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IntroductionLong 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 pro-cesses.1 In fact, it was not until after almost half a century from his seminal experi-ment 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 cre-ation of the new specialty of nuclear medi-cine. 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 Anger’s 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

proven limited when there were multiple overlapping structures containing radio-activity. 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 objects—a forerunner of CT—and estab-lished 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 recon-struction of the distributions of radio activity within the body (emission scans) have funda mentally 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 radio-nuclides 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 Figure 1.

Oncology has benefitted particularly from the development of SPECT capabi-lity on gamma cameras in the 1980s and from the commercial availability of PET scanners that were able to perform whole-body imaging since the 1990s. This benefit was due to the ability of these techniques to localize sites of disease, especially if correla-ted directly with anatomical imaging. This correlative capability was dramatically enhanced by hybrid SPECT–CT and PET–CT systems, wherein CT is integrated into the device to provide contemporaneous anatomical information. The first com-mercial PET–CT 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 PET–CT, particularly in onco logy. Current PET technology has clear techni-cal superiority compared with SPECT, with higher sensitivity for detecting radio-active decay, higher resolution and supe-rior quanti tative capability (Box 1). We will review some advantages of SPECT–CT and the reasons why it currently remains a domi-nant technology. In our opinion, however, arguments in favour of SPECT–CT are becoming increasingly difficult to sustain given the advantages of PET–CT scanner technology and the array of new PET radiopharmaceuticals. As PET techno logy becomes more accessible and cheaper, it is timely to question whether SPECT–CT will have an ongoing role in clinical oncology.

Advantages of SPECT–CTThree reasons have traditionally been given as to why SPECT technology should conti nue 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 difficul t to sustain.

Is there still a role for SPECT–CT in oncology in the PET–CT 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. PET–CT has clear technical superiority including superior resolution, speed and quantitative capability. SPECT–CT 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. PET–CT 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 PET–CT make a cogent argument for it becoming the dominant molecular technique in oncology.

Hicks, R. J. & Hofman, M. S. Nat. Rev. Clin. Oncol. 9, 712–720 (2012); published online 13 November 2012; doi:10.1038/nrclinonc.2012.188

Competing interestsThe authors declare no competing interests.

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There are already thousands of gamma cameras in use globally in the clinic and now SPECT–CT devices are entering the medical environment. These more sophisti-cated SPECT–CT devices are configured with SPECT and multislice CT on a single gantry that enables both functional and anatomic imaging to be acquired simul-taneously.11 The CT data not only enables precise anatomic localization and correla-tion of any SPECT abnormality, but also provides an attenuation map enabling more accurate reconstruction of the SPECT data, including quantitative capabilities.12 SPECT–CT is now used in a wide range of diseases including endocrinology, cardio-logy and neurology.13 Although growing rapidly, the number of installed PET–CT scanners is significantly smaller than the number of SPECT–CT scanners, making this techno logy less accessible to patients with cancer. Lower capital investment, service and maintenance costs for SPECT–CT than for PET–CT currently preserve this imbalance. However, the costs of these technologies are primarily driven by patient throughput.14

The role of SPECT–CT in oncology has also been primarily supported by the availa-bility of a large number of radiotracers, many of which are based on the radio isotope 99mTc.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 1–2 weeks. 99mTc has a decay half-life of 6 h, allowing its use over the course of a day.17 Many 99mTc-based radio pharmaceuticals have a role in oncology, either in detecting and staging malignancies, or in assessing organ function prior to or after treatment.18 These SPECT radio pharmaceuticals are readily available through use of commer-cially available kits that are typically freeze-dried 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 hydroxy methane diphosphonate (HDP) kits used for bone scintigraphy.20

There are large national and inter national infrastructure programmes that support radiopharmaceutical production and deliv-ery, which minimize the operating costs of SPECT–CT. 99mT production from 99Mo occurs predominantly in six nuclear reac-tors located in Canada (National Research Universal reactor [NRU]), Netherlands (High Flux Reactor [HFR]), France (OSIRIS

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 distribu-ting the gener ators are performed to some extent in the private market, the reactor investment and decommissioning is heavily subsidized. None of these multi purpose reactors would be commercially viable for medical isotope production alone.22 The way in which SPECT–CT is subsidized is contrasted by cyclotron- produced PET radio pharmaceuticals, in which the cost

of equipment and staff is usually fully absor bed by the hospital or the commer-cial provider. The radioisotopes used for SPECT–CT that are not produced in nuclear reactors are generally produced in large cyclo trons, including 201Tl, 67Ga and 123I. However, because of the slow radio active decay of these agents, they can be produced in bulk and distributed nationally or inter-nationally, 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 cancer- related processes through SPECT–CT.

Orbital electron

Positron fromnucleus

Annihilation reaction

SPECTDetector

PET

Crystal

Collimator

Photons

511 keV

511 keV

Collimator

Coincidence detectors

Surface rendered SPECT-CT

Volume-rendered SPECT-CT

Volume-rendered PET-CT

Transaxial PET-CT

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 PET–CT for detection of small malignant melanoma metastases. Abbreviations: FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

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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 mol-ecules, including monoclonal anti bodies. For example, radiolabelled anti-CD20 anti-bodies, such as 131I-tositumomab, are avail-able for treating follicular lymphoma.23 Radiometals including 111In and 67Ga, both long-lived and cyclotron-produced radio-nuclides, have also found application in nuclear oncology. 111In has been used to label peptides—such as the somatostatin analogue octreotide—for imaging and treatment of neuroendocrine tumours.24 111In 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. 67Ga-citrate is concentrated in certain lym-phomas and in most melanoma cells that express transferrin receptors, which bind and transport this agent intracellularly.26,27 67Ga scintigraphy provided the cornerstone for functional imaging of lymphoma by assessing whether a residual mass that per-sists after treatment represents viable lym-phoma (which requires further treatment) or benign fibrotic and necrotic tissue.28 The advantage of longer-lived radionuclides

is that they make it feasible to image bio-logical processes that occur slowly, over days, rather than minutes or hours.

By contrast, most of the radionuclides that are produced by small clinical cyclo-trons 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 SPECT–CT.29 The short half-life of 20 min, however, makes it somewhat impractical for routine clinical use. Therefore, the application of PET–CT in oncology has been driven almost entirely by the use of a single radio-nuclide, 18F, which has a half-life of 110 min and is synthesized into a single radiotracer, 18F-fluorodeoxyglucose (FDG). FDG cur-rently accounts for well over 90% of all oncological PET studies.30

Another potential advantage of SPECT–CT is its, theoretically, higher spatial resolu-tion compared with PET–CT.31 This higher spatial resolution occurs because the pro-duction of the photons detected with PET following the annihilation event takes place a short distance away from the actual

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 PET–CTScannersThe growing clinical recognition of the utility of FDG as an oncological tracer has contributed to a dramatic increase in the number of PET–CT scanners installed globally over the past decade. As a result of increasing automation of the manufac-turing process and greater investment in technological innovation, the cost of pur-chasing and operating PET scanners has been reduced considerably. In the 10 years since we installed our first PET–CT, 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 PET–CT dramatically.35 TOF detects small differences (in the order of 500 ps) between photon arrivals, which results in a more accurate localization of positron annihi-lation events.36 This marked improve-ment has led not only to better image quality but also to a dramatic decrease in scan acquisition times with whole-body PET–CT imaging now possible in less than 15 min.37 With conventional gamma camera scintigraphy, a whole-body survey currently takes 15–30 min in planar mode, plus an additional 20–60 min for multiple step SPECT–CT. Accordingly, a PET–CT scanner can be used to scan three to four patients per hour compared with one to two patients when using a SPECT–CT 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 amor-tized 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 data—even within countries—on the true operating costs of SPECT–CT or PET–CT is challen ging.

Box 1 | Technical advantages of PET compared to SPECT

Higher sensitivity for detecting radioactive decayMore 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 (Figure 1) 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 resolutionSPECT requires a physical collimator (Figure 1), 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 resolutionThe 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 capabilityThere 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 doseThe combination of greater sensitivity of the scanner, allowing administration of lower activities of radiotracers—and generally shorter decay periods of PET radionuclides—that 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.

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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 facili-ties documented that the highest-cost provi der 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 specifi-cations of equipment. TOF, extended field of view, and different crystal materials all impact consider ably on the purchase price of the scanner. The type of CT, number of heads, detector type and size, and colli-mator choices, can all similarly affect in a major way the cost of SPECT–CT systems. In the past 15 years, our centre has oper-ated six different PET devices, all with better performance than the last and all less expensive than the one before. In our faci-lity, the resource cost of PET–CT is consi-derably lower than SPECT–CT because of our throughput. We currently perform over 6,000 scans per year on two diagnos-tic scanners and another 1,000 scans on a dedicated radiotherapy planning scanner, which has lower throughput capacity due to patient set-up times. This particular situ-ation, however, cannot be extended to other facilities as few places outside an imaging- dedicated cancer centre could currentl y achieve this throughput.

RadiopharmaceuticalsThe price and range of radiopharma-ceuticals available is a key element that may be a further contributing factor in the decline of SPECT–CT. As stated previ-ously, until recently, the supply of isotopes for SPECT has been largely subsidized by government investment in nuclear techno-logies for strategic and public service moti-vations. 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 reac-tors; 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 reactor-based radionuclides globally, particu-larly with respect to the supply of 99Mo for generators.41

Against this backdrop of increasing SPECT tracer costs, the efficiency of the production and distribution of PET iso-topes along with reduced costs has improved drama tically. In the early years of PET prac-tice, 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 suffici ently slow to allow regional distri-bution of tracers and has created an inter-national industry based on centralized PET radiopharmacies. Now, corporate suppliers can support a large number of PET facili ties that do not have cyclotrons. These facili ties 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 provi der. The ability to perform PET imaging without the need for a cyclotron has been further enhanced by availabi lity of the 68Ge and 68Ga generator.42 This so-called ‘posi-tron cow’ was described by Yukio Yano and Hal Anger in 1964,43 around the same time that interest was growing in medical appli-cations of the 99mTc generator. By 1966, the radiotracer 68Ga–EDTA had been described for the use of imaging of brain lesions in 96 patients,44 but interest sub sequently waned as evolving gamma camera techno-logy was unsuitable for positron imaging due to the high energy photons emitted by PET agents, which require heavy collimation that reduces both resolu tion and sensitivity of photon detection. 68Ga-labelled somato-statin analogue PET–CT has been rapidly adopted (where available) for the staging of neuroendocrine tumours because of its

Table 1 | SPECT tracers with their PET replacement

Cancer type SPECT PET (regulatory status)

General cancer imaging 201Tl, 99mTc-sestamibi FDG (approved)

Lymphoma/melanoma 67Ga-citrate FDG (approved)

Thyroid cancer 123I, 131I, pertechnetate 124I (investigational)85

Peptide receptors 111In-DTPA-peptide 68Ga-DOTA-peptide (institutional clinical use/investigational)86

Sympathetic nervous system tumours 123I-MIBG 124I-MIBG,87,88 18F-DOPA (investigational)89

Glioma 201Tl FET (institutional clinical use)

Bone marrow 99mTc-nanocolloids, etc. FLT (institutional clinical use/investigational)

Antigenic targets 131I-, 111In-MoAb 89Zr-MoAb (investigational)67

Bone metastases 99mTc-MDP 18F-fluoride,77 68Ga-bisphosphonates (institutional clinical use/investigational)90

Renal function 99mTc-DTPA/MAG3/DMSA 68Ga-EDTA (institutional clinical use/investigational)91

Cardiac function 99mTc-RBC 68Ga derivatives (investigational)92

Lung function (ventilation/perfusion) Technegas/99mTc-MAA Galligas/68Ga-MAA (institutional clinical use/investigational)78,93

Hepatobiliary 99mTc-HIDA 68Ga-IDA (investigational)94

Infection 67Ga, 99mTc-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.

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convenience and superior diagnostic capa-bility compared to 111In-DTPA-octreotide SPECT–CT.45,46

The 68Ga generator also provides a conveni ent and economical source of radio-isotope for a range of new PET imaging applications, with a generator shelf-life of approximately 1 year, compared to 1–2 weeks for the 99mTc generator.47 68Ga has ideal prop-erties for imaging with a short half-life of 68 min (minimizing radiation dose to the patient) and the ability to form stable com-plexes with convenient coupling to a variety of small biomolecules such as octreotide or its analogues.48 This approach has the

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 PET–CT compete with SPECT–CT as described above, the major remaining argument in support of the use of SPECT–CT over PET–CT has been the availability of a larger palette of radiopharmaceuticals to address impor-tant clinical problems relevant to patients with cancer. However, this argument can now be countered as well, owing to recent develop ments in PET radio pharmaceuticals.

Although the vast majority of PET–CT studies performed internationally use FDG, it is by no means the only PET tracer perti-nent to onco logy. There is a specific PET radiotracer for almost all current applica-tions for which SPECT tracers are used (Table 1). The major impediment to their routine clinical use is a regulatory environ-ment that requires new standards of evidence for the safety and clini cal utility than those standards that were in place when most SPECT tracers became licensed and eligi ble for reimbursement.49 However, the regula-tory approval processes that apply to PET will also be increasingly relevant to develop-ment 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 appropriat e diagnosis and management plan.

New PET tracers: the game changersThe 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 radio pharmaceutical in clinical oncology for the purpose of staging and therapeutic response assess-ment. Stand-alone PET using FDG has been shown to be substantially more accu-rate than conventional imaging techniques in staging many different cancer types,51 and PET–CT has further improved on this.52 Where available, FDG PET–CT has effectively replaced a range of nonspecific SPECT tumour- imaging agents, including 201Tl, 99mTc-sestamib i and 67Ga-citrate.53,54

There are, however, recognized limita-tions of FDG. For brain imaging, high background cerebral glycolytic activity limits its sensitivity for detection of malig-nancy. Fluorinated amino acids, especially 18F-fluoroethyltyrosine (FET),55,56 have overcome this limitation of PET–CT by virtue of low uptake in normal brain tissue (Figure 2). 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 mem-brane synthesis and phospholipid meta-bolism, with 18F-fluorocholine (FCH).57,58 18F-fluorothymidine (FLT), a tracer of cell proliferation,59 addresses the limita-tion of FDG that results from its uptake in inflammator y processes.

a

c d

b

201TI-chloride T1 MRI with gadolinium contrast

FDG FET

Figure 2 | Brain imaging with 201Tl, 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 PET–CT 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.

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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 reup-take in tumours of the sympathetic nervous system, and 111In-octreotide for imaging somatostatin receptor expression on neuro-endocrine 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 PET–CT imaging of thyroid cancer and, because of the quantitative capacity of PET–CT, it can also be used to estimate the radiation dose to thyroid cancer meta stases.62 However, it must be conceded that the character istics 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 immuno-logical agents entering the therapeutic domain, there is an impetus for this appli-cation to be revisited. There are a variety of positron emitters that have suffici ently slow decay to image the gradual accumulation of anti bodies in cancer deposits, including 64Cu, 89Zr and 124I.64,65 89Zr-labelled mono-clonal 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 PET–CT 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 measure ment, to a role in identifica-tion and quantifi cation of targets suit-able for targeted therapy.68 As described above, 68Ga-labelled somatostatin analo-gue PET–CT has been rapidly adopted, where available, for the staging of neuro-endocrine tumours. Combined with FDG–PET–CT, this approach is providing major new insights by identi fying patients with tumour hetero geneity and sites of well-differentiated (indolent) and poorly-differentiated (aggressive) disease at dif-ferent sites.69 This improvement is enabling

a better selection of the most appropri-ate 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

a

c

b

Tomographic

Planar

99mTc-MDP18F-�ouride PET

99mTc-MDP planar18F-�uoride PET

18F-�uoride PET CT Correlative CT

Figure 3 | Bone imaging with 18F-fluoride and 99mTc-MDP. a | 18F-fluoride PET–CT provides a whole-body tomographic image in around 15 min whereas b | a planar 99mTc- MDP whole-body bone scan takes 15–30 min. Obtaining SPECT–CT adds around 15 min of scan acquisition time per region (of approximately 50 cm length). Detail from the PET–CT study (part a) demonstrates the superior detail compared with planar imaging (part b). c | The superior spatial and contrast resolution of PET–CT enables detection and localization of bone abnormalities that are detected with less sensitivity on SPECT–CT (data not shown). Abbreviations: MDP, methylene diphosphonate; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

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osseous metastases from prostate and breast cancer, as well as primary bone malignan-cies, such as osteosarcoma.74 However, 18F-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 signifi-cantly higher image quality, sensitivity and specificity than the SPECT–CT equivalent (Figure 3).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 99mTc-renography, of cardiac function using 99mTc-gated cardiac blood pool scanning, of respiratory function using ventilation-perfusion 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 availabi-lity 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 PET–CT.78

What factors may save SPECT–CT?Technological advances have the poten-tial to usher a new era of SPECT imaging. Foremost, is the development of new solid-state detectors using compounds such as cadmium zinc telluride (CZT), which clearly outperform current detectors with higher sensitivity, and spatial and tempo-ral resolution.79 Although CZT-based dedicated cardiac devices are available,80 a solid-state SPECT–CT 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 onco logy that underpin the use of SPECT–CT in nuclear medicine, including investigations

used in cardiology and neurology. Similar arguments can be proposed both in favour and against the ongoing use of SPECT–CT compared with PET–CT. We believe that these arguments are as, or more, persua-sive 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 interro-gate different biological functions.81 Such multitracer imaging is possible because different single photon-emitting radio-tracers 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 SPECT–CT and PET–CT.82 Whether these technical perfor-mance enhancements would make SPECT–CT competitive with PET–CT remains to be seen.

ConclusionsThe efficiency inherent to high-throughput PET–CT scanning, combined with its tech-nical superiority and an increasing array of PET tracers, suggests that although SPECT–CT 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 PET–CT need to be re-evaluated given its superior speed, efficiency and cost savings associated with more-accurate diagnosis. Systemic impedi-ments to the wider availability of PET–CT need to be addressed. These include regu-latory 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, 7 St Andrew’s Place, Melbourne, VIC 3002, Australia (R. J. Hicks, M. S. Hofman). Correspondence to: R. J. Hicks rod.hicks@petermac.org

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Author contributionsBoth authors researched the data for the article, discussed its content, wrote the manuscript and edited it before submission.

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