PERSPECTIVES

Is there still a role for SPECTCT in oncology in the PETCT era?

Rodney J. Hicks and Michael S. Hofman
Abstract | For the evaluation of biological processes using radioisotopes, there are two competing technologies: single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Both are tomographic techniques that enable 3D localization and can be combined with CT for hybrid imaging. PETCT has clear technical superiority including superior resolution, speed and quantitative capability. SPECTCT currently has greater accessibility, lower cost and availability of a wider range of approved radiotracers. However, the past decade has seen dramatic growth in PET CT with decreasing costs and development of an increasing array of PET tracers that can substitute existing SPECT applications. PETCT is also changing the paradigm of imaging from lesion measurement to lesion characterization and target quantification, supporting a new era of personalized cancer therapy. The efficiency and cost savings associated with improved diagnosis and clinical decision-making provided by PETCT make a cogent argument for it becoming the dominant molecular technique in oncology.
Hicks, R. J. & Hofman, M. S. Nat. Rev. Clin. Oncol. 9, 712720 (2012); published online 13 November 2012; doi:10.1038/nrclinonc.2012.188

Introduction
Long before the idea of imaging human biological functions was conceived, George de Hevesy developed the fundamental principles for the use of radioactive tracers to study physiological and chemical processes.1 In fact, it was not until after almost half a century from his seminal experiment in 19132 that the rectilinear scanner, invented by Benedict Cassen, came into routine use in medicine.3 This scanner was slow and created 2D images of low contrast and coarse resolution, but it nevertheless revolutionized imaging and aided the creation of the new specialty of nuclear medicine. The rectilinear scanner was soon used to detect metastases from thyroid cancer using radioactive iodine, one of the first established uses of radioisotopes in both the diagnosis and treatment of cancer. 4 The speed, resolution and contrast with which radiotracers could be imaged were dramati cally improved by Hal Angers gamma camera,5 modern versions of which are still the workhorses of nuclear medicine departments around the world. However, this too was a 2D-imaging device that was
Competing interests The authors declare no competing interests.

proven limited when there were multiple overlapping structures containing radioactivity. This problem was solved largely by the development of tomographic imaging, which provides 3D information for analysis. Few realise that tomographic imaging using radioactivity actually preceded the X-ray CT technique that won Allan Cormack and Godfrey Hounsfield the Nobel Prize in 1979.6 In pioneering work, David Kuhl and Roy Edwards7,8 used an external radioactive source to assess the density of objectsa forerunner of CTand established the methodology of single-photon emission computed tomography (SPECT). The principles and mathematical techniques used in the reconstruction of tissue density maps (transmission scans) and in the reconstruction of the distributions of radioactivity within the body (emission scans) have fundamentally influenced medical imaging since that time. Positron emission tomography (PET) uses similar principles to those used in SPECT, but relies on the detection of two, instead of one, higher energy photons that are emitted in opposite direction by radionuclides that undergo positron decay. 9 This principle of coincidence detection,

established by Gordon Brownell, has lead to devices that are now widely used in the diagnosis, staging and therapeutic response assessment of cancer. The principles of SPECT and PET, both molecular imaging techniques that can evaluate physiological, biological and biochemical processes, are described in Figure1. Oncology has benefitted particularly from the development of SPECT capability on gamma cameras in the 1980s and from the commercial availability of PET scanners that were able to perform wholebody imaging since the 1990s. This benefit was due to the ability of these techniques to localize sites of disease, especially if correlated directly with anatomical imaging. This correlative capability was dramatically enhanced by hybrid SPECTCT and PET CT systems, wherein CT is integrated into the device to provide contemporaneous anatomical information. The first commercial PETCT systems became available in the early 2000s following developmental work by David Townsend and colleagues.10 The past decade has seen a rapid growth in use of PETCT, particularly in oncology. Current PET technology has clear technical superiority compared with SPECT, with higher sensitivity for detecting radioactive decay, higher resolution and superior quantitative capability (Box1). We will review some advantages of SPECTCT and the reasons why it currently remains a dominant technology. In our opinion, however, arguments in favour of SPECTCT are becoming increasingly difficult to sustain given the advantages of PETCT scanner technology and the array of new PET radiopharmaceuticals. As PET technology becomes more accessible and cheaper, it is timely to question whether SPECTCT will have an ongoing role in clinicaloncology.

Advantages of SPECTCT
Three reasons have traditionally been given as to why SPECT technology should continue to be the dominant technology in oncology rather than PET. These are: greater accessibility, lower cost, and the availability of radiotracers that can investigate a wider range of biological processes. Although each of these arguments has merit, they are becoming increasingly difficult to sustain.
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FOCUS ON IMAGING
There are already thousands of gamma cameras in use globally in the clinic and now SPECTCT devices are entering the medical environment. These more sophisticated SPECTCT devices are configured with SPECT and multislice CT on a single gantry that enables both functional and anatomic imaging to be acquired simultaneously.11 The CT data not only enables precise anatomic localization and correlation of any SPECT abnormality, but also provides an attenuation map enabling more accurate reconstruction of the SPECT data, including quantitative capabilities.12 SPECTCT is now used in a wide range of diseases including endocrinology, cardiology and neurology.13 Although growing rapidly, the number of installed PETCT scanners is significantly smaller than the number of SPECTCT scanners, making this technology less accessible to patients with cancer. Lower capital investment, service and maintenance costs for SPECT CT than for PETCT currently preserve this imbalance. However, the costs of these technologies are primarily driven by patientthroughput.14 The role of SPECTCT in oncology has also been primarily supported by the availability of a large number of radiotracers, many of which are based on the radioisotope 99m Tc.15 99mTc is a radioactive daughter eluted from generators containing its parent radionuclide, (99Mo).16 These generators can be milked several times per day for 12weeks. 99mTc has a decay half-life of 6 h, allowing its use over the course of a day.17 Many 99mTc-based radiopharmaceuticals have a role in oncology, either in detecting and staging malignancies, or in assessing organ function prior to or after treatment.18 These SPECT radiopharmaceuticals are readily available through use of commercially available kits that are typically freezedried and have a long shelf-life allowing local production or regional distribution from centralized radiopharmacies on demand.19 An example includes the widely used methylene-diphosphonate (MDP) or hydroxymethane diphosphonate (HDP) kits used for bonescintigraphy.20 There are large national and international infrastructure programmes that support radiopharmaceutical production and delivery, which minimize the operating costs of SPECTCT. 99mT production from 99Mo occurs predominantly in six nuclear reactors located in Canada (National Research Universal reactor [NRU]), Netherlands (High Flux Reactor [HFR]), France (OSIRIS
NATURE REVIEWS | CLINICAL ONCOLOGY
2012 Macmillan Publishers Limited. All rights reserved Surface rendered SPECT-CT

SPECT Detector

Collimator

Crystal

Volume-rendered SPECT-CT

Photons Collimator

PET Orbital electron Coincidence detectors Positron from nucleus 511 keV

Volume-rendered PET-CT

Transaxial PET-CT

511 keV Annihilation reaction

Figure 1 | The physics principles of SPECT and PET. SPECT relies on detection of photons of a radioisotope (top panels). These photons transfer energy to the detector of a gamma camera. Because photons are emitted in all directions, a collimator is used to collect only photons that are travelling perpendicular to the detector surface. These detectors are made of a high density material, such as lead or steel, through which there are multiple parallel holes. To collect a tomographic image, the gamma camera rotates around the body collecting a set of overlapping planar images from which images are reconstructed using a technique termed back projection. The right upper panels are an example of use of 99mTc-colloid for sentinel lymph-node detection. PET scanners do not require a collimator, but rely of the near simultaneous arrival of two photons of a characteristic energy in opposed detectors (lower panels). This is termed coincidence. The photons have an energy of 511 keV, which is the energy released when an orbital electron undergoes an annihilation reaction with a positron emitted from the nucleus. 84 By joining many lines of coincidence, a tomographic image is obtained. The right lower panels are an example of FDG PETCT for detection of small malignant melanoma metastases. Abbreviations: FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

reactor), Belgium (BR2 reactor), South Africa (SAFARI reactor) and Australia (Open Pool Australian Light-water reactor [OPAL]). 21 These are all multipurpose research reactors that have been established with public funds. Although the costs of target separation, assembling and distributing the generators are performed to some extent in the private market, the reactor investment and decommissioning is heavily subsidized. None of these multipurpose reactors would be commercially viable for medical isotope production alone.22 The way in which SPECTCT is subsidized is contrasted by cyclotron- produced PET radiopharmaceuticals, in which the cost

of equipment and staff is usually fully absorbed by the hospital or the commercial provider. The radioisotopes used for SPECTCT that are not produced in nuclear reactors are generally produced in large cyclotrons, including 201Tl, 67Ga and 123I. However, because of the slow radioactive decay of these agents, they can be produced in bulk and distributed nationally or internationally, thereby reducing the cost of radiotracers to individual patients. There are other available radionuclides that, because of their biological, physical or chemical properties, lend themselves to be good candidates in the evaluation of cancerrelated processes through SPECTCT.
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PERSPECTIVES
Box1 | Technical advantages of PET compared to SPECT Higher sensitivity for detecting radioactive decay More photons are collected due to the geometry of PET scanners, which surround the body with a ring of detectors, compared with a SPECT system, which is limited by a physical collimator (Figure1) and requires planar detectors to rotate around the body to acquire a tomographic image. Only 0.01% of photons emitted are detected with SPECT, compared with approximately 1% with PET.83 Higher spatial resolution SPECT requires a physical collimator (Figure1), which generally limits the ability of this technique to separate small radioactive objects.83 The crystals in PET are smaller and rely on very accurate timing windows to identify simultaneously released annihilation photons. The smallest objects resolved by PET are less than half the size of those resolved by most SPECT systems used in clinical practice. Positron range and the short distance travelled by the emitted positrons before being annihilated and releasing photons, theoretically limit spatial resolution of PET compared with SPECT, but this is not clinically relevant when using radiotracers with high tumour-to-background contrast. Higher temporal resolution The crystals used in PET scintillate faster than those used in SPECT cameras, enabling faster acquisition of data.84 PET also enables acquisition of dynamic images in tomographic mode allowing three-dimensional analysis of processes that occur over a short timeframe. Quantitative capability There are several corrections that can be performed to enable the images acquired by PET to be calibrated accurately for the amount of radioactivity in a given volume. Such correction factors are generally less robust or not available for SPECT. Lower radiation dose The combination of greater sensitivity of the scanner, allowing administration of lower activities of radiotracersand generally shorter decay periods of PET radionuclidesthat limit cumulative radiation exposure, means that many PET-based studies have more favourable radiation dose characteristics than their SPECT equivalent.
Abbreviations: PET, positron emission tomography; SPECT, single-photon emission computed tomography.

uptake of the radiotracer. This distance is determined by the positron range and can be as high as 1.7 mm for the positron emitter 68Ga.32 This theoretical limitation, however, is not clinically relevant when using radiotracers with high uptake that facilitate confident localization through high contrast.33,34

The appeal of PETCT

Scanners The growing clinical recognition of the utility of FDG as an oncological tracer has contributed to a dramatic increase in the number of PETCT scanners installed globally over the past decade. As a result of increasing automation of the manufacturing process and greater investment in technological innovation, the cost of purchasing and operating PET scanners has been reduced considerably. In the 10years since we installed our first PETCT, these costs have been reduced by approximately 50% in real terms. Technical advances, such as better detectors and time-of-flight (TOF) imaging, have improved performance of PETCT dramatically.35 TOF detects small differences (in the order of 500 ps) between photon arrivals, which results in a more accurate localization of positron annihilation events. 36 This marked improvement has led not only to better image quality but also to a dramatic decrease in scan acquisition times with whole-body PETCT imaging now possible in less than 15 min.37 With conventional gamma camera scintigraphy, a whole-body survey currently takes 1530 min in planar mode, plus an additional 2060 min for multiple step SPECTCT. Accordingly, a PETCT scanner can be used to scan three to four patients per hour compared with one to two patients when using a SPECTCT scanner. Ignoring the technical advantages of PET and provided there are enough patients to use the scanner efficiently, the capital equipment cost per patient of each of these technologies can be similarly amortized to that of SPECT.38 Shorter scan times are also appreciated by patients, particularly those with cancer who are often subjected to multiple investigations and suffer from pain related to their disease. Additionally, more-accurate diagnosis also has the ability to reduce costs associated with treatment by selecting better whom to deliver expensive and potentially toxic therapies.39 Gathering accurate dataeven within countrieson the true operating costs of SPECTCT or PETCT is challen ging.
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Radioiodine (123I) and 131I have already been mentioned in reference to diagnosis and treatment of thyroid cancer, but can also be used to label a range of biological molecules, including monoclonal antibodies. For example, radiolabelled anti-CD20 antibodies, such as 131I-tositumomab, are available for treating follicular lymphoma.23 Radiometals including 111In and 67Ga, both long-lived and cyclotron-produced radionuclides, have also found application in nuclear oncology. 111In has been used to label peptidessuch as the somatostatin analogue octreotidefor imaging and treatment of neuroendocrine tumours. 24 111 In is also used to label cells, including white blood cells, for diagnosis of occult infective processes,25 an important cause of morbidity and death in patients with cancer. 67 Ga-citrate is concentrated in certain lymphomas and in most melanoma cells that express transferrin receptors, which bind and transport this agent intracellularly.26,27 67 Ga scintigraphy provided the cornerstone for functional imaging of lymphoma by assessing whether a residual mass that persists after treatment represents viable lymphoma (which requires further treatment) or benign fibrotic and necrotic tissue.28 The advantage of longer-lived radionuclides
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is that they make it feasible to image biological processes that occur slowly, over days, rather than minutes orhours. By contrast, most of the radionuclides that are produced by small clinical cyclotrons that support PET facilities decay rapidly. A large number of biological compounds have been labelled with 11C and have favourable chemical properties for investigating cancer-related biological processes as they can be incorporated into almost any organic compound of interest unlike radiometals used in SPECTCT.29 The short half-life of 20 min, however, makes it somewhat impractical for routine clinical use. Therefore, the application of PETCT in oncology has been driven almost entirely by the use of a single radionuclide, 18F, which has a half-life of 110 min and is synthesized into a single radiotracer, 18 F-fluorodeoxyglucose (FDG). FDG currently accounts for well over 90% of all oncological PET studies.30 Another potential advantage of SPECT CT is its, theoretically, higher spatial resolution compared with PETCT.31 This higher spatial resolution occurs because the production of the photons detected with PET following the annihilation event takes place a short distance away from the actual

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FOCUS ON IMAGING
Table 1 | SPECT tracers with their PET replacement Cancer type
General cancer imaging Lymphoma/melanoma Thyroid cancer Peptide receptors Sympathetic nervous system tumours Glioma Bone marrow Antigenic targets Bone metastases Renal function Cardiac function Lung function (ventilation/perfusion) Hepatobiliary Infection

SPECT
201 67

PET (regulatory status)

FDG (approved) FDG (approved)
124 68

Tl, 99mTc-sestamibi

Ga-citrate I,
131

123 111 123 201

I, pertechnetate

I (investigational)85

In-DTPA-peptide I-MIBG Tl Tc-nanocolloids, etc.

111

Ga-DOTA-peptide (institutional clinical use/investigational)86 I-MIBG,87,88 18F-DOPA (investigational)89

124

FET (institutional clinical use) FLT (institutional clinical use/investigational)

89 18 68 68 99m

99m 131

I-,

In-MoAb

Zr-MoAb (investigational)67 F-fluoride,77 68Ga-bisphosphonates (institutional clinical use/investigational)90 Ga-EDTA (institutional clinical use/investigational)91 Ga derivatives (investigational)92

99m 99m 99m

Tc-MDP Tc-DTPA/MAG3/DMSA Tc-RBC Tc-MAA

Technegas/
99m 67

Galligas/68Ga-MAA (institutional clinical use/investigational)78,93

68

Tc-HIDA
99m

Ga-IDA (investigational)94

Ga,

Tc-WBC

FDG, FDG-WBC (approved/investigational)95

Abbreviations: DMSA, dimercaptosuccinic acid; DOPA; dihydroxyphenylalanine; DOTA, tetraazacyclododecanetetraacetic acid; DTPA, diethylenetriaminepentaacetic acid; EDTA, ethylenediaminetetraacetic acid; FDG, 18F-fluorodeoxyglucose; FET, 18F-fluoroethyltyrosine; FLT, 18F-fluorothymidine; HIDA, hepatobiliary iminodiacetic acid; IDA, iminodiacetic acid; MAA, macroaggregated albumin; MAG3, mercaptoacetyltriglycine; MDP, methylene diphosphonate; MIBG, metaiodobenzylguanidine; MoAb, monoclonal antibody; PET, positron emission tomography; RBC, red blood cell; SPECT, single-photon emission computed tomography; WBC, white blood cell.

It becomes even more difficult when the variations in costs among providers of the same modality have to be taken into account. For instance, in Australia, an unpublished survey of existing PET facilities documented that the highest-cost provider of PET indicated more than 100% higher costs than the lowest-cost provider. The major factor in this difference was not capital or consumable costs, but the number of scans carried out. The influences of the market determine the capital costs of equipment, as does the technical specifications of equipment. TOF, extended field of view, and different crystal materials all impact considerably on the purchase price of the scanner. The type of CT, number of heads, detector type and size, and collimator choices, can all similarly affect in a major way the cost of SPECTCT systems. In the past 15years, our centre has operated six different PET devices, all with better performance than the last and all less expensive than the one before. In our facility, the resource cost of PETCT is considerably lower than SPECTCT because of our throughput. We currently perform over 6,000scans per year on two diagnostic scanners and another 1,000scans on a dedicated radiotherapy planning scanner, which has lower throughput capacity due to patient set-up times. This particular situation, however, cannot be extended to other facilities as few places outside an imagingdedicated cancer centre could currently achieve this throughput.
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Radiopharmaceuticals The price and range of radiopharmaceuticals available is a key element that may be a further contributing factor in the decline of SPECTCT. As stated previously, until recently, the supply of isotopes for SPECT has been largely subsidized by government investment in nuclear technologies for strategic and public service motivations. However, public concern about the risk of nuclear reactors and the increasing regulatory costs to ensure public safety has made medical reactors less politically palatable. Therefore, many governments are not reinvesting in replacement of reactors; for example, the replacement of the Multipurpose Applied Physics Lattice Experiment (MAPLE) reactors in Canada, which had previously achieved private investment in the production of medical isotopes, has been halted. 40 By reducing public subsidy, the cost of SPECT isotopes has increased significantly in recent years. Furthermore, during a recent period of planned maintenance of some existing reactors and unexpected closure of others, there was a critical shortage of reactorbased radionuclides globally, particularly with respect to the supply of 99Mo forgenerators.41 Against this backdrop of increasing SPECT tracer costs, the efficiency of the production and distribution of PET isotopes along with reduced costs has improved dramatically. In the early years of PET practice, there was typically a cyclotron in each

centre supplying a single PET scanner that was able to perform only a small number of assessments. The physical decay of 18F is sufficiently slow to allow regional distribution of tracers and has created an international industry based on centralized PET radiopharmacies. Now, corporate suppliers can support a large number of PET facilities that do not have cyclotrons. These facilities are able to produce FDG and other tracers under increasingly stringent conditions of good manufacturing practice, amortizing the high compliance costs by delivering a greater number of patient doses.38 Not requiring a cyclotron reduces the invest ment costs for an imaging service provider. The ability to perform PET imaging without the need for a cyclotron has been further enhanced by availability of the 68Ge and 68Ga generator.42 This so-called positron cow was described by Yukio Yano and Hal Anger in 1964,43 around the same time that interest was growing in medical applications of the 99mTc generator. By 1966, the radiotracer 68GaEDTA had been described for the use of imaging of brain lesions in 96patients, 44 but interest sub sequently waned as evolving gamma camera technology was unsuitable for positron imaging due to the high energy photons emitted by PET agents, which require heavy collimation that reduces both resolution and sensitivity of photon detection. 68Ga-labelled somatostatin analogue PETCT has been rapidly adopted (where available) for the staging of neuroendocrine tumours because of its
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a b

201

TI-chloride

T1 MRI with gadolinium contrast

Although the vast majority of PETCT studies performed internationally use FDG, it is by no means the only PET tracer pertinent to oncology. There is a specific PET radiotracer for almost all current applications for which SPECT tracers are used (Table1). The major impediment to their routine clinical use is a regulatory environment that requires new standards of evidence for the safety and clinical utility than those standards that were in place when most SPECT tracers became licensed and eligible for reimbursement.49 However, the regulatory approval processes that apply to PET will also be increasingly relevant to development costs and pricing of novel SPECT tracers. Although regulatory environments may restrict and delay innovations in imaging, this should not prevent making the case that the best technology should be used wherever possible to reach the appropriate diagnosis and managementplan.

FDG
201

FET

Figure 2 | Brain imaging with Tl, FDG and FET. a | SPECT imaging of brain tumours including glioma is generally carried out using 201Tl. b | 201Tl is taken up actively and retained by tumour cells, but requires disruption of the blood-brain barrier as demonstrated on MRI. Therefore, it is not suitable for some low-grade tumours that do not disrupt this barrier. c | The PET tracers FDG and FET do not rely on disruption of the blood-brain barrier. Some brain lesions have sufficiently high uptake of FDG to be visualized above the high background activity in the normal brain, but many do not, especially in the post-treatment setting. d | Because FET is not concentrated to any significant extent by normal brain tissue, it tends to provide higher lesion contrast and, therefore, better delineation of disease. Although both acquired on a PETCT device, these images have been co-registered with MRI to demonstrate the relationship of recurrent tumour to a prior resection cavity. Abbreviations: FDG, 18F-fluorodeoxyglucose; FET, 18F-fluoroethyltyrosine; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

convenience and superior diagnostic capability compared to 111In-DTPA-octreotide SPECTCT.45,46 The 68 Ga generator also provides a convenient and economical source of radioisotope for a range of new PET imaging applications, with a generator shelf-life of approximately 1 year, compared to 12 weeks for the 99mTc generator.47 68Ga has ideal properties for imaging with a short half-life of 68 min (minimizing radiation dose to the patient) and the ability to form stable complexes with convenient coupling to a variety of small biomolecules such as octreotide or its analogues.48 This approach has the
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potential to be performed with kits that are analogous in function to those kits used in conventional SPECT imaging, which enables on-site and on-demand production. If the accessibility, the direct capital and major operating costs of PETCT compete with SPECTCT as described above, the major remaining argument in support of the use of SPECTCT over PETCT has been the availability of a larger palette of radiopharmaceuticals to address important clinical problems relevant to patients with cancer. However, this argument can now be countered as well, owing to recent developments in PET radiopharmaceuticals.

New PET tracers: the game changers The utility of FDG in oncology is such that some would argue that no other PET tracers are required. Since FDG was first recognized as being useful in evaluating brain tumours,50 it has gradually become the most widely used radiopharmaceutical in clinical oncology for the purpose of staging and therapeutic response assessment. Stand-alone PET using FDG has been shown to be substantially more accurate than conventional imaging techniques in staging many different cancer types,51 and PETCT has further improved on this.52 Where available, FDG PETCT has effectively replaced a range of nonspecific SPECT tumour-imaging agents, including 201 Tl, 99mTc-sestamibi and 67Ga-citrate.53,54 There are, however, recognized limitations of FDG. For brain imaging, high background cerebral glycolytic activity limits its sensitivity for detection of malignancy. Fluorinated amino acids, especially 18 F-fluoroethyltyrosine (FET), 55,56 have overcome this limitation of PETCT by virtue of low uptake in normal brain tissue (Figure2). Some malignancies, including more-indolent prostate and breast cancers, have low glycolytic metabolism, but can be detected by imaging choline metabolism, an essential micronutrient for cell membrane synthesis and phospholipid metabolism, with 18F-fluorocholine (FCH).57,58 18 F-fluorothymidine (FLT), a tracer of cell proliferation,59 addresses the limitation of FDG that results from its uptake in inflammatory processes.
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More-specific techniques that target particu lar biological characteristics of cancer subtypes have also been a feature of standard nuclear oncology practice. Examples include 131I-iodide for imaging the sodium-iodide cotransporter (also known as sodium-iodide symporter) on thyroid cancer cells, 131I-metaiodobenzylguanidine (MIBG) for imaging catecholamine reuptake in tumours of the sympathetic nervous system, and 111In-octreotide for imaging somatostatin receptor expression on neuroendocrine tumours. 60,61 All these agents require injection on one day and the patient returning 24 h later. There are now PET equivalents that allow imaging as early as 1 h after the injection of the radioisotopes owing to higher contrast. 124I-iodide has been used for PETCT imaging of thyroid cancer and, because of the quantitative capacity of PETCT, it can also be used to estimate the radiation dose to thyroid cancer metastases.62 However, it must be conceded that the characteristics of some PET radionuclides, including 124I, are less than ideal.63 Imaging of the biodistribution of monoclonal antibodies has long been possible with radionuclides suitable for SPECT imaging, but it has not become a real mainstream clinical application. However, with an increasing number of immunological agents entering the therapeutic domain, there is an impetus for this application to be revisited. There are a variety of positron emitters that have sufficiently slow decay to image the gradual accumulation of antibodies in cancer deposits, including 64 Cu, 89Zr and 124I.64,65 89Zr-labelled monoclonal antibodies are a particularly attractive option, especially with recent antibody-drug conjugates under assessment in early phase clinical trials.66,67 A major advantage of PETCT is the noninvasive quantification of regional radiotracer uptake. This ability is changing the paradigm of imaging from a primary role of anatomic lesion identifi cation and measurement, to a role in identification and quantifi cation of targets suitable for targeted therapy.68 As described above, 68Ga-labelled somatostatin analogue PETCT has been rapidly adopted, where available, for the staging of neuroendocrine tumours. Combined with FDGPETCT, this approach is providing major new insights by identifying patients with tumour hetero geneity and sites of well-differentiated (indolent) and poorlydifferentiated (aggressive) disease at different sites.69 This improvement is enabling
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a
Tomographic

b
Planar

18F-

ouride PET

99mTc-MDP

18F-

uoride PET

99mTc-MDP

planar

18F-

uoride PET CT

Correlative CT

Figure 3 | Bone imaging with 18F-fluoride and 99mTc-MDP. a | 18F-fluoride PETCT provides a whole-body tomographic image in around 15 min whereas b | a planar 99mTc- MDP whole-body bone scan takes 1530 min. Obtaining SPECTCT adds around 15 min of scan acquisition time per region (of approximately 50 cm length). Detail from the PETCT study (parta) demonstrates the superior detail compared with planar imaging (part b). c | The superior spatial and contrast resolution of PETCT enables detection and localization of bone abnormalities that are detected with less sensitivity on SPECTCT (data not shown). Abbreviations: MDP, methylene diphosphonate; PET, positron emission tomography; SPECT, single-photon emission computedtomography.

a better selection of the most appropriate therapy for an individual patient, and highlights the limitations of relying on histopathology obtained from a single site. A similar ability to select and monitor therapy is provided by 18F-fluoroestradiol (FES) and 89Zr-trastuzumab, which allows PET imaging of oestrogen receptor (ER)

and HER2 targets in breast cancer. 70,71 Noninvasive quantification may also enable better dosing and cycling of treatment.72,73 Beyond directly imaging the cancer cell, a common strategy in nuclear medicine has been to image derangement of normal tissue function. A common example is the 99mTc-bone scan used for identifying
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PERSPECTIVES
osseous metastases from prostate and breast cancer, as well as primary bone malignancies, suchas osteosarcoma. 74 However, 18 F-fluoride, a chemical that can be produced in large quantities by clinical cyclotrons, also has high uptake in actively forming bone.75 Its rapid clearance from normal tissues and high localization to bone combined with the technical superiority of PET, leads to significantly higher image quality, sensitivity and specificity than the SPECTCT equivalent (Figure3).76 As well as providing superior images, the time taken for tracer uptake is shorter, and the total imaging time to acquire a whole-body, tomographic image is also much less than the time required for a whole-body planar image of one or more regions of interest.77 These factors increase the convenience for patients considerably. In addition to those investigations that are primarily carried out to identify sites of malignancy, nuclear medicine has had a role in assessing normal organ function to predict or monitor the side-effects of treatment. Common applications include assessment of renal function using 99mTcrenography, of cardiac function using 99m Tc-gated cardiac blood pool scanning, of respiratory function using ventilationperfusion scanning, and of bone marrow function using a range of techniques including 99mTc-labelled white blood cells or micro-colloids that are extracted by the reticuloendothelial system.18 The availability of 68Ga-generators provides the same flexibility and accessibility as 99mTc-agents with the added benefit of the technical superiority of PET and its quantitative potential. Ventilation-perfusion scanning is an example of an area in which we have substituted 99mTc for 68Ga to perform the study with PETCT.78 used in cardiology and neurology. Similar arguments can be proposed both in favour and against the ongoing use of SPECTCT compared with PETCT. We believe that these arguments are as, or more, persuasive in many of these applications than they are in oncology. Another advantage of SPECT imaging is the ability to perform simultaneous imaging of different radiotracers, which can interrogate different biological functions.81 Such multitracer imaging is possible because different single photon-emitting radiotracers emit photons of different energies, as opposed to PET radiotracers, which all result in the emissions of 511 keV photons. With CZT-based devices, it would also be feasible to carry out both SPECTCT and PETCT.82 Whether these technical performance enhancements would make SPECT CT competitive with PETCT remains to be seen.
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Conclusions
The efficiency inherent to high-throughput PETCT scanning, combined with its technical superiority and an increasing array of PET tracers, suggests that although SPECTCT remains a highly valuable tool in clinical oncology, it will eventually have a similar fate to the rectilinear scanner; that is, replaced by a faster, more accurate and convenient scanning technology. Although perceived as being considerably more expensive, the actual costs of PETCT need to be re-evaluated given its superior speed, efficiency and cost savings associated with more-accurate diagnosis. Systemic impediments to the wider availability of PETCT need to be addressed. These include regulatory hurdles to introducing new tracers and restriction of reimbursement that limits efficient use of valuable capital resources.
University of Melbourne, Departments of Medicine and Radiology, The Peter MacCallum Cancer Centre, 7St Andrews Place, Melbourne,VIC 3002, Australia (R. J. Hicks, M.S.Hofman). Correspondence to: R. J. Hicks rod.hicks@petermac.org
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What factors may save SPECTCT?

Technological advances have the potential to usher a new era of SPECT imaging. Foremost, is the development of new solidstate detectors using compounds such as cadmium zinc telluride (CZT), which clearly outperform current detectors with higher sensitivity, and spatial and temporal resolution. 79 Although CZT-based dedicated cardiac devices are available,80 a solid-state SPECTCT for general imaging has not yet reached commercial production because the cost is currently prohibitive. It must be recognized that there are many other disease applications beyond oncology that underpin the use of SPECTCT in nuclear medicine, including investigations
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