Background
Neuroblastoma (NB) is an embryonic tumour deriving from the sympathetic nervous system able to produce an excess of catecholamines. It is the most common extra-cranial tumour of the paediatric age. In high-risk disease, metastatic lesions are often present at diagnosis, giving a poor prognosis with long-term survival of about 40–50% [
1,
2]. In this challenging clinical scenario, intensive and multi-step therapeutic regimens have been developed (i.e., induction chemotherapy, surgery, second-line high-dose chemotherapy, autologous stem cell transplantation, radiation therapy, radionuclide therapy, differentiation therapies, and immunotherapy) to achieve the best treatment for each NB patient [
3]. This approach relies on obtaining an accurate diagnostic disease assessment before proceeding to each subsequent therapeutic step. Therefore, effective and reliable diagnostic procedures are in high demand.
Molecular imaging plays a pivotal diagnostic role in staging and evaluating treatment response in patients with NB. [
123I]-metaiodobenzylguanidine (mIBG) whole-body scintigraphy in combination with SPECT/CT of the chest and abdomen is recognised as the cornerstone imaging procedure to stage and restage NB patients properly [
4]. The main advantages over the other conventional imaging procedures (i.e., CT and MRI) are its high diagnostic accuracy in detecting distant metastases and its ability to provide reliable predictive and prognostic information by applying a dedicated scoring system validated over the years [
5‐
7]. In addition, a positive
123I-mIBG scan paves the way for using radionuclide therapy with
131I-mIBG.
However, the mIBG scan has some diagnostic and practical limitations. Notably, false negative results may occur in about 10% of patients [
8,
9]. Furthermore, the spatial resolution of this imaging technique even when combined with SPECT/CT, is suboptimal compared to other cross-sectional imaging tools. Additionally, the mIBG scan requires adequate thyroid blockade. Moreover, it implies at least a two-day protocol, including time-consuming planar and SPECT image acquisitions usually taking more than one hour [
10].In this context, some PET tracers have been proposed as an effective alternative to mIBG. The most specific ones, which can assess the catecholaminergic NB pathway, can provide additional diagnostic information compared to mIBG scans and especially in high-risk (HR) NB patients, can change the clinical management [
10]. PET/CT with catecholaminergic tracers are rarely used in clinical practice and not included in new therapeutic protocols for HR-NB patients, despite their apparent superiority and the recognition of their relevant diagnostic role by recent international procedural guidelines [
4].
This evidence-based review aims to clarify the emerging diagnostic role of these PET tracers better by performing a systematic search of the literature to identify original studies reporting a head-to-head diagnostic comparison of mIBG to whole-body scan with PET/CT with catecholaminergic tracers such as meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG).
Discussion
In this systematic review, we aimed to clarify the differences in the diagnostic performance of catecholaminergic PET tracers and mIBG SPECT/CT in children with NB. More recently, some metabolic and receptor PET tracers, such as [
18F]FDG or [
68 Ga]-DOTA peptides[
24], have been tested; however, even though they could be of complementary value when tumours show scarce mIBG uptake, their specificity is limited. Moreover, assessing disease extension or response to treatment by using one of these tracers as a single agent can be particularly difficult, especially in high-risk NB patients with predominant bone marrow involvement [
25‐
27]. Currently, the most attractive and promising PET tracers remain those able to describe the catecholamine metabolic pathway, characterising with high specificity the neuroblastic tumours. In this study, we collected all the available evidence on the sensitivity of these tracers in patients affected by NB compared to mIBG scans. This is the first effort to analyse the evidence-based data of this special class of PET tracers in a non-negligible number of patients. Particularly, we evaluated the role of four catecholaminergic tracers such as [
18F]DOPA, [
11C]C-HED, [
124I]mIBG and [
18F]mFBG. Among these, one contains the same carrier molecule of the SPECT tracer (mIBG), adopting a different, positron-emitting isotope of the same element; mFBG also uses the same base structure, but it replaces iodine with fluoride. Finally, HED represents a catecholamine analogue, and DOPA is a precursor of dopamine and catecholamines [
28].
Our qualitative assessment showed no significant differences in sensitivity between PET imaging and mIBG scan in the PBA, with both modalities providing similarly high sensitivity. However, the clinical setting and the selection of patients included in the analysis can explain the inconstant presence of significant differences between these imaging methods. Indeed, these patients were mostly affected by HR-NB and mainly evaluated at the time of first diagnosis when there is a high prevalence of true positive lesions [
10,
13,
16]. Indeed, when we consider the studies including predominantly patients evaluated at restaging when highly sensitive procedures are required to identify even small persistent or relapsing lesions, a slight difference in favour of PET imaging was observed [
15].
When we investigated the diagnostic sensitivity of these diagnostic tools using an LBA, we found that the sensitivity of PET with catecholaminergic tracers was reported to be significantly higher than that of mIBG-based tracers in 7 out of 10 studies. Particularly, the pathological distribution of the tracers seems to be very similar to that of mIBG; no mIBG-positive lesion was missed by [18F]- or [124I]-based PET. The higher ability of PET to disclose sites of disease was confirmed both for soft tissue and osseous/bone marrow metastases. This last finding has an influence on the Curie or SIOPEN scores which are based on the bone marrow disease extension. In addition, due to the higher diagnostic accuracy of catecholaminergic tracers, PET/CT can prompt modifications in the clinical management and therapeutic strategy in up to 32% of patients. However, the actual clinical impact of PET on clinical decision-making remains untested.
When analysing the sensitivity of the two methods, it must be pointed out that not all studies included SPECT/CT imaging as a part of the standard scintigraphy protocol. Moreover, even those who did employ SPECT/CT used somewhat inconsistent protocols, ranging from one-bed position to a PET-like field of view. This discrepancy could have theoretically affected the comparison between [123I]mIBG. On the other hand, it must be considered that three-dimensional hybrid imaging is more likely to improve the sensitivity of the method in specific bodily districts, which can normally be encompassed in a single SPECT/CT bed position. Consequently, even though the sensitivity of the scintigraphic method on LBA showed significant variation, this variability did not appear to be linked to the acquisition protocol (SPECT vs one-bed SPECT/CT vs “PET-like” SPECT/CT).
All this growing body of evidence indicates that these PET imaging procedures are effective and reliable in detecting NB localisation. In addition, their accuracy is significantly higher than that of mIBG scans. This important diagnostic advantage over mIBG is accompanied by numerous practical advantages. [
123I]mIBG scanning is a time-consuming procedure, requiring at least one acquisition to be performed the next day after the tracer injection [
10]. In paediatric hospitals not equipped with nuclear medicine capabilities, the patient must be transferred at least twice to an external facility. Achieving adequate image quality requires a long scanning time (up to one hour), which decreases patients’ comfort and compliance; moreover, in smaller children, extended periods of sedation may be required [
4]. Planar images are often difficult to interpret, with high tracer background contribution, and decisions with relevant therapeutic impact must sometimes be made based on the presence of faint areas of uptake. The advent of SPECT/CT has significantly improved the accuracy of lesion detection; however, this technique comes at the cost of yet another acquisition time increase and whole-body SPECT/CT is rarely achieved [
29,
30]. Moreover, validated interpretation scores are not yet calibrated to account for the information provided by SPECT/CT [
30].
We believe the limitations described with [
123I]mIBG imaging can be mitigated using PET/CT with appropriate neuroblastoma tracers. PET images can be acquired a mere hour after tracer injection; they have superior resolution with little background noise and include the anatomical information for the entirety of the field of view, with a scanning duration of 15–20 min [
10]. Newer devices feature a long axial field-of-view detector set, allowing scans to be made in as little as two minutes or using one-tenth of the activity required for regular tomographs [
31]. With a long axial-field-of-view device, whole-body imaging will allow true quantification of the tracer distribution, as well as kinetics analyses; advanced image analysis, such as texture analysis and potentially machine learning algorithms, to be developed [
32]. Considering these data, PET/CT appears to be superior in all aspects compared to [
123I]mIBG scanning; moreover, when using tracers labelled with [
18F]- or [
124I], it appears to identify all of, and occasionally more than, the lesions identified on [
123I]-mIBG planar and SPECT imaging.
It has to be pointed out, however, that not all PET radiopharmaceuticals are equal. [
11C]HED is one of the oldest ones and bears the disadvantages linked to [
11C] labelling, namely short physical half-life (requiring an on-site cyclotron) and a relatively poor PET resolution[
33]. Accordingly, this tracer did not perform better than [
123I]MIBG in the head-to-head [
15]. As such, it does not represent a promising [
123I]mIBG alternative. [
124I]mIBG is, on the other hand, a theragnostic tracer, sharing the same molecular structure as [
123I]mIBG, and its long half-life (4.2 days) allows for dosimetry application [
18,
34]. On the other hand, such a long decay time implies a higher radiation exposure for the children; moreover, [
124I] has a very complex decay scheme, with only roughly 20% of the emitted radiation being high-energy positrons. These characteristics can degrade the image quality [
35]. [
18F]F-DOPA represents the most studied PET tracer in children with NB, making up more than half of the patients in the current review. It is an FDA/EMA-approved radiopharmaceutical which can be used in many clinical settings, even beyond oncology; its use in NB is supported by the most current diagnostic guidelines [
4]. Even though it does not represent a theragnostic tracer, there is evidence that its distribution mirrors the one of mIBG [
36]. Finally, [
18F]mFBG also uses the same base structure as mIBG and is labelled with [
18F], the most commonly used PET isotope is the most promising alternative to [
123I]mIBG but is not yet widely available [
19,
37].
Managing children with HR-NB is a complex endeavour, requiring multiple stages of disease assessment and an accurate therapy response evaluation. Treatment of metastatic NB relies heavily on molecular imaging, which can track the presence of residual clonal burden and identify the disease relapse that can have relevant therapeutic consequences. Children facing this ailment are often infants and almost ever scared of undergoing imaging; their discomfort is paralleled only by that of their parents or caregivers. In this setting, having a two-day or a one-hour procedure can make an enormous difference in their well-being; the shorter alternative could be associated with greater patients’ compliance, leading to better image quality. Moreover, the ease of interpretation provided by PET fosters smoother and more confident decision-making in the context of the nuclear medicine physician evaluation and the multidisciplinary board meeting. Finally, the accumulating evidence on the advantages of PET in NB[
38] should promote its use in research studies as well; however, current trials still rely on single-photon catecholaminergic imaging [
5]. Considering all these points, it is clear that efforts should be made to promote PET imaging in HR-NB, both in day-to-day use and in clinical research. Such a transition would bring about better imaging, better patient care, and a higher chance of improving the current treatment standards through focused research.
This systematic review has some limitations, such as the low number of patients and articles included. The relatively low number of patients is coherent with the disease prevalence. The number of articles included is explained by the strict inclusion criteria used in our systematic review (only studies comparing [
123I]mIBG scans with PET using catecholaminergic tracers were included); moreover, the comparison between [
123I]mIBG with PET tracers was always of direct nature (i.e., based on a head-to-head analysis rather than on two separate comparisons with the gold standard). Moreover, half of the studies were prospective investigations, limiting the possible selection and information bias strongly. In almost all cases, the proof of truth consisted of the follow-up imaging, while a histological confirmation was only rarely available; this limitation stems from the impossibility of obtaining a biopsy from each disease localisation in patients with diffuse metastatic disease and cannot be easily circumvented in such analyses. In one case, PET imaging was compared with [
131I]mIBG [
17]; this radiopharmaceutical has an inferior spatial resolution as compared with [
123I]mIBG (due to the higher energy of the gamma photons emitted by [
131I]I) and a longer uptake time. Moreover, the dose burden of [
131I]mIBG is higher than [
123I]mIBG, thus limiting the activity that can be safely administered and reducing the resulting counting rate. These characteristics could impact the sensitivity of the method. On the other hand, [
131I]mIBG is significantly cheaper than [
123I]mIBG and could represent an accessible diagnostic resource in low-income or emerging countries in the coming years
. Also, the included data allowed calculation of the sensitivity of the methods but not their specificity. The SPECT or SPECT/CT field-of-view did not match the one of PET/CT in all cases, being limited to a single bed position in some studies. However, since most patients were children, even such a field of view could likely encompass most patients’ thoracic and abdominal regions. Furthermore, the superiority of the PET-based tracers on LBA appears to be independent of the disease localisations (axial skeleton vs. the appendicular segments). As shown in the tables, heterogeneous findings among the included studies should be recognised. For this reason, we did not perform a pooled analysis (meta-analysis) of diagnostic performance.
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