spatial distribution ofhe tracer within the patient (Fig. 2). Images can be presenteds slices (“Tomography”) or as 3D data.

The patient bed can move progressively through the ringetector, so that a large part of the body may be scanned. The

ositron–electron couple, which gives two gamma rays emitted inpposite directions; the information is kept if two detectors in theing-shaped detecting device receive a gamma ray of selected energy;tarting from all detection lines, the computer calculates the position of theifferent radioactive sources in the volume.

D. Papathanassiou et al. / Critical Reviews in Oncology/Hematology 72 (2009) 239–254 241

F ased glm “Maximp

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ig. 2. Initial assessment of a lung carcinoma: the tumor exhibits an increetastasis is also detected (left: tridimensional FDG-PET representation,

resence of the tracer in the brain and the urinary tract.

.2. Why use radioactivity?

The major advantage of Nuclear Medicine devices is highhysical sensitivity (ability to detect signal). The mass ofhe administered tracer in human, in case of PET, is about0−10 g. For example, a tumor clearly seen on a FDG-PETtudy contains about 10−14 g of tracer per millilitre. Othermaging techniques commonly used in oncology (sonogra-hy, X-ray CT, MRI) require, when they use contrast media,much higher concentration of these molecules.

In the new biomedical research field called molecularmaging, defined as “the visual representation, character-zation, and quantification of biological processes at theellular and sub-cellular levels within intact living organ-sms” [2], PET has a special place. Molecular imaging usesrobes designed to reach cellular or molecular targets. Theadionuclide-based approach is historically the first molec-lar imaging technique with in vivo applications in bothnimals and humans. It is also the most sensitive and one ofhe modalities with the largest number of available molecu-ar probes. Many biological molecules could be radio-labelednd become PET tracers.

.3. What are the information provided by PET images?

By itself the PET technique does not mean an insight intone particular function or metabolism. What is observed onhe images depends on the tracer and its metabolism. Each

ll

ucose metabolism, two mediastinal lymph nodes are involved, and a liverum Intensity Projection”; right: PET/CT fused slices); note the normal

ew tracer is theoretically able to provide new information,hen PET is an open field with many potential applications.here are chemical and physical limitations, but the limitsf clinical applications are mostly financial. Tracers are con-idered as drugs, and developing and registering a new drugs a long and expensive process. Furthermore, a completeET research unit involves a cyclotron (device producingositron emitters radionuclei), which have its own costs (aso installation and running).

The whole body mode of the PET scan is a major advan-age, since it allows the detection of active lesions throughouthe body (however, for practical reasons due to the examina-ion time, by now the scanning does not usually cover inferiorimbs).

The computed PET images are quantitative, i.e. they areeasurements – although not perfectly accurate – of the

eal concentration of the tracer in the organ. This is partic-larly important in the field of research and animal studies.ore or less complex compartmental models can be used

o quantify the kinetic of PET tracers. However, in clini-al practice, a simple index called the Standardized Uptakealue (SUV) is generally used. It is defined as the ratiof the concentration of the tracer in a region to the mean

ows (although there are variations, such as taking in accountean mass or body surface instead of body mass) [3]:SUV =

tissue concentration (MBq/ml)injected radioactivity (MBq)/body weight(g)

2 s in Oncology/Hematology 72 (2009) 239–254

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Table 1Metabolism or function disturbed in cancer and the PET tracer used for theirstudy.

Function/metabolism Tracer

Glucose metabolism 18F-fluoro-deoxy-glucose(FDG)

DNA replication/cellular proliferation 11C-carbon-thymidine18F-fluoro-thymidine (FLT)

Protein synthesis, amino acid transport 11C-carbon-methionine(MET)18F-fluoro-ethyl-tyrosine(FET)18F-fluoro-methyl-tyrosine(FMT)18F-fluoro-dihydroxy-phenylalanine(F-DOPA)

Membrane lipid synthesis 18F-fluoro-acetate11C-carbon-choline18F-fluoro-choline (FCH)

Hypoxia 18F-fluoro-misonidazole(FMISO)64Cu-copper-ATSM

Apoptosis 18F-fluoro-annexin VAngiogenesis 18F-fluoro-galacto-RDGReporter genes 18F-fluoro-deoxy-

arabinofuranosylnucleosides(FEAU, FIAU, FMAU)

Tumor therapy control 18F-fluoro-uracil (FU)Receptor binding (estrogen) 18F-fluoro-oestradiol (FES)R

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42 D. Papathanassiou et al. / Critical Review

Tumor SUV is usually over 2 in malignant tissue. TheUV could be useful in the diagnosis and follow up of can-er diseases, but there is no cut-off value, which accuratelyeparates malignant and non-malignant uptake [4]. Moreover,imitations of SUV are known [5]: many confounding factorsnfluence SUV determination and criticism of SUV method-logy has been made [6]. Limitations include variability inbese patients, and using lean mass seems to be appropriateo avoid overestimation [7] in that specific group of patients.he SUV is not always powerful for discrimination betweenenign and malignant tissue (depending on the type of lesion).hen its usefulness lies more in the longitudinal follow-up

han in information in a unique examination.

.4. What are the technical limitations of PET?

The radioactive half-lives – the period of time over whichalf the radioactive nuclei undergo disintegration – of theositron emitters are often very short (a few minutes in thease of radioactive 11C carbon, 15O oxygen and 13N nitrogen,nd less than 2 h in the case of 18F fluorine [8]). Then, onlyhe early phase of metabolisms can be studied.

18F fluorine is the only largely available PET emitterhose half-life is not too short. Its 110 min half-life makes

t possible to deliver tracers many kilometers away from theroduction centers, in “satellite centers” equipped with a PETamera but without cyclotron. The implementation of thiselivery logistics has made possible the large clinical use ofuorine-labeled glucose in oncology during the last 10 years

n many developed countries. An alternative solution coulde the production of the radionuclide by using generatorsi.e. a device containing atoms of a “parent” isotope whichives the “daughter” isotope that is used, e.g. 68Ge germa-ium giving 68Ga gallium), thereby allowing tracer labelingn the imaging department itself, like the widespread processsed for the well-known 99mTc technetium.

The spatial resolution of the human PET cameras is low,etween 6 and 8 mm for most of the commercially availableET scanners [9,10]. As a consequence, lesions under 1 cmould be missed on the images, although smaller lesions cane seen if they highly concentrate the tracer. This is prob-bly the most limiting parameter in medical practice. PETcanners dedicated to laboratory animal have a better reso-ution, i.e. a few millimeters. As compared to CT and MRI,ET remains a low-resolution technology in both humansnd animals.

Finally, PET is a very expensive technique. The productionf positron emitters by cyclotron, the tracer-labeling pro-esses, the delivery of the tracer and the PET camera arexpensive.

.5. Which tracers are used?

The most commonly used PET tracer in clinical oncol-gy is fluoro-desoxy-glucose (FDG) (more than 95% of theolecular imaging procedures make use of FDG at present).

pepa

eceptor binding (somatostatine) 68Ga-gallium-DOTATOC/DOTANOC

his is a glucose molecule in which one hydroxyl groupas been exchanged for a 18F fluorine atom. This molecules incorporated in the cells via the same paths as glucose11]: the expression of glucose transport proteins (espe-ially GLUT 1) allows FDG to enter the cell, and FDG,ike glucose, is phosphorylated by hexokinase. However itsegradation within the cell is stopped at its second step (FDG--phosphate, unlike glucose-6-phosphate, is not metabolizedurther by glucose-phosphate-isomerase, and can leave theytosol only by hydrolysis back to FDG, depending on thehosphatase activity [12], which is usually rather low). Then,h after injection, its distribution within the body depicts

he distribution of the glucose uptake. It has been known forong [13] that the glucose metabolism in most – but not allneoplastic tissues is higher than in normal tissues: primary

umors, recurrences and metastases of many solid tumors cane visualized with FDG-PET as a hot spot amongst low back-round. The test is performed on fasting (in order to increasehe tracer uptake; hyperglycemia has been shown to decreaseDG uptake in tumors [14]) and resting (in order to avoiduscular uptake) patients.Beside the glucose metabolism, many other metabolic

aths, which are disturbed in neoplastic tissues, can bexplored using PET tracers [11]. Table 1 lists some of theseaths relevant in oncology, which can be explored using PET,nd the corresponding most studied tracers. This list is far

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D. Papathanassiou et al. / Critical Review

rom being exhaustive because in this expanding field manyew molecules are candidates.

.6. The place of FDG-PET studies in oncology

Localizing viable tumor tissues in the patient body isxtremely useful at all phases of the diagnostic and therapeu-ic (i.e. in order to tailor the strategy) processes. This includesnitial diagnosis and staging, early and late assessment of theherapeutic response, follow-up and diagnosis of recurrence.herefore FDG-PET is essential in the management of manyf human cancers (see Section 3) even though it is not alwayshe best imaging technique. For example, the affinity of FDGor prostate cancer tissues is low, then the sensitivity of FDG-ET is low and its use is not recommended in prostate cancer.n the contrary, as compared to other imaging techniques,DG-PET is the most efficient technique in the initial stagingf lung cancer.

Normal uptake reduces the usefulness of FDG: this tracers not efficient for the diagnosis of brain metastases sincehere is a high physiological uptake of FDG by the normalrain. Another limitation of FDG is the non-specific uptakey inflammatory and granulomatous lesions. This can lead toverestimate the spread of a malignant disease or to doubt-ul interpretation. Finally FDG uptake is influenced by bothnsulin and blood glucose levels. The performance of theDG-PET could then be altered in non compliant patientsr in diabetic patients (if the timing between anti-diabeticreatment and the injection of FDG is not carefully planned).

.7. Why associate X-ray CT scanner with PETetector?

Since 2003, the majority of new clinical PET devices haveeen associated with a CT scanner. This multimodality imag-ng device performs a PET and a CT acquisition while theatient remains on the same bed and provides fused images9] (where the CT information is usually coded in gray levelsnd the tracer uptake in colors). The two images are perfectlyegistered [15], assuming that the patient does not move andhat the organs do not move, which is true in most parts ofhe body but could generate artifacts in some areas such ashe diaphragm region [16,17]. Computer-assisted techniquesso-called gating techniques) are currently being validated inrder to remove or decrease those breathing artifacts [18,19].

The utility of this dual acquisition procedure is twofold.irst, in order to calculate the spatial distribution of the tracer,

he computer software has to perform some corrections,hich take into account the physical processes of detection,

ncluding the correction of the gamma rays attenuation by theatient’s body. This can be corrected if the spatial distributionf the attenuation process is known, which is exactly what
he CT images provide [20]. Compared to the stand aloneET, which uses a rotating radioactive source to estimate theamma rays attenuation, the use of CT data for this purposeas achieved a major reduction in the acquisition time.
3

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cology/Hematology 72 (2009) 239–254 243

The second and more visible advantage of multimodalityoncerns the medical interpretation of the images. A tracerike FDG has some physiological non-specific (i.e. in normalissues) uptake, which varies from one patient to another. Weave already mentioned the brain uptake, which is constant.he heart, the liver, the urinary tract, the bowels and manyther organs may concentrate the tracer at different levelsFigs. 2 and 3). When PET acquisition is done alone thison-specific uptake could be helpful for localizing abnormalptake but this does not allow a precise localization. Mostmportantly, non-specific uptake could often be misleading oread to an undetermined imaging. On the other hand the fusedET–CT images are very helpful in localizing the abnormalptakes (such as neck or mediastinum lymph nodes) and inifferentiating physiologic from abnormal uptake (for exam-le in urinary tract, bowels, or in the laryngeal cavity). Usingontrast media for CT even increase the accuracy of anatomi-al information. In spite of causing problems in the correctionor attenuation, intravenous iodinated contrast media injec-ion has several potentials: better delineation of tumor, mostlyor dosimetric planning of 3D conformal radiotherapy andon-conventional surgery [21] or when vascular involvements suspected; more accurate anatomical localization of tumorsn the head and neck, the abdomen and the pelvis (for instanceocalization of an hepatic segment involved by a lesion).

The combination of a so-called functional imaging tech-ique (PET) with an efficient anatomical imaging techniqueCT) is a major breakthrough in modern cancer imaging.his first wide clinical application of multimodality imagingppears as a paradigm from which other clinical or labora-ory multimodality imaging techniques have evolved in theractice.

. Clinical applications in oncology

PET has now been used for several years in the field ofncology, and many of its indications are well established inhe patient management setting. The present section summa-izes essentially the applications of FDG (Table 2), which ishe main tracer used. Nevertheless, other tracers than FDG arender validation before their eventual daily use. On the otherand, the greatest part of published evidence does not con-ern PET/CT but PET alone, because this technique withoutombined CT was used for a longer time. Most of the aspectsf the global impact of stand alone PET can be transposedo PET/CT, because the sensitivity of the PET device and theunctional information that it brings are the same. However,he overall accuracy is likely to be improved with combina-ion of the CT; moreover, specific applications of combinedET/CT are currently arising and being validated.

.1. The validated results

The largest evidence about the interest of PET imagingn oncology concerns FDG, as a result of the great number


Fig. 3. therapy evaluation by PET/CT in a case of lymphoma (top row: tridimensional representation of the PET data; middle row: CT slice through the mainlesion; bottom row: corresponding PET slice); a large thoracic mass corresponds to an important FDG uptake before treatment (left column); the volume of thelesion and the metabolism decrease after the first part of the treatment, but two tiny foci (arrows) remain visible (middle column); after the treatment completion,there is no longer any metabolism abnormality, whereas an inactive mass is always visible on the CT (right column). Note the normal variable uptake by themyocardium.

Table 2Main indications for FDG-PET in oncology in 2008.

Malignancy Initial diagnosis Staging Therapy monitoring Recurrence

Lymphoma ++ ++ +Lung ++ ++ + +Head and neck + + +Colorectal + ? ++Oesophageal + ?Gastrointestinal stromal +Pancreatic + +Liver +/− +/− ?Breast ? ? ++Ovarian ++Uterine + ? +Testicular + + +Renal +/− +/−Bladder ? ?Melanoma ++ ++Thyroid (iodine negative) +Sarcoma ? ? ? +/−++: fully validated or with large practical usefulness; +: validated or with recognized practical usefulness; +/−: evidence still lacking or with limited practicalusefulness; ?: expected to be useful, not already validated.

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f patients whom it already benefited, and the subsequentumber of trials using this tracer. Several reviews have beenublished and evidence-based recommendations were estab-ished [22,23].

.1.1. LymphomaThe lymphomas (Hodgkin’s disease as well as non-

odgkin’s lymphoma) represent a major indication forDG-PET imaging. It is widely accepted for the initial stag-

ng of lymphomas [24–26] due to a more accurate detectionf the extent of the disease compared to other imaging meth-ds, such as CT (for nodal disease and particularly extranodalisease) and bone scan. According to a recent meta-analysis24] the pooled sensitivity is about 91% and the pooled falseositive rate is 10%, while the change-in-management rateesulting from PET findings is as high as 30%. Similar con-lusions could be drawn focusing on Hodgkin’s disease, withhange in management up to 25% [26].

The sensitivity of FDG-PET for bone marrow involve-ent is rather low (51%), while the specificity is about 91%

27]. PET appears as useful for guiding biopsy althoughonventional biopsies remain necessary (the strengths andeaknesses of FDG-PET in bone lymphoma lesions are not

he same as for metastasis in other malignancies, where itslace might be redefined in a next future with a critical role).

FDG-PET has been shown useful for the early treat-ent response evaluation (even if the optimal timing for

maging after chemotherapy is a matter of debate) andhe evaluation after completion of treatment [26,28,29].

residual FDG uptake is suggestive of treatment failure,nd FDG-PET is accurate in differentiating residual dis-ase from necrotic tissue mimicking persistent lymphoman morphologic imaging (Fig. 3). The metabolic classifi-ation improves the discrimination between patients withifferent prognosis [30], and present criteria for definitionf response in malignant lymphoma include PET in theuidelines [31].

.1.2. Lung cancerLung cancer is a main application of FDG-PET, notably

ncluding the initial diagnosis of solitary pulmonary nodule:y increasing the probability of malignancy if the metabolismn the nodule is increased, FDG-PET allows curative surgeryn high-risk patients, whereas avoiding futile surgery in low-isk patients. Indeed the negative predictive value in low-riskatients makes it possible to choose simple follow-up. How-ver in high-risk patients, a negative PET is not sufficient tovoid further investigation [23]. The specificity (about 78%)s lower than sensitivity (about 96%) [32,33]. False positivere mainly due to infection, while bronchiolo-alveolar car-inoma and carcinoid tumors are associated with a higherrobability of false negative FDG-PET. Small lung nodules
for which a less large amount of evidence is available) areowever a persistent limit of the PET, as explained in Section, because the sensitivity decreases as the nodule’s size getsmaller under 1 cm.
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Staging non-small cell lung cancer with PET (Fig. 2) isecommended [23] due to its sensitivity, superior to con-entional imaging’s one, including for mediastinal staging34–37]. FDG-PET has a substantial impact on metastasesetection [33,34] mainly by upstaging patients (unsuspectedetastases revealed in up to 20% of patients).FDG-PET used for treatment evaluation has a prognostic

alue [34,38,39]: it is predictive for treatment outcome andatient survival and may be helpful in restaging after therapy,elying on ability to assess residual tumor viability. However,urther studies will be necessary before FDG-PET become atandard evaluation in this setting. FDG-PET is also efficientn recurrence detection [40,41].

In spite of elements in favor of a possible use of FDG-ET for the small cell lung carcinoma management, includingadiotherapy planning or treatment response evaluation, theack of evidence for reliably establish this role remains aimitation of the technique in the field of lung cancer (despiteDG uptake by these tumors, current therapeutic options areenerally less modified by the information provided by PEThan for non-small cell lung cancer).

.1.3. Head and neck cancerFDG-PET is notably useful for head and neck cancer

anagement [42,43]. The addition of PET to conventionalmaging tests is useful for local staging. Its superiority overoth CT and MRI is admitted. The detection of loco-regionaletastases is an important element in the treatment plan-

ing. It is not established that a negative PET may rule outodal metastasis without addition of sentinel node mapping,ut PET is able to identify normal sized nodes involved byetastasis. With a 82–87% sensitivity and a 94–100% speci-city, PET performs better neck nodes metastasis detection

han CT (65–81% and 47–80%, respectively) [44].Its ability to detect distant disease is another important

otential for modifying treatment, but further evidence iseeded about the role of FDG-PET in screening for distantetastases and synchronous primary tumors.PET is useful in carcinoma of unknown primary origin

n patients with head and neck metastatic lymph node, withsuccess rate of about 27% when all other modalities are

egative [45]. However the sensitivity is low for base-of-ongue lesions and the specificity is low for tonsillar tumors45]

FDG-PET is also used for assessment of the responseo therapy. However the delay after radiotherapy or chemo-adiotherapy to avoid falsely negative or positive results isontroversial (although generally 3–4 months seem suitable43]). The risk of false positive results is expected to be moremportant with radiotherapy, and of false negative results withhemotherapy. Nonetheless, information brought by FDG-ET in therapy assessment depends on the particular case
tudied: evaluating response to treatment after one or twoycles of chemotherapy does not require the same optimalegative predictive value as excluding residual tumor activitynd classifying a remission as complete or partial.

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FDG-PET proved more sensitive and specific than conven-ional morphological imaging for the detection of recurrencef squamous cell carcinoma of the head and neck [42,46].ecent meta-analysis showed a 94% sensitivity and about0% specificity in this setting [47,48].

.1.4. Digestive cancersFDG-PET is not recommended for detection or primary

iagnosis of colorectal cancer, but is a major tool in the scopef liver or extra-hepatic metastasis, and local recurrence ofhis cancer. For initial staging, PET is suitable in a subgroup ofatients at high risk of metastases in order to ensure that therere no metastasis ruling out surgical option [49]. PET shoulde used as a preoperative tool in patients with potentiallyesectable liver metastases [50–52], owing to its accuracyn detecting other metastases, which allows avoiding futileurgery. Although monitoring of response to therapy appearss a future application of FDG-PET [53], there are not enoughvidence by now to recommend such a use of the technique.n the other hand FDG-PET is known as particularly valu-

ble for the search for a recurrence (with up to 29% of casesith change in management [54]), especially in the case of

ncreasing biological marker; it is also used for discriminatingecurrent tumor and changes following treatment, or benignnd malignant lesions such as indeterminate lymph node. Aimitation of FDG-PET in colorectal cancer is its low sensi-ivity to detect mucinous adenocarcinoma (probably due toow cellularity in such tumors).

FDG-PET may be an additional examination in stagingesophageal cancer, not for the detection of local-regionalisease, but of distant metastases [55,56]. With respect toherapy evaluation and prognosis [53], PET findings corre-ate with clinical response and survival, but using PET in thisetting has not been yet validated. As for other malignan-ies, the delay after therapy before PET is not clearly defined.adiation oesophagitis and dilation of recurrent stenoses mayause false positive results. Local recurrence is best studiedith endoscopy, but the accuracy of whole body PET for dis-

ant metastases (superior to conventional techniques) makest a useful tool when recurrence is detected [53].

Gastrointestinal stromal tumors [53] are a successfulpplication of FDG-PET through the prognosis evaluationn restaging.

FDG-PET is efficient in initial diagnosis of pancreatic can-er [57] due to its ability to distinguish between benign andalignant lesion, and also in staging [58], although it appears

ess efficient for nodal involvement. There is no evidence forsing PET in treatment evaluation or follow-up of pancreaticalignancies.The contribution of PET in liver cancers [59] work-up

elies on distinguishing between metastasis or cholangiocar-inoma and benign tumor in the case of isolated hepatic lesion
or in patients with chronic sclerosing cholangitis). FDG-ET can be an important factor for deciding therapy when
here are conflicts in the results of other investigations. It maylso be used in staging of hepatocarcinoma, despite a rela-

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cology/Hematology 72 (2009) 239–254

ively low sensitivity (when gluconeogenesis is maintained,epending on cellular differentiation). Although other appli-ations such as monitoring treatment efficacy are envisioned60], there are not enough evidence to support a wide use forhose situations.

The detection of peritoneal carcinomatosis may be chal-enging, and clinical oncologists need improvements in theechniques to assess this condition. Although its accuracy isot recognized to be high enough in all the studies address-ng this issue, FDG-PET is generally seen as able to add toonventional imaging, and particularly when the combinedT is used [61–64].

.1.5. Breast and gynecological cancersFDG-PET is not recommended for initial diagnosis,

creening or axillary involvement assessment in breast can-er. Although some studies brought elements in favor of thesendications [65,66], especially axillary staging, they remainery controversial and are not recommended [23] to datebecause of the risk of false negatives). Micro-metastasesould not be detected with PET, and the sentinel node tech-ique is far more useful for node involvement staging. Inpite of the interest of a precise delineation of the malig-ant area in order to plan surgery, FDG-PET has not beenroved to allow determining the local extent of the disease.n other limitation of FDG-PET in breast cancer is its rela-

ively poor sensitivity in lobular cancer [67,68]. For staging, its not established that FDG-PET could replace conventionalechniques, such as bone scan [69]. On the other hand, theensitivity reaches 90%, with a false positive rate of 11%,or detecting breast cancer recurrence and metastases [70]nd this constitutes the main indication of PET in breast can-er. FDG-PET is particularly useful when arises a biologicaluspicion of recurrence, or when a lesion is not definitelylassified using other modalities, in the initial staging orecurrence assessment. There is not enough evidence by nowoncerning evaluation of the response to treatment in breastancer.

PET efficiency in diagnosing recurrent ovarian carcinomas higher than that of CT or MRI [71]. Its sensitivity andpecificity have been estimated at 90% and 86%, respectivelywhereas they are 68% and 58% for conventional imaging),nd 96% and 80% in case of elevated Ca-125 with nega-ive conventional imaging [72]. PET seems less useful foretection of microscopic residual ovarian cancer, but is use-ul when the recurrence is accessible to treatment or when aT guided biopsy is not feasible [73].

In uterine malignancies [72–74], FDG-PET is valuable inre-treatment staging of advanced cervical cancer (but noto far evidenced in early-stage resectable cervical cancer),y improvement of node metastasis detection (higher sensi-ivity than CT). It is also of value in detection of suspected
ocal or metastatic recurrence and in therapeutic decision forevealed potentially curable cervix cancer recurrence. Theole of FDG-PET in the management of endometrial cancers less clear, but recommendations are evolving about this

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ndication because the clinical impact seems positive, andhey might rapidly include primary staging and post-therapyollow-up.

.1.6. Genito-urinary tract cancersFDG-PET has no application in initial diagnosis of tes-

icular cancer, but is useful in staging this cancer [75–77],specially seminoma (PET must be used while keeping inind that the FDG uptake in teratoma is expected to be low).

t also can be used [78] for follow up after treatment [77]nd recurrence detection [79] or residual mass evaluationexcluding teratoma) [79].

For renal cancer 18F-fluorodeoxyglucose is of no evi-enced use for primary diagnosis but has a role in both stagingnd restaging of the disease [77,80]. It can be used for localr distant recurrence due to its positive predictive value, butoes not rule out such recurrences when negative [79].

For bladder cancer, there are not enough data about the rolef PET in initial diagnosis or staging, but locally recurrent oresidual bladder tumor may be detected [77] after diuretic.ndeed, urinary elimination of the radioactivity is known toead to hide some tumors or at least to lessen the sensitivityf PET; however, intravenous hydration and forced diuresisave been shown to eliminate residual activity, and reducehis limitation of FDG in pelvic tumors [81–83]. FDG-PET isble to detect distant metastases [80] or discriminate betweenost-therapeutic fibrosis and recurrence, but the evaluation ofhese applications remains to be extended [79].

For prostate cancer FDG-PET is known to be poorlyffective. It has no evidenced-based application in primaryiagnosis or staging [79] but can have a limited role in recur-ence detection [79,80]. Prostate cancer is the malignancyor which other tracers than FDG are the most expected torove useful in clinical setting when more widely available84]: 11C-choline, 18F-fluorocholine, 11C-acetate showedromising results, but others such as 11C-methionine, 18F-uoro-5-alpha-dihydrotestosterone will also have to be morevaluated [80].

.1.7. MelanomaFDG-PET allows initial staging of cutaneous melanoma

ith a high risk for potential metastases, and is also usefulefore the treatment of a metastasis assumed to be uniquefor ascertaining that the disease has not spread more thanuspected), or in the case of suspected metastasis [85,86]. Thehange-in-management rate using FDG-PET reaches 22%87]. PET has superior overall efficiency than other imagingodalities for the detection of melanoma metastases, except

n lung and brain [86,88].The role of FDG-PET is now well established in the

anagement of cutaneous melanoma, but its value in otherelanomas is not yet evidenced.

.1.8. Thyroid cancerFDG-PET is nowadays used in thyroid cancer when the

lassical iodine scintigraphy is not sufficient, that is in the

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ase of an histological form without iodine uptake (includ-ng medullary) or when the classical radionuclide imaging isegative (metastases that lost the capability of 131I uptake)89]. Then there is no place for FDG-PET in initial diag-osis, or staging, treatment evaluation, or follow-up in theery most common case of differentiated thyroid cancer with31I uptake. The essential impact of FDG-PET appears toe the detection of lesion in patients with elevated serumhyroglobulin and negative 131I scan [90].

.1.9. SarcomasFDG-PET may be used in soft tissue sarcomas in the scope

f local recurrence or biopsy guiding [91]. It can also helpharacterizing a primitive bone lesion, due to the possible dis-rimination between benign tumor or low grade sarcoma andigh grade sarcoma [91–93]. Evidence is by now lacking forecommending the use of FDG-PET in the standard manage-ent of sarcomas, but the research of distant metastases, of

ecurrence, and therapy evaluation are potential indicationsf this investigation tool.

.1.10. Unknown primary cancerFDG-PET may be a resort for patients presenting with a

ancer without known primary location, due to its sensitiv-ty and power to pinpoint increased metabolic foci, therebyllowing the detection of primaries missed using morpho-ogic imaging. Then it allows the detection, in 25% [45]o 41% [94] of cases, of primary tumors undetected usingther modalities, and in 27% [45] to 37% [94] of cases, ofndetected other regional or distant metastases.

The impact has been particularly studied in cervical nodeetastasis, as already stated in 3.1.3. The specificity seems

ow for tumors of the lower digestive tract [94]. Overall sen-itivity has been estimated to 87% [95] or 92% [94], and thelinical management is altered in approximately one third ofatients [94].

.1.11. Brain tumorPET may be used with different purposes in primary brain

umor imaging [96] such as differential diagnosis, determi-ation of recurrence, grading, biopsy guiding or treatmentesponse evaluation, etc. In spite of important impact, therere no evidenced-based generalized guidelines in this setting.DG-PET may be used for identifying anaplastic transfor-ation, or discriminating recurrent tumor and local changes

especially radio-necrosis) induced by treatment [97]. How-ver, brain tumor imaging is a field where other tracers, whenvailable, are more often used than in other malignancies.uch tracers (11C-methionine, 18F-FET, 18F-DOPA [98], 18F-holine, 18F-fluorothymidine, 18F-FMAU, 18F-FMISO [99])ppear more accurate than FDG.

.2. The applications under validation

The sensitivity and the specificity of FDG-PET are nowell known for the main cancers. No new dramatic advance

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s likely to emerge in this scope, except for the expectedethodological improvements (mostly related to the device’s

echnology) that might further increase the diagnostic per-ormance of PET or PET/CT. However, the accuracy ofDG-PET is not definitely established for all of the cancers,nd still requires evaluation for the less frequent malignan-ies. Other advances in clinical setting are related to the facthat some applications of PET in the management of canceratients are being redefined.

.2.1. Therapy monitoringMost applications under validation are related to the ther-

py monitoring using PET. For example, the prognostic valuef FDG-PET in lymphomas is accepted (as stated in para-raph 3.1.1.), but all the optimal adaptations of the treatmentre not yet clearly established [100] (including the impactn radiation dose or planning). Therapy evaluation is beingtudied in breast [65] and lung cancer, and might also showsable in malignant melanoma, head and neck, oesophagealr colorectal cancers, or sarcomas. The notion of biologicalumor response is a possible future element established inhe management of cancer, beyond the volumetric responseidely used nowadays.The role of FDG-PET in therapeutic evaluation is not only

elated to conventional chemotherapy, but it also applies toolecular targeted anticancer drugs, and showed promising

esults in this field [101,102].Among the therapeutic applications, PET-based radiother-

py planning is a promising field. The value of PET forelineating the target volume has already been shown forertain cancers, and the same use for other tumors is beingnvestigated, or even adaptation during the course of the treat-

ent [103]. Moreover, PET/CT might be a tool of choice forultimodal image-guided radiotherapy.

.2.2. Full validation of PET/CT in clinical activityIndeed, among the methodological advances, the inte-

ration of the CT information together with the molecularmaging PET information has been a breakthrough in medi-al imaging, as explained in Section 2. It notably allows anncrease in specificity compared to PET alone, and in sen-itivity compared to CT alone. In a 5 years period, PET/CTas become the most important examination for numerousancers. In many fields, for staging [104], monitoring ther-py [105], recurrence detection [106], radiotherapy guiding107] the dual modality PET/CT is of demonstrated interestr at the very least highly promising. Nowadays, an impor-ant and growing number of publications in the field of PETeals with PET/CT studies.

However the way of using the CT in PET/CT is not defini-ively fixed, and the combined CT, as predominantly used (i.e.

ainly as a localization tool) may appear as underemployed
rom certain viewpoints in some instances. The diagnosticerformances of this hybrid modality are then extensivelyeing studied, owing to issues resulting from this recentossibility, as “could PET/CT replace the combination of
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ET alone and CT alone?”, or “could PET/CT replace theombination of PET/CT and CT alone?” [108,109]. The CTomponent of the PET/CT might have a redefined role in theuture, with consequences on technical parameters and real-zation, and on absorbed dose or side effects (for instance asresult of CT contrast media).

.2.3. Other tracers than FDGWe already reminded that not all the malignancies can be

tudied with FDG. In part, this is due to particular metabolismisturbances without prominent glucose uptake increase [12],r to relatively low proliferation rates in some histologicalubgroups.

On the other hand, FDG is not a specific tracer for malig-ant diseases (but for increased metabolism), and tracers withigher specificity seem necessary for going deeper in molec-lar imaging. Several tracers, that are not by now available invery PET facility, are under evaluation for clinical applica-ions, with promising preliminary results [110–115]. Indeed,molecule designed to depict the DNA or protein synthesisr the cell membrane building up, or the receptor expressionTable 1), is expected to be less sensitive to inflammatory pro-ess than FDG, and is sometimes more highly specific of theumor studied. Not only other 18F fluorine-labeled moleculeshan deoxy-glucose are used, but there are tracers labeled withther radionuclides (for example 68Ga gallium, 64Cu coppernd 124I iodine). 18F fluorine alone is a bone-seeking agent116] with high performance, but its position with respect tohe widespread 99mTc technetium–biphosphonate scintigra-hy will depend on its higher cost.

FDG accumulation is rather faint in most renal tumorsbecause of a low expression of glucose transporters) and theensitivity and specificity of FDG-PET for renal cancer didot allow overall improvement in the management of thoseancers. The same is even more true for prostate cancer, withow uptake except for high grade carcinomas. Other trac-rs are more and more studied for these cancers, as statedn the paragraph concerning urologic malignancies, includ-ng acetate or choline labeled with 11C carbon or 18F, and1C-methionine [78]. The impact of these tracers in the man-gement of bladder malignancies remains to be evaluatedurther in clinical studies [80].

PET imaging using peptides is an other application relatedo treatment planning, employed in the field of peptideeceptor radionuclide therapy, of neuroendocrine tumors fornstance [117]. Compounds are now used with PET that havepplications similar to 111In indium-pentetreotide’s ones. Theptake is then an element able to predict the effect of theadionuclide therapy.

.3. What can we expect?

Methodological improvements will go further on duringhe next years. They are likely to concern the PET image res-lution, which is expected to allow detecting smaller lesionsy PET, such as smaller lung nodules. On the other hand,

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he trend is to increase the sensitivity of the devices, whichill reduce the duration of the examination for the patient

nd increase throughput in clinical practice, or decrease thefficient dose (by reducing the necessary injected activity), oroth. The CT component of the PET/CT will also be furthermproved in order to decrease the radiation burden.

Tumor volume determination for radiotherapy plannings expected to become a standard practice, and sophisti-ated techniques such as respiratory gating are expected toevelop [118]. Through fusion imaging, the functional vol-me in tumors will probably be more and more used in thisadiotherapy planning.

Combined PET/MRI is an other possible hybrid modality,hich could prove useful in daily practice. Such devices haveeen realized for small animal imaging and are under eval-ation for brain imaging in neurological purpose. PET/MRIs theoretically possible for whole body imaging, but by nowts applications in oncology are undefined (in which casesill it be superior to PET/CT?), and an important question ishether its cost will be reasonable.Exciting progress in the imaging field will undoubt-

dly be brought by further advances in molecular imaging,s new tracers are expected to be used in clinical set-ing [11,119–122]. Those forthcoming tracers (Table 1) willllow assessment not only of energy metabolism, but alsof enhanced amino-acid metabolism [111,113,123], hypoxia114,124,125], cell proliferation [112], angiogenesis [126],poptosis [125,127], and cancer hallmarks [11,120]. Local-zation and functional assessment of proteins, receptors,nzymes are in this way likely to shift from exclusive researcheld to clinical applications, and so will do oligo-nucleotiderobes [128] or the study of the activity of an exogenouseporter gene [129,130]. Those future probes will help prac-ice a more preventive, predictive and personalized medicine.

The issue of screening for cancer by PET [131], has arisenue to its high sensitivity but its imperfect specificity, its cost,nd the use of ionizing radiations appear as critical limitationsith respect to the whole population. This question howeverave to be addressed for selected groups of patients.

. Animal studies

.1. Background of the animal studies with PET

Molecular probes have been used for many years in pre-linical studies and biological research, allowing transitionrom in vitro to in vivo models. Bio-distribution studies wereerformed by introduction of a radio-labeled probe into annimal which was sacrificed for counting radioactivity ex-ivo on excised tissue samples [132–134]; cross-section andutoradiography may be used to picture the distribution of
he probe. Each animal then contributes to a single timeoint of the evolution of the probe [135], the process isime-consuming and requires to sacrifice a lot of animals.owadays, PET can provide metabolic or functional infor-
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ation in vivo, non-invasively, quantitatively and repeatedly132] (however subjects must be kept motionless during themage acquisition procedure, which often necessitates anes-hesia [136]). PET studies spatial distribution of a moleculeut also gives dynamic data (Fig. 4) in a single animal,voiding sacrifice and reducing the number of animals used134,137]. PET may assess the cellular activity in target tis-ues, detect the spread of the disease, verify hypotheses aboutts onset and assess treatment of many processes. Moreover,y employing the same technology (PET) for preclinical stud-es and clinical practice, the verification of the clinical utilityf a new treatment is faster [134].

.2. Micro-PET development

Small animal PET was initially limited by the spatial res-lution achievable [132,138]. PET was only used for largenimals such as primates, especially for neurosciences andardiologic research, because the sizes of the organs allowedhe use of conventional clinical human PET scanners. Buthis was expensive and not applicable for large-scale studies.herefore new technologies were needed for small animalsasily used for laboratory tests, such as rats or mice. Theapid rate of reproduction and short life span of these ani-als reduce the cost for maintaining a large population andice can easily be used to simulate many human diseases,

ncluding by the creation of transgenic mice, which makesossible human tumor graft.

The first small animal PET was built in the 1990s, with aesolution above 5 mm. Nowadays, resolution in all directionss approximately 1 mm [137,139,140]. Today, as in humans,

icro-PET can be combined with high-resolution anatomicalmaging (CT or MRI), which allows direct registration of bothiological function and anatomy [141,142].

.3. Applications of micro-PET

Thanks to the diversity of positron-emitter-labeled com-ounds, the variety of applications is wide, and includeotably neurology, cardiology, and oncology. The study ofransplanted primary tumors is often simple. The entire ani-

al can be explored and metastases observed and monitored.ach subject is its own control, decreasing the variabilityaused by inter-animal differences. The drug efficacy is testedn the same tumor in the same subject [134]. PET quicklyerforms in vivo pharmacokinetic (the drug is labeled) andharmacodynamic (the drug effect is evaluated) investiga-ions [138]. Micro-PET can also be used with classical

arkers such as FDG to determine the effects of a radiationose on a tumor [143–145], determine necrosis and viableumor regions [132]. For example PET has been used in miceor studying head and neck [144] or lung [132,146] squa-
ous cell carcinoma, gastrointestinal stromal tumor [147],
rostate cancer [148], etc. Evaluation of gene expression byET is also feasible: the interaction of a labeled molecule with

he product of a reporter gene is proportional to the level of


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nd evaluation of gene therapy vectors efficiency [136,137].

.4. Perspectives of micro-PET

Using very small detector elements will allow sub-illimeter resolution, with high sensitivity. Nevertheless, a

esolution of 0.5–0.75 mm is reasonably adequate for manypplications. An other way of research is the developmentf multimodality, particularly of combined micro-PET/MR,hich improves soft tissue contrast thanks to the multiple

ontrast mechanisms available with MR and allows the usef fast MR sequences for motion correction [149]. Gating forardiac and respiratory motions is also a challenge for smallnimals, with the problem of the very high cardiac rate ofice [135].Micro-PET will probably develop as a research tool among

ther small animal imaging techniques, the choice for imple-entation of such a device depending on its initial and

unning costs compared to other available tools.

. Conclusion

PET and later on PET/CT have stood out in the man-
gement of many malignancies. Besides further clinicalvaluation of its usefulness in diverse instances, the futureill bring advances in the daily use of this part of the nuclearedicine, by the addition of new tracers beyond FDG, and by
g K. Abbey, Ph.D., via Siemens): the functionally active volume of a tumoratment.

echnological improvements such as future detectors notablyllowing faster image acquisition and many ensuing applica-ions.

eviewers

Dr. Jean-Pierre Papazyan, Clinique de Genolier, Nuclearedicine, 1 route du Muids, CH-1272 Genolier, Switzerland.Dr. Mohamed Ehab Kamel, Centre Hospitalier Univer-

itaire Vaudois (CHUV), Division of Nuclear Medicine,H-1011 Lausanne, Switzerland.

onflict of interest

The authors of the article “Positron Emission Tomographyn oncology: present and future of PET and PET/CT”, haveo conflict of interest to declare.

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iographies

Claire Bruna-Muraille, M.D. Assistant in the Departmentf Biophysics and Nuclear Medicine at the University ofeims-Champagne Ardenne and in the Nuclear Medicineepartment of the Institut Jean-Godinot.

Hervé Curé, M.D., Ph.D. Professor of Oncology at theniversity of Reims-Champagne Ardenne. Head of thelinical Oncology Department and Director of the Institut

ean-Godinot, Reims, France.

Jean-Claude Liehn, 59-year old, M.D., Ph.D. Professorf Biophysics and Nuclear Medicine at the University ofeims-Champagne Ardenne. Head of the Nuclear Medicineepartment of the Institut Jean-Godinot, Reims, France.

Tan Dat Nguyen, M.D., Professor of Radiation Oncol-gy at the University of Reims-Champagne Ardenne. Head,epartment of Radiations of the Institut Jean-Godinot,eims, France.

ersity of Reims-Champagne Ardenne (Biophysics anduclear Medicine) and the Nuclear Medicine Departmentf the Institut Jean-Godinot in Reims.

Documents

Positron Emission Tomography in oncology: Present and future of PET and PET/CT