Multi-technique imaging of bone metastases: spotlight on PET-CT

Clinical Radiology xxx (2016) 1.e1e1.e12

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Multi-technique imaging of bone metastases: spotlight on PET-CT Gurdip K. Azad a, Gary J. Cook a, b, * a

Cancer Imaging Department, Division of Imaging Sciences and Biomedical Engineering, King’s College London, St Thomas’ Hospital, London, UK b Clinical PET Centre, St Thomas’ Hospital, London, UK

art icl e i nformat ion Article history: Received in revised form 30 December 2015

There is growing evidence that molecular imaging of bone metastases with positron-emission tomography (PET) can improve diagnosis and treatment response assessment over current conventional standard imaging methods, although cost-effectiveness has not been assessed. In most cancer types, 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG)-PET is an accurate method for detecting bone metastases. For example, in breast cancer, combined 18F-FDG-PET and computed tomography (CT) is more sensitive at detecting bone metastases than 99mtechnetium (Tc)-labelled diphosphonate planar bone scintigraphy (BS) and there is increasing evidence to support the use of serial 18F-FDG-PET for the assessment of osseous response to treatment. Preliminary data suggest improved diagnostic accuracy of 18F-FDG-PET-CT in a number of other malignancies including lung, thyroid, head and neck, gastro-oesophageal cancers, and osteosarcoma. As a bone-specific tracer, there is accumulating evidence to support the use of sodium 18F-fluoride (18F-NaF) PET-CT in the diagnosis of skeletal metastases in breast and prostate cancer, although relatively little data are available to support its use for assessment of treatment response. In prostate cancer, 11C-choline and 18F-choline PET-CT have better specificities than 18F-NaF-PET-CT, but equivalent sensitivities in the detection of bone metastases. We review the current literature for staging and response assessment of bone metastases in different cancers. Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Skeletal metastases are common in breast, prostate, lung, thyroid, bladder, and renal cancers and rare in other cancers. The incidence of bone metastases is up to 75% in metastatic breast and prostate cancers, 60% in thyroid cancers, and 40% in bladder and lung cancers.1 Solid

* Guarantor and correspondent: G.J. Cook, Clinical PET Centre, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. Tel.: þ44 207 188 8364; fax: þ44 207 620 0790. E-mail address: [email protected] (G.J. Cook).

tumours that initially present with osseous metastases alone have a better prognosis2 than those with soft-tissue metastases. Patients presenting with an isolated bone lesion tend to survive longer, making early diagnosis essential for prompt treatment instigation.3,4 Timely management of bone metastases can prevent significant complications and morbidity. Autopsy studies show that bone metastases are not commonly demonstrated by conventional radiographic examination until they are approximately 1e2 cm in diameter or until 50e75% of bone mineral is lost and radiographs are therefore insufficiently sensitive.5

http://dx.doi.org/10.1016/j.crad.2016.01.026 0009-9260/Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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No standard has yet been established to ascertain the best technique for diagnosing bone metastases in solid tumours. Heterogeneous studies on small cohorts of patients have been reported using various imaging techniques, making it difficult to draw definitive conclusions. Planar 99mTc-labelled diphosphonate (99mTc-MDP) bone scintigraphy (BS) can diagnose bone metastases 2e18 months earlier than a plain x-ray and is the commonest imaging technique currently used for diagnosing bone metastases and assessing treatment response.6 BS, however, has some limitations. Firstly, the uptake and accumulation of the tracer does not reflect the true tumour burden in the bone marrow as uptake depends predominantly on osteoblastic activity. Secondly, the existing response evaluation criteria in solid tumours (RECIST), usually considers bone disease to be “non-measurable” unless it is associated with a soft-tissue component, thus making treatment response assessment difficult7; however, attempts have been made to amalgamate bone imaging data from all techniques to improve response assessment, specifically in bone metastases.8 Lastly, reparative osteoblastic activity in the bone may delay accurate response assessment on the BS with a paradoxical increase in activity in a responding lesion if the BS is performed too early, the so-called flare phenomenon.9 A flare may also result in the appearance of a “new”, previously occult lesion on BS whilst on treatment. New lesions appearing on BSs or plain radiographs after starting treatment would normally be assumed to represent progressive disease but new lesions due to osteoblastic healing of previously occult lesions has been described up to 6 months.10 It may therefore take 6e8 months to determine response on BS, with a previous report of only 52% of responders showing scintigraphic improvement and 62% of non-responders showing scintigraphic deterioration, potentially causing a delay before patients can switch to an alternative effective treatment.11 The study of hybrid imaging, combining molecular, functional, and anatomical data, has been used in this context in the expectation that synergies from combining imaging of morphology and underlying tumour cells or tumour microenvironment may improve both diagnosis and treatment response assessment.12 Various radiotracers are being used to explore molecular and cellular events in bone disease, each of which selectively target specific cellular or molecular functions. Some tracers target osteoblast activity, mineralisation, and local blood flow and are bone-specific such as 18F-fluoride (18FNaF) and 99mTc-MDP. Others, target glucose metabolism (e.g., 2-[18F]-fluoro-2-deoxy-D-glucose [18F-FDG]) or biosynthesis of cell membranes and phospholipid metabolism (e.g., 18F/11C-choline) and are tumour-specific. Imaging of osteoclast activity is now potentially possible by targeting alpha(v)beta(3) integrin using Arg-Gly-Asp (RGD) single photon emission computed tomography (SPECT) or positron-emission tomography (PET) tracers.13,14 Although these studies showed osteoclast-specific targeting in preclinical models, the methodology may also target angiogenesis as a surrogate of the extravascular changes and is still under investigation in man.

Suboptimal sensitivity and specificity reported with BS in the diagnosis of bone metastases15 can be enhanced by modern imaging techniques such as SPECT or combined SPECT and computed tomography (CT), even though the impact of SPECT or SPECT-CT on treatment response assessment is unclear. Advances in magnetic resonance imaging (MRI), including whole-body (WB) diffusionweighted (DW) MRI (WB DW-MRI), have also shown promising results in detecting, characterising, and monitoring response in bone metastases16,17 and these have briefly been discussed below.

Pathophysiology of bone metastases Metastasis is dependent upon cross-talk between cancer cells (seeds) and specific organ microenvironments (“the soil”) as suggested by Paget.18 Bone marrow stromal cells attract tumour cells by the expression of chemotactic elements, thus providing the tumour cells with an environment to grow. The ability of cancer cells to adhere to bone matrix and to promote osteoclast formation are the main steps in the development of bone metastases. Based on radiographic appearance and underlying pathophysiology, bone metastases can be osteoblastic, osteolytic, or mixed and differ in their impact on bones, therefore influencing the optimal imaging technique in order to best illustrate these lesions. Two main processes in the development of bone metastases are osteoclast-mediated bone resorption and osteoblast-facilitated bone formation and mineralisation. Normal bones are constantly remodelling in order to maintain a dynamic balance between osteoblast and osteoclast activity. This balance is disrupted once bone metastases develop. Bone resorption occurs in all types of metastases, but the elements responsible for increased osteoclast activity vary among different tumour types19 resulting in some being predominantly osteolytic (e.g., myeloma, lung, thyroid) and some osteoblastic (e.g., prostate), whereas some types can show mixed morphology (e.g., breast). Osteoblastic activity can be mediated directly by tumourassociated growth factors20 or as a reparative effect following successful therapy, and it may not be possible to differentiate these two processes with bone-specific imaging agents, hence leading to problems with early treatment response assessment. Tumour cells also secrete a number of growth factors, including TGF-b (transforming growth factor) and endothelin-1, that stimulate bone formation via increased osteoblast activity and either directly or indirectly stimulate osteoclasts.21 In lytic bone metastases, parathyroid hormone related protein (PTHrP), along with interleukin-6, is secreted by the cancer cells, stimulating the production of receptor activator of nuclear factor-kB ligand (RANKL), thereby initiating bone resorption.21 RANK, and its ligand RANKL, are the final common mediators leading to osteoclast maturation and activation in bone metastases. A human monoclonal antibody to RANKL, denosumab, is currently being used in the treatment of cancer-related bone disease.

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Imaging modalities SPECT and SPECT-CT SPECT identifies bone lesions more sensitively compared to planar BS and improves characterisation of equivocal lesions.22 This is clinically relevant as certain sites, particularly the spine, tend to be affected by degenerative disease and it is vital to differentiate these benign lesions from skeletal metastases. The greater contrast resolution and anatomical localisation via SPECT offers higher sensitivity in comparison to planar BS (87% versus 74%, respectively) and specificity (91% versus 81%, respectively) in diagnosing spinal metastases.23 Other studies have reported similar results.24,25 SPECT alone has poor spatial resolution, but this can be compensated for by using hybrid SPECT-CT imaging.26 In addition, SPECT-CT surpasses SPECT in interpreting equivocal bone lesions.27 Quantification has also improved with SPECT-CT imaging, although the benefits in bone metastasis imaging are still to be assessed.

WB DW-MRI DW imaging uses the apparent diffusion coefficient (ADC) as a parameter to measure and quantify the differences in diffusion of water molecules within the tissues, thus complementing WB morphological imaging. Tumours are highly cellular compared to normal tissues and the ADC is low but following successful treatment the ADC increases due to loss of cell membrane integrity and reduced cellularity. A meta-analysis in 2011 reported that WB-MRI accurately identified bone metastases from various primary tumours and was cost-effective; however, the addition of DWI reduced the specificity from 96% to 86%, although the sensitivity was comparable.16 Since then, a similar study of 17 patients with bone metastases showed a sensitivity and specificity of 100% with WB DWMRI.17

PET Given the recognised deficiencies in morphological imaging, PET using different radiotracers reporting different aspects of the abnormal underlying biology of bone metastases, is being more widely studied in the evaluation of staging and treatment response of the skeleton. PET alone, however, lacks anatomical detail and is now routinely supplemented with CT, considerably improving the specificity and to a lesser extent sensitivity of the combined technique. Combined PET-MRI is also now commercially available and is the subject of a number of clinical trials. Quantitative criteria for PET, including the EORTC criteria and PET Response Criteria In Solid Tumours (PERCIST),28 can be used to measure response, even in the absence of anatomical change, through assessment of changes in metabolic activity, thereby overcoming some of the deficiencies of RECIST 1.1 related to the skeleton.

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Despite better efficacy of PET in the detection of bone metastases, its cost-effectiveness still needs to be shown as this is now a requirement for approving novel imaging in the current healthcare environment. 18

F-FDG PET

Compared to normal tissue, cancer cells have a higher glycolysis rate as demonstrated in the 1930’s.29 Consequently, 18F-FDG accumulates within them at a higher level than normal tissues giving us information on the increased cellular energetics of malignant tumour cells. 18F-FDG-PETCT is capable of identifying bone metastases that other imaging modalities fail to identify as will be discussed later in this review. 18

F-NaF PET 18

F-NaF is a marker of osteoblast activity in metastatic bone deposits. It was first described in 196230 as a positron-emitting bone tracer, but only recently, due to the development of more modern scanning hardware such as PET, it has renewed interest. A preclinical study reported that 18F-NaF is not bound to protein and is rapidly taken up by bone with almost a 100% first-pass extraction31 making it possible to acquire high contrast images 1 hour after injection.32 The uptake of 18F-NaF depends on local blood flow and osteoblastic activity thus raising the possibility of false-positive uptake in benign bone lesions similar to BS33; however, in combination with CT, one prospective study of 42 patients with various primary malignancies, reported that 18F-NaF-PET-CT had high sensitivity (100%) and negative predictive value (100%) for excluding bone metastases even in patients with equivocal BS.34

Choline PET After intracellular transport, choline is phosphorylated by upregulated levels of tumour choline kinase and as a constituent of phosphatidylcholine, is incorporated into cell membranes. The greatest evidence for use of choline tracers is in prostate cancer; however, a correlation between oestrogen-receptor-positive breast cancer and choline metabolism has been suggested urging further investigation as a breast cancer imaging agent.35 MRI spectroscopy has demonstrated high levels of choline in prostate cancer, and minimal choline uptake in normal and benign prostate.36 choline tracers, labelled with 11C or 18F are being investigated in metastatic bone disease as higher 11C-choline levels are present in related bone metastases compared with 18F-FDG.37 Despite these properties, 11C-choline use is limited because of its short half-life (20 minutes) requiring an on-site cyclotron for production.38 18F-choline has a longer half-life (110 minutes) and therefore greater availability. Despite this, the overall imaging results are similar between both choline agents39 and there is no evidence to suggest superiority of either tracer in imaging skeletal metastases.

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Bone metastases in breast cancer 18

F-FDG PET in breast cancer

In primary breast cancer, the uptake of 18F-FDG is affected by various factors, it is higher in ductal carcinoma, in patients with higher ki-67 proliferation index, and negative oestrogen receptor (ER) status.40 Studies suggested that knowledge of these parameters may help select the right patients for initial staging with 18F-FDG-PET-CT imaging.41 A more recent study, however, has confirmed the superiority of 18F-FDG-PET-CT over BS in detecting bone metastases in breast cancer irrespective of the receptor status.42 Osseous metastases in breast cancer may be lytic, sclerotic, or mixed. It has been reported that lytic lesions have a higher standardised uptake value (SUV) and are better detected by 18F-FDG-PET than sclerotic lesions in patients with progressive disease43 and similar conclusions have been drawn by other studies where the difference in visualisation rates of the different types of bone metastases was found to be statistically significant44e46; however, primarily sclerotic, treatment-naïve bone metastases that show low FDG avidity should not be confused with the situation where bone metastases become sclerotic and FDG-negative posttreatment as a direct outcome of successful therapy.46,47 Uematsu et al.48 reported far lower sensitivity of 18FFDG-PET at identifying sclerotic lesions than with BS augmented SPECT (6% versus 92%, respectively); however, most recent studies using hybrid 18F-FDG-PET-CT have reported that the combined imaging technique is as good as, if not better than, BS at detecting both lytic and sclerotic lesions.49,50 This is likely to be due to a combination of tumour specificity in lytic lesions and improved image contrast from tomographic acquisitions together with the additional information from the CT component of PET/CT in sclerotic disease. Two meta-analyses have reported a higher performance of 18F-FDG-PET in the diagnosis of breast cancer-related metastases, with a pooled sensitivity as high as 93%, compared to 81% with conventional imaging techniques.51,52 Shie et al.53 in another meta-analysis once again concluded that 18F-FDG-PET had a better pooled sensitivity (81% versus 78%) and specificity (93% versus 79%) than BS on a per-patient based analysis. In view of the high specificity, it has been suggested that 18F-FDG-PET be potentially used as a confirmatory test for bone metastases and in the evaluation of disease response.53 This meta-analysis, did not study any differences in detection rates between lytic and sclerotic lesions. 18 F-FDG-PET may be better than conventional imaging in identifying responders or non-responders to systemic therapies earlier thus limiting potential toxicities from ineffective treatments and accelerate change in treatment in non-responders. A change in SUVmax in bone metastases could predict response to systemic treatment in breast cancer, correlate with clinical and tumour marker response assessment,54 and be predictive of time to progression and time to

skeletal related events,55 thereby supporting the use of serial 18F-FDG-PET-CT examinations. A correlation between circulating tumour cell counts and response or progression on 18F-FDG-PET has also been reported.56 Compared to morphological changes in bone lesions on CT, progressive lesions become more lytic and 18FFDG-avid whereas increased sclerosis may indicate response or progression.57 Such findings have also been observed in a retrospective series.58 Another retrospective study of bone metastases in breast cancer revealed that a fall in SUV after treatment was a predictor of response duration.59 One pilot study reported statistically significant differences in progression-free survival (PFS) between patients with progressive metabolic disease and non-progressors.60 18

F-NaF PET-CT in breast cancer

One team of researchers have reported that both sclerotic and lytic lesions are highly 18F-NaF avid61 and 18F-NaFPET-CT showed superiority to 18F-FDG-PET-CT and BS in detecting sclerotic bone lesions in breast cancer in a small study of nine patients.62 18 F-NaF-PET-CT is reliable in investigating suspicious bone metastases in breast, prostate and lung cancers. The sensitivity and negative predictive values are reported as 100% with 18F-NaF-PET-CT in all three cancers compared with 18F-FDG-PET-CT and BS.63 One prospective study of 34 patients with breast and prostate cancers, compared BS combined with single fieldof-view (FOV) SPECT and 18F-NaF-PET-CT in the detection of bone metastases using thin-section CT and MRI as reference standards. Patients with suspected bone lesions on BS, high carcinoma antigen (CA)15-3 or prostate-specific antigen (PSA) or clinical suspicion of bone metastases were included. On a per-lesion basis, 18F-NaF-PET-CT had higher sensitivity (76% versus 45%), specificity (84% versus 79%) and accuracy (80% versus 60%) than BS. On a patient-basis, all patients with bone metastases were correctly identified with 18F-NaF-PET-CT; however on a lesion basis, the detection rate of osteolytic lesions was only 58.3% (Fig 1). There were 12% equivocal lesions on BS, which were confirmed as metastatic on 18F-NaF-PET-CT and would have changed clinical management.64 Doot et al.65 reported that 18F-NaF-PET-CT may be useful for evaluating treatment response in a feasibility study in breast cancer.65 A National Oncology PET Registry trial of 476 patients with breast cancer evaluated the effect of 18FNaF-PET-CT in monitoring treatment response66 (Fig 2). The frequency in change of management plan in patients with breast cancer was 39.3%. Of note, initial reports of a flare phenomenon with 18F-NaF-PET in breast cancer following chemotherapy and endocrine therapy have highlighted the importance of timing of follow-up examinations.67,68 18

F-fluoro-17beta-oestradiol PET in breast cancer

One study of 33 patients reported that 18F-fluoro-17betaoestradiol (18F-FES), which is an ER-specific PET tracer was

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Figure 1 There is minimal osteoblastic activity in a lytic lesion in the right ilium on 18F-NaF PET (left) on both axial and maximum intensity projection (MIP) images in a patient with metastatic breast cancer. In contrast, there is intense focal tumour activity on the corresponding 18 F-FDG PET image (right).

particularly sensitive for bone metastases, detecting 341 osseous lesions compared with 246 with conventional imaging, such as CT and BS, in patients with ER-positive disease. It was concluded that this method was of clinical use in patients in whom there remains a diagnostic dilemma after conventional investigations.69

however, no single method has been shown to be superior. Skeletal metastases are predominantly osteoblastic in nature and so bone-specific tracers tend to be particularly sensitive in this cancer.

Prostate cancer and 11C-choline-PET-CT, 18F-choline-PETCT and 18F-fluoride-PET-CT

Bone metastases in prostate cancer In metastatic prostate cancer a number of radiotracer imaging techniques are available to detect bone metastases;

Patients with prostate cancer and one equivocal lesion on BS underwent 11C-choline-PET-CT, showing that 36% of patients in fact had multiple osseous metastases and 20%

Figure 2 (a) A 65 year old patient with metastatic breast cancer. Pre-treatment (left) and 8-weeks post-endocrine treatment (right) showing response to treatment. Axial 18F-FDG PET, 18F-FDG MIP (right from top to bottom), fused PET-CT, CT (left from top to bottom) at the level of L5 (SUVmax decreased from 11.9 to 4.9). (b) The equivalent 18F-NaF PET-CT MIP and axial sections showing treatment response at L5, pre- (left) and 8-weeks post-endocrine treatment (right). SUVmax decreased from 42 to 32.5. MIP ¼ maximum intensity projection, SUVmax ¼ maximum standardised uptake value. Please cite this article in press as: Azad GK, Cook GJ, Multi-technique imaging of bone metastases: spotlight on PET-CT, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.01.026

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had previously unknown visceral metastases.70 In 2012, the same group showed that 11C-choline-PET-CT was able to detect previously undetected bone metastases in 14.6% of patients with biochemical recurrence and negative BSs.71 A similar study reported that 11C-choline PET-CT was able to correctly predict the presence of bone metastases and had higher specificity compared with BS (98% versus 75%), but in view of its lower sensitivity (89% versus 100%), it would not replace BS; however, 1% of lesions were reported as equivocal on 11C-choline-PET-CT as opposed to 27% on BS.72 Sensitivity as high as 100% with 18F-cholinePET-CT and 18F-FDG-PET-CT was reported in the detection of bone metastases in prostate cancer compared with BS (67%); however, no subanalysis was done to specifically assess the behaviour of bone metastases alone.73 In the preoperative staging of high-risk prostate cancer patients, 18F-choline-PET-CT can detect metastatic disease, changing management in about 20% of cases.74 One prospective study comparing 18F-choline-PET-CT with 18F-NaFPET-CT in patients with newly diagnosed prostate cancer or suspected recurrence presenting with bone pain, reported no statistically significant difference in performance between the two imaging techniques; however lesion-based analysis showed higher specificity of 18F-choline, but only in the group referred for suspicion of metastatic disease.75 Another prospective study reported higher sensitivity of 18 F-fluoride-PET-CT (81% versus 74%) and lower specificity (93% versus 99%) than 18F-choline-PET-CT,76 but these results did not reach statistical significance. Lesions that were extremely sclerotic on CT were not avid on subsequent 18Fcholine-PET-CT, and this discordance between PET and CT findings was potentially due to metabolically inactive sclerotic lesions post-treatment. Interestingly, about 40% of sclerotic lesions were also not avid on 18F-NaF-PET-CT, but this was seen at a much later point of treatment when the lesions had an even higher density and a likely result of increasing reparative sclerosis following treatment.74,76 A retrospective study of 140 patients reported higher uptake of 11C-choline by lytic lesions than sclerotic lesions. Lytic lesions correlated with faster tumour growth and targeted treatment could therefore be instituted early.77 These findings were similar to Beheshti et al.74 who reported differential uptake of 18F-choline tracer, although the number of lytic lesions in this study were very small.74 A study of 44 patients with high-risk prostate cancer or non-specific sclerotic lesions compared 18F-NaF-PET-CT with 18F-NaF-PET alone, planar BS and single FOV-SPECT, reporting a 100% sensitivity and specificity with 18F-NaFPET-CT, a statistically significant better result compared with the other modalities. The inclusion of the CT component of PET-CT improved specificity compared to PET alone and PET-CT improved sensitivity and specificity compared to BS with or without SPECT. A limitation of this study was the lack of costebenefit analysis, which is now becoming more necessary for healthcare systems to approve novel imaging in the current healthcare environment.78 One prospective study of 18 prostate cancer patients, analysed the detection of skeletal disease comparing BS with 18FFDG-PET-CT and 18F-NaF-PET-CT, and reported sensitivities

of 87.5% versus 55.6% versus 100%, respectively, and specificities of 80% versus 100% versus 80%, respectively.79 A multicentre prospective trial using co-administered 18 F-NaF and 18F-FDG radiotracers in the detection of metastases in cancer patients (41 prostate cancers) reported better performance of the combined radiotracer imaging technique compared to either tracer on its own. In prostate cancer, the combined radiotracer imaging technique detected five more lesions than 18F-NaF-PET-CT and 18 more than 18F-FDG-PET-CT; however, the costebenefit ratio was not evaluated.80 More recently a prospective study of 75 patients published in 2015 reported superior performance of co-administered 18F-NaF and 18F-FDG-PET-CT as a combined radiotracer imaging technique in the diagnosis of bone metastases when compared with CT alone. The patients mainly had sarcoma or prostate cancer. In the prostate cancer group, the sensitivity of the combined tracer PET-CT when compared with CT was much higher (100% versus 60.8%, respectively) with similar specificities (75% versus 68.8%, respectively). This was, however, a singlecentre study and again did not address the costebenefit ratio.81 A group from the Netherlands in 2013 conducted a literature review comparing the performance of planar BS, 18 F-choline, 11C-choline and 18F-NaF-PET-CT in the detection of bone metastases in prostate cancer, concluding that there was sufficient evidence to propagate the use of choline and 18F-NaF-PET-CT. The sensitivities of 11C-choline PET-CT and 18F-choline PET-CT were equivalent; however, 18 F-NaF-PET-CT had a significantly lower specificity on both patient and lesion based analyses,82 likely because of the non-tumour specific nature of 18F-NaF accumulation. 18 F-FDG-PET-CT has been compared with 18F-NaF-PETCT for the detection of occult metastases in patients with biochemical relapse of prostate cancer with either normal BS or equivocal findings. 18F-18-NaF-PET-CT was able to detect occult metastases at much lower PSA levels than 18FFDG-PET, leading to earlier detection of metastases and revised disease management.83 A recent review reported that 18F-NaF-PET-CT would be particularly useful in patients with rising PSA in the presence of negative conventional staging scans. It may also be helpful in symptomatic patients with low PSA as 18F-NaFPET has been reported to detect occult disease with potential advantages over BS and WB DW-MRI.84 There is a potential role of 18F-NaF uptake in quantifying prostate cancer bone metastases. Two studies of 98 and 129 patients with castration-resistant prostate cancer (CRPC) have demonstrated a SUV cut-off of 10 between normal bone and metastatic disease.85,86 In one study, patients with high-risk prostate cancer with planned curative treatment and negative or inconclusive BSs went on to have 18F-choline and 18F-NaF-PET-CT scans. 18F-choline-PET-CT suggested either bone or lymph node metastases in 39% of patients and 18F-NaF-PET-CT suggested bone metastases in 41% of cases. PET changed management in 20% of patients.87 One meta-analysis in 2014 revealed that in a patientbased analysis, MRI had the highest pooled sensitivity

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(97%) but choline PET-CT had the highest specificity (99%) in both patient- and lesion-based analyses. Overall, MRI was markedly better than choline PET-CT and BS at detecting bone metastases in prostate cancer (p<0.05).88 A recent study using PET-MRI (18F-choline-PET and DW-MRI complemented by T1- and T2-weighted sequences), to explore the correlation between SUV and ADC in order to evaluate bone metastases in prostate cancer, has shown significant expected inverse relationship between the two parameters89; however, further studies are still to be reported. Although it would be tempting to be able to recommend one tracer to optimally stage the skeleton in prostate cancer, it seems likely that 18F-NaF may detect some choline-negative metastases and vice versa.76 Of course, choline has the advantage of also detecting softtissue disease. Limited data are available on the role of 18F/11C-choline PET-CT or 18F-NaF-PET-CT in the assessment of treatment response in prostate cancer and is currently the subject of a number of clinical trials (Fig 3). One preclinical study in 2010 identified the role of 11C-choline in monitoring early response to docetaxel in metastatic prostate cancer90; however, no clinical studies have yet been reported. A feasibility study, assessing treatment response to 223Rachloride using 18F-NaF-PET-CT has been reported. The change in SUVmax on follow-up imaging was consistent with the PSA response.91 In 2013 Yu et al.,92 demonstrated that 18F-NaF-PET-CT was useful in assessing treatment response to dasatinib, and that there were differences in changes of SUVmax between normal bone and tumour bone.

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F-FDG-PET in prostate cancer

Skeletal metastases in prostate cancer tend to have a low glycolysis rate, and it is likely that other metabolic mechanisms are more dominant in prostate cancer cells. As a result, limited studies have been performed using 18F-FDGPET in prostate cancer. A retrospective study of 91 patients, reported that 18FFDG-PET identified local or systemic disease in 31% of patients with PSA relapse. The probability for detection increased with increasing tumour burden and PSA levels.93 In 2002, Morris et al.94 carried out a lesion-based analysis on 17 patients with metastatic prostate cancer and reported that 18F-FDG-PET was able to differentiate between active and dormant bone lesions and recognised new lesions earlier than BS; however, two studies have reported inferior performance of 18F-FDG-PET in the detection of bone metastases when compared with BS.95,96 18 F-FDG-PET SUVmax strongly correlates with unfavourable prognosis in patients with progressive prostate cancer.97 This group suggested that previous studies showing low detection rates for bone metastases with 18F-FDG-PET were likely to be due to a heterogeneous group of patients. They advocated that in non-progressive metastatic prostate cancer, hormone-responsive tumours are likely to have a very low glycolytic rate, so 18F-FDG-PET may not be useful in assessing treatment response, whereas in CRPC, 18F-FDG uptake can be used as a treatment response indicator. Morris et al.98 in 2005 proposed using 18F-FDG-PET as a single technique to monitor treatment response to anti-

Figure 3 (a) An 81-year-old man with metastatic prostate cancer. Pre-chemotherapy (left) and 8-weeks post-chemotherapy (right) showing disease progression. Axial 11C-choline PET, 11C-choline MIP (right from top to bottom), fused PET-CT, CT (left from top to bottom) in the cervical spine. SUVmax increased from 10.5 to 16.3. (b) The equivalent 18F-NaF PET-CT MIP and axial sections showing disease progression in the cervical spine, pre-chemotherapy (left), and 8-weeks post-chemotherapy (right). SUVmax increased from 74.4 to 111. Please cite this article in press as: Azad GK, Cook GJ, Multi-technique imaging of bone metastases: spotlight on PET-CT, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.01.026

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microtubule chemotherapy compared with a combination of PSA, BS, and CT; however, this study did not specifically look into treatment response of bone metastases. Currently, molecular imaging probes specifically targeting the androgen receptor signalling pathway are being assessed in prostate cancer. One study analysed different patterns of bone metastases on CT and their associated glycolytic activity based on uptake of 18F-FDG and relative androgen receptor expression based on uptake of 18F-16bfluoro-5-dihydrotestosterone (18F-FDHT) in CRPC. The intensity of 18F-FDHT uptake inversely correlated with overall survival.99

Bone metastases in lung cancer It has previously been shown that symptomatology and serum bone biochemistry is insufficiently reliable to guide investigations for bone metastases in patients with lung cancer.100 Two early studies reported that 18F-FDG and BS have similar sensitivities, but 18F-FDG-PET is more specific at detecting bone metastases.101,102 Metser et al.103 retrospectively reviewed spinal involvement in patients with a variety of primary cancers including lung, breast and colon cancer, concluding that 18F-FDG-PET had higher sensitivity compared with CT alone (96% versus 68%, p<0.001). Patients with non-small cell lung cancer (NSCLC) and bone metastases often have discordant findings between BS and 18F-FDG-PET-CT. In one study, 20% of patients with normal BSs had disseminated skeletal metastases on 18FFDG-PET-CT.104 Song et al.105 reported similar findings. One study in 2011 reported that 18F-FDG-PET-CT was more sensitive at detecting bone metastases in lung cancer and melanoma compared with WB MRI, but this difference was not statistically significant and both techniques showed significant false-negative rates requiring close follow-up of the disease.106 A year later, one meta-analysis reported that 18 F-FDG-PET-CT had the highest sensitivity (92% versus 77% versus 86%, respectively) and specificity (98% versus 92% versus 88%) at diagnosing lung cancer-associated bone metastases compared with MRI studies and BS.107 Another meta-analysis reported similar findings.108 A meta-analysis in 2012, assessed the diagnostic performance of 18F-FDG-PET-CT in the diagnosis of bone metastases in NSCLC reporting a pooled sensitivity of 91% and specificity of 98%. Significant heterogeneity was found in the sensitivity, likely related to the heterogeneity in the studies.109 A further meta-analysis in the same year reported similar sensitivities of 18F-FDG-PET-CT compared with BS (93% versus 87%, respectively) in the diagnosis of bone metastases in lung cancer.110 The “flare phenomenon” has been described in lung cancer-associated bone metastases on 18F-FDG-PET-CT in a case series, in patients treated with bevacizumab. In three of the four patients, subsequent imaging showed a decrease in SUV with ongoing systemic treatment, suggesting flare as the likely cause of the initial increase. This phenomenon was thought to represent rapid bone repair around the

responding lesion due to increased osteoblastic activity and may be predictive of successful systemic therapy.111 Of interest, soft-tissue lesions did not show a “flare”. A recent retrospective study of 30 patients mainly with breast and lung primaries, reported that 18F-FDG-PET-CT is more sensitive and specific at detecting treatment response of bone metastases compared with CT. They reported a correlation between decreasing metabolic activity and increasing CT attenuation of the target lesions in responders, the reverse was true for non-responders. In addition, progressing baseline blastic lesions had noticeable increase in metabolic activity, size and attenuation.112 In small cell lung cancer (SCLC), a prospective study of 95 patients reported higher sensitivity of 18F-FDG-PET-CT than BS in the detection of bone metastases (100% versus 37%, respectively).113 Similar results have been reported by another study.114 One prospective study of both SCLC and NSCLC patients reported that 18F-NaF-PET was more effective at diagnosing bone metastases than BS and SPECT but was associated with higher incremental costs.115 Another study reported similar results but also suggested that SPECT improved the accuracy of BS and was more cost-effective.116 Since then, one study of 107 patients reported a sensitivity of 100%, specificity of 98.7% and accuracy of 99% with 18 F-NaF-PET-CT in the detection of bone metastases in lung cancer.117

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F-FDG-PET-CT is more accurate than PET or CT alone at detecting distant metastases, including skeletal lesions in pancreatic cancer.118 In differentiated thyroid cancer (DTC), the presence of distant metastases reduces the 10-year survival by 50%. BS depends on the detection of an osteoblastic reaction, but in thyroid cancer, osseous metastases are predominantly lytic, resulting in high false-negative and false-positive rates.119 Imaging the whole body using 131I or 123I, or even the positron-emitting isotope 124I, are both more specific and sensitive than BS, but only for well-differentiated, sodium iodide symporter (NIS)-positive thyroid tumours.120,121 In 2006, a retrospective study of 24 patients reported that 38% of bone metastases in patients with DTC were identified by BS only and not by 18F-FDG-PET suggesting that BSs could not be replaced by 18F-FDG-PET.122 Another study reported that 18F-FDG-PET had a lower incidence of false-positive rates and was, therefore, superior to BS in the detection of DTC-associated bone metastases, even though the difference in accuracy and specificity between the two modalities did not reach statistical significance.119 Another study highlighted that in DTC, both BS augmented with SPECT-CT and 18F-FDG-PET-CT had a higher diagnostic performance than BS in the detection of bone metastases and 18F-FDG-PET-CT positivity was an independent factor associated with poor prognosis.123 Ota and colleagues124 reported that the sensitivity and accuracy of 18F-NaF-PET-CT was considerably higher than

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BS in the detection of bone metastases in DTC; however, the performance of BS improved near to that of 18F-NaF-PET-CT when SPECT was added to the planar scan. The sensitivity of 18 F-FDG-PET-CT was lower than both BS and 18F-NaF-PETCT124 as would be expected in DTC. 18 F-FDG-PET-CT has higher sensitivity than BS at detecting bone metastases in hepatocellular carcinoma (99% versus 85%),125 head and neck cancers (85% versus 55%),126 osteosarcoma (100% versus 95%)127 and muscle invasive bladder cancer (100% versus 82%).128 In gastric cancer, one retrospective study revealed that 18 F-FDG-PET-CT was superior to BS in the detection of synchronous bone metastases, although both techniques performed similarly in the detection of metachronous bone metastases. In this study, 15% of solitary bone metastases were found to be positive on 18F-FDG-PET-CT only.129 Another study of 39 patients with metastatic gastric cancer reported that 18F-FDG-PET-CT was more sensitive at detecting bone metastases than 18F-30 -deoxy-30 -F-fluorothymidine (18F-FLT) PET-CT (100% versus 20%, respectively, p<0.05).130 One study reported higher sensitivity of 18F-FDG-PET-CT than BS (92% versus 77%) in the detection of bone metastases in oesophageal cancer, although this study did not reach statistical significance.131 One pilot study of 14 patients using combined 18F-NaF and 18F-FDG-PET-CT for the assessment of bone metastases in various primary cancers, reported comparable results to the PET/CT performed separately, indicating that the combined approach may be more cost-effective without compromising the osseous metastases detection rate132; however, larger prospective studies are required to optimise protocols and to look at any potential confounding factors, such as osseous flare, in the assessment of treatment response with this combined approach.

Conclusion In prostate cancer, 18F-FDG-PET has no routine role in the detection or treatment response assessment of bone metastases, although it may be useful in monitoring treatment response in CRPC when metastases become more 18F-FDGavid. In breast cancer, however, 18F-FDG-PET is an accurate method for detecting bone metastases, and there is increasing evidence to support the use of serial 18F-FDG-PET for the assessment of osseous response to treatment. As yet, there is little evidence to establish which imaging technique has the greatest sensitivity in diagnosing skeletal metastases in breast cancer, but there is no doubt that the diagnostic accuracy can be improved with SPECT/CT, 18FNaF-PET-CT or with 18F-FDG-PET-CT compared to conventional imaging. In prostate cancer, 11C- and 18F-choline-PETCT have better specificities than 18F-NaF-PET-CT, but equivalent sensitivities in the detection of bone metastases, and at present, a combination of bone-specific and tumourspecific imaging techniques are, therefore, recommended. In NSCLC, 18F-FDG-PET-CT is much more accurate than BS at picking up early bone metastases, and there is a potential

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role of 18F-FDG-PET-CT in the detection of bone metastases in DTC, but this may not be cost-effective. In gastro-oesophageal, head and neck cancers, and osteosarcoma, preliminary data suggests 18F-FDG-PET-CT is more sensitive at detecting bone metastases than BS. Going forward, results from comparative trials of tumour-specific and bone-specific PET together with WB DW-MRI are eagerly awaited both to guide the most accurate and cost-effective method for bone metastasis detection as well as offering better response assessment in routine practice and clinical trials.

Acknowledgements The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and the King’s College London/ University College London Comprehensive Cancer Imaging Centres funded by Cancer Research UK and Engineering and Physical Sciences Research Council in association with the Medical Research Council, the Department of Health (England) (16463), Prostate Cancer UK (PA12-04) and Breast Cancer Now (2012NovPR013).

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Please cite this article in press as: Azad GK, Cook GJ, Multi-technique imaging of bone metastases: spotlight on PET-CT, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.01.026