The new bone WB-SPECT/CT: hybrid, from head-to-toe and digital! Is it worth the effort?

ABSTRACT Introduction A bone scan (BS) plays a pivotal role in many oncological and non-oncological conditions. The planar BS is characterized by high sensitivity but low specificity. With respect to planar imaging, the implementation of single-photon emission computed tomography (SPECT) has allowed increased image contrast and more accurate tracer localization. Areas covered Recent technological innovations in the field of BS are treated, with a particular focus on multi-field-of-view devices allowing to cover the entire scan length with a 3D acquisition (WB-SPECT/CT). In addition, the applications of cadmium zinc telluride/CzT detectors capable of converting gamma photons directly into electrical impulses (i.e. ‘digital SPECT’) are discussed. Expert opinion Initial clinical experiences indicate that WB-SPECT/CT is characterized by higher sensitivity, diagnostic accuracy, and increased confidence in image interpretation with respect to the ‘old-fashioned’ BS (planar images with or without a single field-of-view SPECT). Furthermore, CzT-based detectors, thanks to their superior sensitivity, might be helpful to implement fast acquisition protocols. Further studies are needed to better define the clinical impact of bone CzT WB-SPECT/CT on patients’ management and outcome, as well as its cost–benefit ratio.


Background
For many years, Bone Scan (BS) has represented the most popular application of nuclear medicine in clinical practice.This is not surprising, since the skeleton is a frequent site of metastatization, preceded only by the lung and liver [1].Bone metastases more often occur at the late stage of cancer, gradually progressing and determining the so-called skeletal-related events (SREs), which, in turn, deeply impact patients' quality of life.Early detection of bone metastases is of crucial importance both for accurate staging and adequate therapy planning [2,3].The most appropriate imaging method to diagnose bone metastases should be chosen on a caseby-case basis, depending on tumor type and clinical setting (i.e.staging, re-staging, or response assessment).However, BS is commonly employed as the first-line imaging for bone lesions detection thanks to its high sensitivity and availability [4].
The first attempts to obtain a BS were carried out in the '50s, employing fluorine-18 ( 18 F), which is now the most widely used radionuclide for positron emission computed tomography (PET/ CT) [5].The choice of 18 F as an imaging agent for BS was mainly due to its affinity for hydroxyapatite, the basic constituent of bone matrix.There have been two crucial steps in BS history: the development of the molybdenum-99/-technetium-99 m ( 99 Mo/ 99m Tc) generator and the synthesis of 99m Tc-labeled polyphosphates, particularly 99m Tc-methylene diphosphonate ( 99m Tc-MDP) and 99m Tc-hydroxymethylene-diphosphonate ( 99m Tc-HMDP), whose mechanisms of incorporation are mainly dependent on vascularization and absorption onto the surface of hydroxyapatite crystals [6].
Although BS is extensively employed in clinical practice, scientific data on its diagnostic accuracy are limited by the lack of a precise reference standard [7].In addition, BS, when carried out using planar images, has poor spatial resolution, and its specificity, in spite of its high sensitivity, is low due to increased osteometabolic activity detectable in benign diseases such as trauma, infection, inflammation, and degenerative joint diseases [8].In the past two decades, several innovations have been implemented in the field of BS, ranging from hybrid tomographic imaging modality (i.e.hybrid SPECT/ CT) to the development of highly performing semiconductorbased digital detectors.Here, we briefly summarize the latest advances in the field of BS, trying to delineate how these technological improvements are expected to impact daily clinical practice.

From SPECT to hybrid SPECT/CT
A crucial first step forward in the field of BS has been represented by the implementation of the single photon emission computed tomography (SPECT) technique.SPECT consists of gamma-camera rotation around the patient so that projections of the radiopharmaceutical's distribution in a certain body district can be acquired under multiple views and subsequently reconstructed into a 3D volume by a dedicated software package [9].The main advantage of SPECT over planar images is that higher diagnostic accuracy can be obtained.As early as in 1999, it was shown that BS carried out through SPECT can detect more numerous metastatic lesions than planar images, especially in the case of osteolytic lesions, with clearly positive findings even in the case of negative or borderline abnormal planars [10,11].However, it has to be underlined that SPECT does not allow precise anatomical localization, which is often crucial to gaining a differential diagnosis between pathological and benign foci of increased tracer uptake.In this respect, hybrid imaging, consisting of single-photon emission computed tomography (SPECT) combined with computed tomography (CT), namely SPECT/CT, had a revolutionary impact in clinical practice, particularly for the imaging of skeletal metastases [7,[12][13][14].
In a comparative study, Sharma and colleagues investigated the added value of hybrid SPECT/CT with respect to planars and SPECT alone in patients affected by metastatic breast cancer: 52 indeterminate lesions were detected on planar images, 15 on SPECT, and 3 on SPECT/CT, thus supporting the higher diagnostic accuracy of hybrid SPECT/CT over both planars and SPECT alone.In addition, the area under the curve was meaningfully higher for hybrid SPECT/CT than for the other two modalities, and the improvement in diagnostic accuracy was mainly seen for osteolytic lesions [15].Aside from oncological applications, hybrid SPECT/CT was also successfully employed to improve BS accuracy in other pathological conditions.As an example, Linke and coworkers submitted 71 patients with no history of cancer or pain from the extremities to BS with SPECT/CT.Among 34 lesions categorized as osteoarthritis on planar and SPECT images, hybrid SPECT/CT reclassified seven lesions as fractures and one as benign tumor [16].A recently published review further highlighted that hybrid SPECT/CT, especially when integrated with a dedicated multi-slice CT device, can improve diagnostic accuracy and confidence in BS interpretation among readers with different experiences, while also impacting patients' management and outcome [17].In addition, it is worth mentioning that hybrid SPECT/CT systems paved the ground for quantitative measures of radioactivity concentration within a specific volume in absolute units (i.e.kBq/mL).The CT-component of the hybrid SPECT/CT system, in fact, allows precise accurate attenuation correction, while dedicated reconstruction algorithms have been developed to correct for scatter and partial volume effect [18].

From single field-of-view to whole-body SPECT/ CT
A recent innovation in SPECT imaging has been represented by the transition from a single field-of-view (covering a certain district where an abnormal tracer accumulation is detected) to whole-body SPECT/CT (WB-SPECT/CT).WB-SPECT/CT employs multi-field-of-view devices capable of covering the entire body length (i.e. usually three field-of-views/FOVs are used to cover from the skull base to mid-femur) [19].In this respect, the diagnostic performance of WB-SPECT/CT was compared by Abikhzer and colleagues with that of 'standard' whole-body BS: on a patient-based analysis, WB-SPECT/CT outperformed standard BS on detectability rate (100% vs. 97%), while on a lesion-based analysis, 266 lesions were identified by WB-SPECT/CT versus 195 detected by standard BS [20].Bone WB-SPECT/CT was compared with FDG PET/CT for the detection of skeletal metastases in 25 breast cancer patients.While perpatient analysis registered no differences in detection rate of bone metastases among WB-SPECT/CT and PET/CT, per-lesion analysis showed that a greater number of lesions were identified by WB-SPECT/CT with respect to FDG PET/CT, thus suggesting the possible integrated use of both imaging modalities for staging high-risk breast cancer, the former for an optimal evaluation of bone involvement and the latter for the detection of visceral metastases (e.g.lung and liver) [21].

From analogue to digital detection
The introduction of solid-state detectors based on materials (such as cadmium telluride/CdTe and cadmium zinc telluride/ CzT), capable of converting gamma photons directly into electrical impulses, has given the development of the 'new' BS another boost.CzT-based detectors are distinguished from conventional photomultiplier tube (PMT)-based detectors by better energy and spatial resolution [22].However, up until now, CzT-SPECT has mostly been used for myocardial perfusion imaging due to its ability to cut down on administered activity and acquisition time while maintaining image quality [23].
To extend the potential usefulness of this new technology to additional nuclear medicine applications, such as BS, some unique gamma-cameras equipped with wide-field CzTdetectors have recently been developed [24].Two large, flat detectors with the same detection-geometry as typical PMTbased devices were included in the first CzT WB-SPECT/CT scanner (Discovery NM/CT 670 CZT; GE Healthcare, Chicago, IL) [25,26].More recently, VERITON CzT camera (Spectrum Dynamics, Caesarea, Israel), characterized by a new detection architecture, has been introduced.This new device consists of 12 columns of detectors disposed in a ring configuration, being each column composed of a 16 × 128 array of CzT pixel units with high-sensitivity tungsten parallel-hole collimators.In addition, each detector surface is equipped with skin sensors so that it can get as close as possible to the body contour.Preliminary data indicate that VERITON CzT device outperforms on sensitivity, energy resolution, and image contrast the traditional PMT-based gamma-camera, while the two types of device had similar performance as concerns spatial

Article highlights
• Bone Scan (BS) with 99m Tc-labeled poly-phosphates is widely employed in clinical practice for the diagnosis of skeletal metastases.resolution [24].Figure 1 schematizes the innovative architecture of VERITON CzT gamma camera.

Expert opinion
Relevant technological innovations (i.e.WB-SPECT/CT and CzTbased detectors) have been recently implemented and have moved the field of BS forward (Table 1).However, some questions arise about the potential role of this 'new' BS with respect to the 'old-fashioned' one (planar images with or without a single field-of-view SPECT).The first question is: 'Is bone WB-SPECT/CT of clinical value?'Although preliminary, first clinical experiences seem to point to this direction, since WB-SPECT/CT showed higher detection rate of bone metastases and more reliable diagnostic performance, when compared to planar BS.A recently published systematic review and meta-analysis including 1,265 patients from eight studies showed significantly higher sensitivity (92% versus 74%) and specificity (93% versus 80%) for WB-SPECT/CT with respect to conventional BS (i.e.planar images) in the case of positive equivocal findings, while for negative findings WB-SPECT/CT showed superior sensitivity (91% versus 70%), but not meaningfully greater specificity [27].
The duration of a certain diagnostic procedure is particularly important for cancer patients.Therefore, the second question is: 'Is bone WB-SPECT/CT time-consuming?' Initially, one of the most relevant drawbacks of WB-SPECT/CT was the lack of fast protocols, since its total acquisition-time according to the current guidelines resulted in 50-40 min [28].In this respect, Arvola and colleagues investigated the feasibility of fast protocols for bone WB-SPECT/CT in prostate cancer patients by exploiting the superior sensitivity of CzT-detectors: 30 subjects were submitted to 99m Tc-HMDP WB-SPECT/CT (from vertex to mid-femur) by the Discovery NM/CT 670 CzT device with a 50-min acquisition protocol [29].Subsequently, the acquired list-mode data were resampled to produce data sets with shorter acquisition times of 41, 38, 32, 26, 20, and 16 min and image quality was assessed by three experienced nuclear medicine physicians both qualitatively and quantitatively.Although the original images (50 min) showed the best quality, the authors showed that the scan duration can be reduced to 16 min without significantly hampering diagnostic performance, as shown in Figure 2. From this perspective, CzT WB-SPECT paves the ground for a personalized acquisition protocol that might be adapted to patient clinical status and pathological condition (e.g.subjects debilitated by pelvic or spine localizations), while at the same time increasing patient procedure acceptability and reducing the risk of movement artifacts.In this respect, to the best of our  knowledge, the potential of the VERITON CzT device to implement fast protocol for WB-SPECT/CT bone imaging has yet to be evaluated and should be a topic of future investigations.Notably, due to its peculiar geometry-detection, particular attention should be paid when VERITON CzT is employed in claustrophobic patients, although a preliminary report showed no significant differences in patient acceptance between VERITON and traditional gamma camera [30].
Our conclusive question to be answered is, ultimately: 'Is bone WB-SPECT/CT worth the effort?'Although nuclear medicine has been revolutionized in the last years by the advent of the so-called 'theranostic era' mainly based on the administration of molecularly targeted tracers [31][32][33], BS still covers a crucial role in the staging and follow-up of many oncological and non-oncological conditions.However, the comparison with other cutting-edge imaging modalities will play a key role in defining the future place of bone WB-SPECT/CT in clinical practice.In this regard, a recently published metaanalysis compared PET with radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA-PET) with conventional imaging modalities (CT + BS) for the initial staging of intermediate-high-risk prostate cancer [34].As concerns the detection of bone metastases, PSMA-PET resulted more sensitive and specific than BS with or without SPECT (98.0%versus 73.0%, 96.2% versus 79.1%).Furthermore, the prospective, single-center trial PROSTAGE compared PSMA-PET (i.e. 18F-PSMA-1007 PET/CT) with respect to conventional imaging (CT + 'old fashioned' BS), whole-body magnetic resonance imaging (WB-MRI), and bone SPECT/CT for the diagnosis of skeletal metastases in high-risk prostate cancer [35].In the examined cohort (n = 79), PSMA-PET outperformed the other imaging modalities, showing superior diagnostic accuracy and the highest inter-reader agreement.Although the previously cited papers [34,35] seem to suggest that PSMA-PET might replace BS for the initial staging of high-risk prostate cancer, a head-to-head comparison between PSMA-PET and CzT WB-SPECT/CT has not been performed yet.
CzT WB-SPECT/CT holds the promise to further boost the impact of BS in clinical practice thanks to its exquisite sensitivity, the possibility to carry out reliable quantitative measures and the feasibility of fast acquisition protocols.However, since there is no technological advancement without cost, it remains to be established how much the higher diagnostic performance of bone CzT WB-SPECT/CT can influence patient management and outcome, as well as its cost/ benefit analysis and sustainability in various health-care systems.These issues should be addressed through further welldesigned and ideally prospective clinical investigations.

Figure 1 .
Figure 1.Illustration of the geometric design of VERTON CzT device, depicting movement of the 12 detectors (a), swipe motion of the detectors to cover the region of interest represented in dark gray (b), the array of 16 by 128 pixel units in each column (c), the photo of the device (d).Reprinted from [24], under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).No changes were made.
• Planar BS is characterized by high sensitivity but low specificity.With respect to planar imaging, single photon emission computed tomography (SPECT) has allowed increased image contrast and more accurate tracer localization, but it does not provide anatomical information.Cadmium zinc telluride/CzT detectors, capable of converting gamma photons directly into electrical impulses, gave birth to the so-called 'digital SPECT', which allows low-dose and fast acquisition protocols. •

Table 1 .
A summary of the technological advances in bone scintigraphy from planar images to CzT WB-SPECT.