Clinical Radiology (2005) 60, 11431155

REVIEW

PET/CT in oncologya major advance

K. Wechalekar, B. Sharma, G. Cook*
Department of Nuclear Medicine and PET, Royal Marsden Hospital, Sutton, Surrey, UK
Received 11 February 2005; received in revised form 15 April 2005; accepted 27 May 2005

KEYWORDS
18

F-uorodeoxyglucose; Positron emission tomography/ computed tomography (PET/CT); Oncology

The concept of hardware fusion between positron emission tomography (PET) and computed tomography (CT) has only been introduced commercially in the last 4 years. The advantages of this combined technique over PET alone have become obvious. There is increasing evidence to suggest that PET/CT adds complementary information in staging, re-staging and follow-up in oncology patients, leading to changes in management plans. The present paper is a review of the strengths, weaknesses, current evidence and future directions of this technique. Q 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction
Positron emission tomography (PET) is a sensitive and specic functional imaging method that allows metabolic mapping of disease processes in man. Modern PET machines allow whole-body imaging, and are therefore, ideally suited to oncological imaging. The most widely used tracer, 18F-uorodeoxyglucose (18FDG), acts as a glucose analogue allowing imaging of glucose utilization, a process that is known to be enhanced in many malignant tumours.1 The exible chemistry afforded by a number of PET radionuclides, including 18F-uorine, 11C-carbon, 13N-nitrogen and 15O-oxygen, provides the potential to investigate multiple aspects of tumour biology in addition to glucose utilization, including cellular proliferation, hypoxia, neo-angiogenesis and apoptosis. One of the disadvantages of 18FDG PET is that glucose utilization is not entirely specic to malignant tissue, some benign processes being associated with enhanced glycolysis.2 In addition, normal variation of uptake of 18FDG in some tissues, including bowel, urinary tract, muscle and brown fat, can cause interpretative pitfalls, particularly
* Guarantor and correspondent: G.J.R. Cook, Department of Nuclear Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, UK. Tel.: C44 208 661 3921; fax: C44 208 661 3290. E-mail address: gcook@icr.ac.uk (G. Cook).

considering the poor anatomical localization inherent to 18FDG PET imaging. Without good anatomic reference it is difcult to accurately localize tumour tissue or to assess invasion into neighbouring structures with 18FDG PET imaging alone, a problem that will be accentuated when using even more tumour-specic radiopharmaceuticals where there may be little or no uptake into normal structures. It is accepted that applying correction for the attenuation of photons as they leave the body improves image quality and is a requirement for accurate quantitation in PET imaging but the acquisition of a transmission study from radioactive rod sources adds signicantly to the total time of a PET acquisition, in total taking up to an hour or longer. In contrast, CT achieves excellent anatomical resolution, tissue differentiation and high imaging speed but offers little functional information, largely depending on size and morphology to differentiate tumour from normal structures. However, CT data can be used to provide a high-speed, low-noise attenuation map for correction of PET for attenuation effects. In view of the different but complementary advantages and short-comings of PET and CT it makes eminent theoretical sense to combine both techniques within one scanning gantry. Combining PET and CT has the potential to improve lesion localization, increase specicity, reduce interpretative pitfalls and to allow fast,

0009-9260/$ - see front matter Q 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2005.05.018

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low-noise attenuation correction, signicantly increasing throughput. In short, combining PET with CT should maximize the strengths of each technique whilst minimizing the weaknesses. Traditionally, imaging techniques such as CT and PET have been applied sequentially in the diagnosis and staging of cancer and in monitoring the effects of therapy. Indeed, in many cases anatomic imaging is used exclusively, although functional imaging with PET is fullling an increasingly important role in the staging and therapy monitoring processes, particularly when the CT image is equivocal. Visual side by side fusion of the anatomic and functional image sets has often been considered sufcient to extract additional information. In cases where more accurate localization is required, software fusion can be used to align the two sets of images. Outside the brain, however, software fusion is difcult and often unsuccessful because of the many degrees of freedom accessible to the human body when imaged by two different techniques on two different occasions. At best, the alignment process is labour intensive and far from routine in most clinical imaging departments. This situation changed dramatically with the recent introduction of the combined PET/CT machine, an approach that solves the fusion problem primarily through hardware rather than software. Such a device provides a medical imaging department with the capability to acquire accurately aligned anatomic and functional images of a patient from a single investigation. Additionally, as the patient remains positioned on the same bed for both imaging techniques, temporal and spatial differences between the two sets of images are minimized. The technology, more than just the fusion of two accepted techniques, represents an evolution in imaging instrumentation. The availability of this technology has realized aspects of combined imaging that are difcult or impossible to appreciate with separate devices, such as the use of CT for attenuation correction of PET, the convenience for both physician and patient of a single investigation for both techniques, and increased condence in study interpretation that originates from having co-registered anatomy and function available immediately after the investigation.

has remained a major imaging method with steadily improving performance. Conversely, PET began primarily as a neuropsychiatric and cardiac research tool until the 1990s when reimbursement was approved for whole-body 18FDG imaging for certain cancers in a number of countries. The rst PET/CT prototype was trialled in clinical practice in 1998 by Townsend and colleagues.3 As the efcacy and power of a combined machine became apparent, it was not long before the major medical imaging manufacturers were able to supply similar systems incorporating fullring PET machines combined with high-end multislice CT as recently as 2001. PET/CT machines are now available with two-dimensional and threedimensional PET capability with either bismuth germinate (BGO), lutetium oxyorthosilicate (LSO) or gadolinium oxyorthosilicate (GSO) scintillation crystals, with or without additional rod-source attenuation correction. Single slice, up to 16 slice CT machines have been available as the CT component of the combined imaging systems (Fig. 1). Although there is an option to retain radioactive rods for transmission imaging on some systems, all machines allow the CT data to be used for attenuation correction after appropriate correction factors to allow for photon energy differences between CT ( w mean 70 keV) and PET (511 keV). Using CT for attenuation correction is not without its own problems with some of its own artefacts resulting.2 Although PET/CT design parameters may vary considerably, all devices are able to produce essentially good quality whole-body PET/CT images in less than 30 min. It is the ability to use the rapidly acquired and near noiseless CT data for attenuation correction that has enabled a reduction of imaging times by as much as 40% compared with PET-only machines. 3 In the short 34 years since the installation of the rst clinical PET/CT machines, the market has completely changed, with the vast majority of PET systems now being sold as PET/CT machines across the world. Since initial PET/CT

History and development

Despite continued development in software registration algorithms, the need for hardware fusion of functional PET and anatomical CT data remained apparent. Since its inception in the early 1970s, CT
Figure 1 Schematic diagram of a commercially available PET/CT machine. The CT machine is attached in line with the PET machine with a common moving bed passing through them. The CT part of the machine is on the left.

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systems were marketed there has been an improvement in the integration of acquisition and processing software, as well as the development of image viewing software that can display the different data sets as separate but linked studies, allowing appropriate windowing and image manipulation, and the ability to view the fused data sets.

Artefacts and pitfalls in PET/CT

Many of the pitfalls and artefacts that may be experienced with PET are also seen with PET/CT,2 but some new problems have been encountered that are specic to combined PET/CT. CT and PET acquisitions are made sequentially in PET/CT systems, with the data sets acquired from the two parts of the gantry being intrinsically aligned and allowing accurate registration provided that there is no difference in position of organs between the two images. CT images are often acquired during a single breath-hold over the thorax whereas PET images are acquired during tidal breathing over 2030 min, and the resultant PET image represents an average position of the thoracic cage during this time. The use of CT for attenuation correction can result in artefacts when there is misregistration due to breathing differences. The most commonly encountered artefact is an apparent loss of counts in the corrected PET image at the level of the diaphragm. Differences in breathing patterns between CT and PET images may lead to misregistration of pulmonary nodules, particularly in the peripheral and basal lung regions where the differences may approach 15 mm.4 It is also possible for objects just below the diaphragm (e.g. liver metastases) to appear in the lung bases on corrected PET images. Misregistration artefacts can be minimized by performing the CT examination during normal relaxed expiration,5 but it is likely that when accurate registration in the thorax is very important (e.g. radiotherapy planning for lung cancer), then respiratory gating techniques will be developed. Voluntary motion between CT and PET acquisitions is minimized by ensuring patient comfort on the scanning couch. This is particularly important in head and neck studies where adequate immobilization is essential. It is unusual for other involuntary motion (e.g. bowel peristalsis) to cause signicant artefacts or misregistration. High-density contrast agents, e.g. oral contrast mediums, or metallic objects can lead to an overestimation of PET activity if CT data are used for attenuation correction, leading to development

of artefactual hot spots.611 Such artefacts may be recognized as such by studying the uncorrected image data. Low-density oral contrast agents can be used without signicant artefact12 or the problem may be avoided by using water as a negative bowel contrast agent. Algorithms have been developed to account for the overestimation of activity when using CT-based attenuation correction that may minimize these effects in the future.11 The use of intravenous contrast medium during the CT acquisition may be a more difcult problem. Similarly, a concentrated bolus of contrast in the large vessels may lead to over correction for attenuation, particularly in view of the fact that the concentrated column of contrast medium has largely dissipated by the time of the PET acquisition. This may also lead to artefactual hot spots in the attenuation corrected image10 or quantitative overestimation of 18FDG activity. Despite new artefacts being introduced by combined PET/CT imaging, it is likely that many pitfalls caused by normal variant uptake on PET imaging alone may be avoided by the ability to correctly attribute 18FDG activity to a structurally normal organ on CT. This may be particularly evident in the abdomen when physiological bowel activity or ureteric activity can otherwise cause interpretative difculties. PET/CT also has the potential to limit false-negative interpretations in tumours that are not very 18FDG avid by recognizing uptake as being related to structurally abnormal tissue and increasing the diagnostic condence in tumour recognition by the use of the combined structural and functional data. Similarly, it may be possible to detect small lung metastases on CT lung windows that are beyond the resolution of 18FDG PET.

Imaging protocols and image interpretation

All current PET/CT machines perform a CT scanogram to help dene the extent of the scan followed by a CT acquisition (attenuation correction G diagnostic) and then by a PET emission scan. With regard to the PET emission component of a PET/CT study there is little difference from studies acquired on a PET machine without combined CT. Patient preparation is the same as for standard PET protocols with PET emission imaging usually starting at approximately 1 h after injection of 18FDG. Images are routinely acquired from head to thighs over a period of 2030 min. The lower legs might also be included when this region is of potential

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interest, e.g. melanoma of the leg or peripheral sarcoma. PET and PET/CT machine axial elds of view vary from w1118 cm with body acquisitions being performed as a sequence of overlapping steps over approximately ve to nine bed positions each lasting 35 min. It is the CT part of a PET/CT protocol where there is most variability, and the main question that remains to be answered is what CT acquisition protocol is optimum for each specic clinical indication. At its simplest, the CT can be used solely for attenuation correction of the PET data. Here a low current (e.g. 15 mA or less) CT scan is acquired over the area where the PET acquisition is planned. The CT data are not used for diagnostic purposes as the quality of the CT at this low current setting is usually poor. At the opposite end of the spectrum a full diagnostic CT can be acquired with intravenous and bowel contrast medium administration at conventional diagnostic CT parameters. Although PET reconstruction artefacts can be avoided by using dilute bowel contrast medium or water as a negative contrast agent, the issue of artefacts due to a bolus of intravenous contrast medium has not been fully resolved. If a full diagnostic CT with intravenous contrast medium is required as part of a PET/CT protocol then it is possible to perform this as a third acquisition after a low-dose CT attenuation correction study and PET emission study before the patient leaves the couch. Most departments operating PET/CT machines have opted for a middle of the road CT protocol using an intermediate current (w80 mA)6 without intravenous or bowel contrast medium unless there is a special indication. This would seem to be a reasonable compromise at the present time until specic protocols are compared in clinical trials to optimize diagnostic gain. Certainly it would appear that an increase in tube current above these levels does not increase the diagnostic accuracy in an oncology setting, and the CT image quality is good enough for diagnostic purposes and more than adequate for attenuation correction.6 It is possible that as we get used to PET/CT as an entity on its own rather than as a combination of PET and CT, the requirement for CT contrast media will reduce to a few specic indications, given that the diagnostic benet of contrast enhancement is likely to be diminished when there is avid tumour uptake of 18FDG. Examples of areas where intravenous contrast medium administration may remain benecial include central bronchial tumours where there is a question of vascular invasion, or in anatomically complex regions, such as the head and neck, where denition of vascular structures is more difcult. Certainly it is more difcult to

justify, from the radiation protection point of view, a full CT protocol as part of a PET/CT study if a patient has already undergone a recent diagnostic CT. As referring clinicians become more familiar with PET/CT then certain oncology patients may only need referral for a single PET/ CT examination. There is early evidence to suggest that a PET/CT protocol using the intermediate CT acquisition parameters leads to better diagnostic accuracy than PET alone, diagnostic CT with contrast medium alone, or PET and diagnostic CT with contrast medium viewed side by side, in staging lung cancer.13 Similarly, in lymphoma staging this PET/CT protocol has been shown to be more accurate than diagnostic CT with contrast medium.14 Other challenges in PET/CT protocols relate to the extended imaging time of PET compared with CT. These include the discomfort related to patients needing to raise their arms for a period of 30 min or more to avoid CT beam-hardening artefacts and the problem of a rapidly lling bladder and subsequent discomfort if large volumes of oral bowel contrast medium have been used. Most would agree that the use of CT only for attenuation correction is underutilizing the technique and unlikely to be obtaining optimal diagnostic information. Most are convinced that PET/CT imaging should consist of a combination of PET with at least some form of diagnostic CTjust how much CT needs to be resolved by clinical trials in different oncological situations. Similarly, in interpretation of PET/CT images it is important to make best use of the available data, and at the very least, provide an interpretation of the precise location and anatomical relationships of 18 FDG abnormalities. Optimally, a fully integrated report can be issued where PET abnormalities can be accurately localized, and the relationship to and invasion of adjacent structures described. For the rst time this approach has allowed more accurate T-staging of some tumours than previously possible with CT or PET on their own.13 An integrated report will also allow more accurate N and M-staging, as well as the description of pertinent 18FDG-negative lesions (e.g. enlarged reactive lymph nodes) and incidental clinically relevant non-oncological abnormalities (e.g. abdominal aortic aneurysm). A full inspection of all the available data is required including the corrected and non-corrected PET images, as well as soft tissue, bone and lung windows of the CT component. Various types of software are available that allow the data sets to be viewed side by side with a linked cursor or as overlapping images. A full inspection of all of the available data to formulate an integrated PET/CT

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report often takes in excess of 2030 min and should be adequately accounted for when resourcing a new unit. At this point in time when there are few who are trained in both CT and PET interpretation and even fewer specically trained in PET/CT interpretation, most reporting is likely to be performed as a joint approach by at least two imaging specialists working together with individual skills in each method. As PET/CT develops it is hoped that more individuals will obtain dual training in both functional and cross-sectional anatomical imaging, and more importantly in PET/CT itself as an individual technique.

Potential advantages of PET/CT: A clinical perspective

Throughput
The use of CT for correcting attenuation effects on the PET data has been estimated to increase patient throughput by as much as 40%.3 There is therefore potential to reduce waiting lists for PET imaging and to minimize patient discomfort and reduce artefacts due to movement. As discussed above, patient comfort compared with PET alone is not necessarily reduced if patients are required to hold their arms above their heads but there is a constant drive by manufacturers to reduce PET acquisition times further with hardware developments and to innovate and improve devices to aid comfort.

Localization
The most obvious potential advantage of PET/CT compared with PET is the ability to accurately anatomically locate an 18FDG-positive lesion with regard to relationships to neighbouring structures and the presence of local invasion. One particular example where improved localization makes an obvious difference is in the investigation of head and neck cancers. The complex anatomy of the head and neck region poses difculties in the interpretation of PET images without anatomical registration. Image software co-registration with CT or magnetic resonance imaging (MRI) has been shown to increase the specicity of lesion localization in head and neck cancers.15 However, if the PET and anatomical data sets are obtained at different times on different machines, patient repositioning and intercurrent anatomic changes can cause difculties and inaccuracies.16 These factors can largely be overcome with an

integrated PET/CT machine. The intrinsic hardware approach of PET/CT has been shown to be advantageous for staging and treatment planning.6,17 A specic example of the power of PET/ CT in this setting is illustrated with the detection of occult primary tumours in patients with head and neck cancer who present with cervical lymphadenopathy18 (Fig. 2). A number of primary tumours that remains occult after conventional investigations can be detected and accurately located for guiding subsequent biopsies. Further potential advantages of combined PET/CT can be predicted in guiding biopsies in heterogeneous tumours where it may be possible to differentiate active tumour tissue from areas of surrounding brous or inammatory reactive tissue or areas of necrosis. There is also the potential to detect and locate lesions that are more amenable and suitable for biopsy in patients with multiple lesions or to detect and locate small sub-centimetre lymph nodes that contain tumour that can be targeted for biopsy or treatment. One special area in which it is rapidly becoming obvious that PET/CT is to have a major future role is in radiotherapy planning. PET on its own has the potential to improve tumour coverage by including involved locoregional lymph nodes, reducing normal tissue exposure by allowing accurate measurement of the metabolically active tumour volume and to guide intensity-modulated radiotherapy (IMRT) by measuring relevant aspects of tumour biology, e.g. hypoxia, but is hampered by the difculties in applying PET data directly to a radiotherapy plan. This is now overcome with PET/CT where planning can be performed on the anatomical CT dataset with reference to the accurately registered functional data, whether it be tumour glycolysis, hypoxia or other biological parameter. Now that using these combined data are technically feasible, studies are required to ensure the efcacy of the method and to measure the benets with regard to outcome.

Sensitivity
There is substantial evidence that 18FDG PET improves sensitivity in the detection of malignant tissue when compared with conventional anatomical imaging,19 frequently upstaging patients and leading to changes in subsequent management. However, there are situations where the combination with CT has the ability to make a very sensitive imaging technique even more sensitive. Not all malignant tumours are readily detected by 18FDG imaging, some because the tumour or its

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metastases are not particularly 18FDG-avid (e.g. bronchioloalveolar carcinoma20 or prostatic carcinoma metastases21 ). With PET/CT, low-grade uptake within a malignant mass that has suspicious CT characteristics is more likely to be correctly identied and categorized than on PET alone, where it may even be overlooked completely (Fig. 3). Another common situation where the sensitivity of 18FDG PET is limited is in the detection of small sub-centimeter lung metastases. Here the limited spatial resolution of PET compared with CT, combined with movement of lung nodules due to respiration through the PET acquisition, limits sensitivity unless the nodules are very 18FDG-avid. These nodules are usually adequately detected by CT, although specicity when apparently 18FDGnegative remains limited unless serial imaging is available for comparison. There are times when the signicance of an area of uptake on 18FDG PET alone or a nodule on CT alone may be difcult to determine but the combination of ndings on PET and CT increase the diagnostic condence of an interpretation (Fig. 3). An example where this synergistic relationship exists is in the detection of small-volume peritoneal metastases that may not be easily differentiated from normal bowel loops and other structures with 18FDG PET or CT but in combination may become more obvious. A recurring theme in much of the PET/CT literature that exists is that it is possible to issue more condent interpretations with fewer equivocal results compared with PET and CT on their own, a factor that is in part due to an increase in sensitivity resulting from combining the two techniques.

Specicity
Probably the most important reason for fewer equivocal scans and an improvement in diagnostic accuracy is an improvement in specicity that results from combined PET/CT compared with PET alone. Although most malignant tumours accumulate 18FDG at a higher level than normal tissues there are some normal physiological variants and some benign disease processes that can also result in uptake of this radiopharmaceutical leading to possible interpretative pitfalls.2 Usually the degree of uptake in a benign process is less than that seen

Figure 2 (a) Cervical transaxial 18FDG PET and (b) fused PET/CT. A patient presented with a right cervical squamous cell carcinoma lymph node metastasis (demonstrated on the images) but the primary tumour was

occult. Asymmetric increased uptake is demonstrated in the right side of the pharynx, localized to the base of the tongue on the fused PET/CT image. Subsequent biopsies of this region conrmed this as the site of the primary tumour.

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Figure 3 Corresponding transaxial pelvic CT and 18FDG slices from a patient with a history of carcinoma of the prostate with a rising prostate specic antigen (PSA). Conventional imaging had not detected a site of recurrence. The study shows a small sub-centimetre presacral nodule that demonstrates only low-grade FDG accumulation (a). On CT this was not considered signicant and on PET alone the low-grade nature of uptake in this deposit makes the signicance of this focus difcult to ascertain. In combination the PET and CT data increase the condence in identifying this as a small site of recurrent disease. The presence of the node was subsequently conrmed with MRI (b).

in malignant tissue but overlap may occur. There is little doubt that combining the anatomical information from CT reduces the number of these potential pitfalls. This is particularly so in normal physiological variants where an area of 18FDG uptake can be correctly ascribed to a normal tissue (e.g. active brown fat, muscle, ureteric activity or bowel; Fig. 4) and a false-positive interpretation avoided. Similarly, some benign disease processes that are associated with increased 18FDG activity may have characteristic features on CT, although this is less often the case. An example where specicity is improved by the PET component of the examination is in the correct identication of 18 FDG-negative enlarged but reactive non-malignant lymph nodes. Conversely, CT may aid PET

specicity by identifying a simple fracture that is associated with focal 18FDG activity, for example.

The evidence
Although there is no doubt amongst most PET/CT users that this combined technique is a signicant step forwards in oncological imaging, the evidence for the advantages over PET alone or other conventional imaging techniques is only now starting to accumulate. However, even before these data were available, imaging specialists and their referring clinicians were voting with their feet, the sales of PET/CT far outstripping PET

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Figure 4 (a) Coronal 18FDG PET image demonstrating extensive symmetrical uptake in the neck and supraclavicular regions. (b) On transaxial CT (left) and fused PET/CT images (right) it can be seen that the abnormal uptake corresponds to fat and is therefore the physiological variant of active brown fat, commonly seen particularly in young thin females on cold days.

within a year or two of rst being commercially available.

Lung cancer
One of the important areas where there is evidence to support the use of PET/CT is in the staging of non-small cell lung cancer (NSCLC). It is already accepted that 18FDG PET should be used in the staging of all patients being considered for curative surgery or radical radiotherapy.22 Lardinois et al.13 compared the diagnostic accuracy of integrated PET/CT with PET alone, CT alone and PET and CT

viewed side by side (mental fusion). They prospectively compared the results from these four imaging strategies with histopathological surgical staging in 50 patients and found that PET/ CT provided additional information in 41% of cases compared with PET and CT viewed side by side. PET/CT T-staging was statistically more accurate than the other three methods (Figs. 5 and 6) and N-staging was more accurate than with PET. In M-staging PET/CT increased diagnostic condence in two of eight patients. A similar study compared PET/CT (contrast-enhanced) with PET and contrastenhanced CT alone in 27 patients with NSCLC23

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Figure 6 Transaxial (a) 18FDG PET and (b) fused PET/CT of a NSCLC. Due to peripheral collapse and consolidation the exact extent of the tumour was difcult to ascertain on CT or PET alone but on the combined image the differentiation can be clearly appreciated.

and 75%, respectively). PET/CT results also changed management in 29% of cases.

Gastrointestinal tumours
Figure 5 Transaxial (a) 18FDG PET, (b) CT and (c) fused PET/CT images of a NSCLC. Using either PET or CT alone it is difcult to be sure whether there is early invasion of the chest wall but on the combined image it can be seen that the abnormal metabolic activity within the tumour does not reach the pleural surface.

PET/CT resulted in more accurate staging compared to histopathological results than either PET or CT and resulted in management changes in four patients compared with PET and ve patients compared with CT. A further study compared PET/CT with PET and CT viewed side by side in patients with suspected NSCLC recurrence.24 The specicity and positive predictive values for PET/CT were much better than with PET and CT (82 and 89% compared with 53

In colorectal cancer staging and restaging, accuracy was improved from 78 to 89% by using PET/CT compared with PET alone,25 and fewer equivocal lesions resulted from the use of PET/CT. In the investigation of colorectal liver metastases with PET/CT, contrast-enhanced diagnostic CT and PET/ CT have been reported as showing similar sensitivities in lesion detection (95 and 91%, respectively).26 However, PET/CT proved more specic than contrast-enhanced CT for detecting liver metastases in patients with prior hepatectomy (100 and 50%, respectively). PET/CT also proved more sensitive in detection of recurrence at the primary site (93 and 53%), as well as extra-hepatic disease (89 and 64%), than contrast-enhanced CT. In the detection of post-operative recurrence of

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colorectal cancer in the pelvis Even-Sapir and colleagues27 showed the superior diagnostic potential of 18FDG PET/CT over PET alone in 62 patients with an accuracy of 93% compared with 74%. In a subgroup of 30 patients with presacral masses on CT, PET/CT was able to differentiate viable tumour from scar with a sensitivity and specicity of 100 and 96%, respectively. The use of PET/CT in gastrointestinal stromal tumours (GIST) would appear to be complementary to contrast-enhanced CT.28 As 18FDG activity may show heterogeneity between lesions within the same patient, contrast-enhanced CT has been described as being more sensitive for detection of metastases. However, two studies have conrmed the superiority of PET/CT in assessing the response of these tumours to imatinib therapy compared with contrast-enhanced CT.28,29

Unknown primary and occult tumours

In a series of 45 patients with an unknown primary tumour (18 with cervical and 27 with extra-cervical metastases) PET/CT (contrast-enhanced) successfully detected more primary tumours than PET, CT or PET and CT side by side (33% compared with 24, 18 and 29%, respectively).18 The differences were not statistically signicant, and it is noted that the majority of tumours remain occult whichever method is used. A comparison with MRI would be of value, particularly in occult head and neck cancers. The presentation of patients with rising tumour markers suggesting recurrent disease with negative conventional imaging is a relatively frequent occurrence in clinical oncological practice. In a series of 36 patients in this clinical situation PET/CT proved more accurate than PET alone but particularly with regard to specicity on a site-based analysis (97% compared with 50%).30 Sensitivities were similar (100 and 96%) suggesting the predominant strength of PET/CT in this situation is the avoidance of false-positive interpretations of areas of 18FDG activity. PET/CT directed further management and treatment planning in (33%) of patients.

compared with contrast-enhanced CT (88 and 86%, respectively). For extra-nodal disease the sensitivity and specicity for PET/CT were 88 and 100%, respectively compared with 50 and 90% for contrast-enhanced CT. In detection of nodal disease the advantage of PET/CT was demonstrated in restaging after treatment where correct analysis of residual masses was more frequent, there being good agreement in initial staging of nodal disease. The major advantage of PET/CT in extra-nodal staging was mostly seen in the evaluation of the lungs and bone marrow (Fig. 7). The overall conclusion of this study was that PET/CT, with low-dose non-enhanced CT, is sufcient for staging and restaging these types of lymphoma, a signicant difference being found in the ability to exclude disease with PET/CT compared with contrastenhanced CT. However, due to its retrospective nature prospective studies are required for conrmation of these ndings.

Gynaecological tumours
Grisaru et al.31 compared 18FDG PET/CT with conventional imaging techniques (CT, MRI and ultrasound) in 53 patients with mixed gynaecological malignancies of whom 18 were undergoing initial staging and in 35 patients in whom recurrence was suspected. PET/CT correctly identied metastatic disease in ve of the 18 patients undergoing initial staging and correctly detected recurrence in 16 patients in whom it had not been detected with conventional imaging. The image produced using PET/CT was false-negative in a case of miliary peritoneal disease and false-positive in one patient for pelvic recurrence. Results for 18FDG PET alone have previously been disappointing in staging and restaging of ovarian cancer but this initial small study suggests that the additional anatomical information available with PET/CT may be advantageous.

The skeleton
Metser et al.32 evaluated the role of 18FDG PET/CT in the diagnosis of spinal metastases in 242 lesions (217 malignant, 25 benign) in 51 patients. The major nding was that PET/CT increased specicity in lesion detection compared with PET or CT alone, largely by showing degenerative changes on CT corresponding to foci of 18FDG accumulation and by demonstrating that some apparent lesions were in fact due to physiological paravertebral muscle activity. PET/CT was more accurate than PET alone in dening the vertebral level of disease and

Lymphoma
Schaefer et al.14 retrospectively compared PET/CT (low-dose non-enhanced CT) with diagnostic contrast-enhanced CT in 60 patients with either Hodgkins disease or high-grade non-Hodgkins lymphoma who required staging or restaging. Sensitivity and specicity for staging and restaging nodal disease were 94 and 100%, respectively

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Figure 7 Transaxial CT (top left), 18FDG PET (top right), fused PET/CT (bottom left) and anterior projection PET image (bottom right). A patient with high-grade non-Hodgkins lymphoma presented with a large, right-sided, anterior mediastinal mass and areas of consolidation in the right lung. It was uncertain whether the consolidation represented lymphomatous inltration. The PET/CT image clearly demonstrates that uptake of 18FDG is signicantly less in the areas of consolidation in the right lung compared with the anterior mediastinal mass indicating the benign nature of the consolidation and hence down-staging the patient.

the part of a vertebra involved and in one third of patients it was possible to more accurately identify the extent of soft-tissue involvement. The same group have also studied the role of PET/CT using the PET bone tracer 18F-uoride ion.33 Uptake of this radiopharmaceutical is by similar mechanisms to conventional bone scintigraphy agents such as 99m Tc methylene diphosphonate (MDP) and therefore suffers from lack of specicity when trying to differentiate benign from malignant lesions. A major benet of 18F-uoride PET/CT compared with 18F-uoride PET alone, in this study was an increase in specicity on a lesion-based analysis from 72 to 97% (p!0.001) by having the anatomical CT correlate at sites of increased activity that helped avoid false-positive diagnoses. Both lytic and sclerotic metastases were accurately detected

and either a malignant or benign cause found for patients symptoms in the majority of a small subgroup who had normal conventional bone scintigraphy.

Miscellaneous tumours
A small number of studies have examined PET/CT in a general oncological setting with mixed groups of patients. Bar-Shalom et al.34 included 204 patients and compared PET/CT with PET alone. Previous contrast-enhanced CT images were also reviewed separately together with the low-dose, nonenhanced part of the PET/CT protocol. The major ndings were that PET/CT provided additional information in 49% of patients, impacting on subsequent management in 14%. Fewer equivocal

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lesions were noted with PET/CT and more accurate anatomic placement of 18FDG abnormalities was possible in 6%. In an earlier study Hany et al.6 included 53 consecutive patients with various malignant tumours who had been referred for PET/CT examination. Fewer false-positive and false-negative lesions resulted from PET/CT compared with 18 FDG PET alone. Thirty-eight of the 53 patients were correctly staged using PET and 49 using PET/ CT (p!0.05). This study also compared different protocols with regard to the CT component of PET/ CT. All patients had 10, 40, 80 and 120 mA CT studies without contrast medium. It was found that the 80 mA protocol was optimal with regard to accuracy and minimizing equivocal lesions, and that no further benet was found from the 120 mA protocol. It was estimated that additional effective dose from this protocol was w2 mSv. A further study of 260 patients with varied malignancies has been reported by Antoch et al.35 Unlike the majority of other PET/CT studies this group employed a diagnostic CT protocol with both intravenous and bowel contrast agents. PET/CT proved signicantly more accurate in correctly staging tumours with regard to T, N and M compared with PET alone, contrast-enhanced CT alone or PET and contrast-enhanced CT viewed side by side. PET/CT impacted on treatment on 43, 39 and 16 patients compared with PET alone, CT alone and PET viewed with CT, respectively.

diagnostic algorithms. Further prospective clinical trials will help clarify the optimal protocols for different clinical indications. The immediate requirements are for more machines, ready access to 18FDG and other PET radiopharmaceuticals, training of medical and technical staff specically in PET/CT and adequate funding to cater for the number of investigations that are required.36 We have only seen the tip of the iceberg with regard to clinical PET imaging as there are many more radiopharmaceuticals being developed that can explore different aspects of tumour biology and that may show advantages over 18FDG in specic clinical situations. Many of these future radiopharmaceuticals may be even more tumour-specic with little or no uptake within normal organs, thereby increasing the need for the anatomical correlation with sensitive functional data that combined PET/CT provides.

References
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Conclusion
There are undoubted advantages of PET/CT over PET alone with regard to speed of throughput, increased condence and fewer equivocal interpretations, as well some benets in diagnostic accuracy and changes in patient management. It seems certain that PET, as an imaging method on its own, will be replaced in the majority of oncological indications by this combined technique. PET/CT has only been available for approximately 4 years but in that short time it has become obvious that it is a clinical imaging technique that can offer additional and complementary information in the staging and restaging of oncology patients, frequently leading to appropriate changes in clinical management. The evidence is continuing to accumulate on the value of this technique in oncology, but there is little doubt that the clinical indications are likely to grow, and it is likely that as referring clinicians gain condence in the results, it may be used earlier and more routinely in many

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