Background
Since its introduction as a positron emission tomography (PET) tracer back in the early 1970’s, [
18F]-fluorodeoxyglucose (
18F-FDG) has been widely utilized and now comprises more than 96% of PET studies worldwide [
1]. Even though
18F-FDG is mainly a radiotracer for oncology, it is not a tumor-specific PET tracer, since it is essentially based on the presence of elevated glucose uptake [
2]. Many malignant lesions, in fact, are poorly imaged with
18F-FDG; some due to their slow growth or low metabolic nature, and others due to their location within highly metabolic organs such as the brain and liver [
3]. Various alternative PET tracers have been synthesized and evaluated over the last decade to overcome the limitations of
18F-FDG, including tracers based on amino acid metabolism such as
l-3-
18F-α-methyl tyrosine (
18F-FAMT) [
1,
4].
18F-FAMT has been validated in several clinical studies to be useful for the prediction of cancer prognosis and to rule out benign lesions from malignant neoplasms [
5‐
13]. The tumor accumulation of
18F-FAMT is exclusively facilitated by the L-type amino acid transporter 1 (LAT1), which is highly upregulated in malignant cells [
14]. Unlike other amino acid PET tracers that are not specific to a single amino acid transporter,
18F-FAMT has a α-methyl moiety that allows it to be transported only by LAT1, making it highly specific for malignancies [
15]. Although a handful of clinical studies have investigated its potential in malignant tumor detection, the overall diagnostic performance of
18F-FAMT remains unknown. The present meta-analysis aimed to determine the diagnostic performance of
18F-FAMT PET for detection and evaluation of malignant lesions in a direct side-by-side comparison to
18F-FDG PET.
Discussion
This meta-analysis summarized the diagnostic performance of
18F-FAMT PET for detection of various malignancies in six studies with total 278 patients. Overall, the included studies have a low risk of bias with good methodological quality based on QUADAS tool. Our results demonstrated that
18F-FAMT is comparable with
18F-FDG for its diagnostic performance in detecting malignancies by either visual assessments or diagnostic cut-off values. Moreover,
18F-FAMT capability is coherent in several types of tumors, where all individual diagnostic test studies directly compared the two radiotracers on the same patients in a prospective study design. Additionally, the potential for selection bias can be safely ignored due to the sufficient number of lesions evaluated in each study included (
n > 20). Another strength of this meta-analysis is that even though the study number is limited, heterogeneity was not substantial. The source of observed mild heterogeneity was likely due to threshold effects, which was found in studies based on visual assessment. However, other potential sources of heterogeneity should not be neglected since subgroup analysis was not applicable [
25]. Publication bias is an important consideration in any meta-analysis. However, DOR heterogeneity observed in our results precludes the necessity for a funnel plot asymmetry test [
26].
In the current recommendation for meta-analysis of diagnostic test accuracy from The Cochrane Collaboration, bivariate approach meta-analysis is preferred over the traditional univariate meta-analysis [
17]. However, guidance for determining methodological approaches for meta-analysis with small numbers of studies is currently lacking. In this case, Doebler et al. and Takwoingi et al. encouraged the use of univariate approaches excluding pooling sensitivities and specificities [
21,
27]. Eventually, both univariate and bivariate methods were conducted in the current study, and the diagnostic performance of
18F-FAMT against
18F-FDG was consistent under both approaches. The more conservative approach for HSROC estimation (Rücker-Schumacher’s method) also showed a similar tendency to the traditional HSROC parametrization (Rutter-Gatsonis’s method) [
19].
Despite the limited number of studies included, results of our meta-analysis reflect the natural characteristics of both radiotracers that assess malignant lesions via different metabolic processes. The key feature of
18F-FDG is its superior capability to depict increased metabolic activity reflected by cell glucose consumption. The price of this high sensitivity is the detection accuracy that is prone to being obscured by normal physiological uptake, inflammation, and active benign tumors [
2]. In a recent large-size meta-analysis,
18F-FDG PET failed to maintain its diagnostic accuracy for lung cancer in populations with endemic infectious lung disease [
28].
18F-FDG PET was also only moderately accurate for differentiating benign from malignant pleural effusions [
29].
In another meta-analysis, whole-body
18F-FDG PET/CT remained superior to conventional imaging in the detection of distant malignancies, regardless of the primary tumor site and type [
30]. However, the diagnostic accuracy of a PET radiotracer for lesions in the thorax and abdomen, where most primary lesions are located, is essential. It is well known that the role of
18F-FDG PET in oncology is often mitigated by many pitfalls, including background physiological uptake of major organs [
31].
On the other hand,
18F-FAMT specific uptake depicted the actual malignant process.
18F-FAMT uptake reflects excessive transport of amino acids via LAT1, which is absent in normal cells and pathology other than malignancy [
15]. However, the trade-off of
18F-FAMT’s high specificity is the relatively small absolute uptake in tumor cells, as a consequence of the nature of the LAT1 transporter. The influx of one amino acid substrate into tumor cells via LAT1 is mandatoryly coupled to the efflux of another amino acid substrate, resulting in
18F-FAMT’s relatively fast clearance from the tumor [
14]. Nonetheless, the advantage of
18F-FAMT is the minimal background uptake in all organs except kidney and urinary tracts, allowing one to obtain high contrast images clearly depicting various types of malignancy including brain tumors [
6,
13].
Meta-analyses evaluating the diagnostic performance of
18F-FDG PET in malignancy detection were mostly limited to a particular cancer type, or in comparison with conventional imaging (CT or MRI) or hybrid imaging (PET/CT or PET/MRI). Currently, only a few tumor-specific PET radiotracers are continuously investigated in a clinical setting for various type of cancers [
32].
18F-FET is probably the closest to
18F-FAMT in terms of chemical compound, radiochemistry, and clinical applicability. While
18F-FET has higher diagnostic accuracy than
18F-FDG, its effectiveness is limited for brain tumors [
33].
l-[methyl-
11C]-methionine (
11C-MET), the most popular amino acid-based PET radiotracer to date, also has excellent diagnostic accuracy for glioma compared to
18F-FDG [
34]. However, both
18F-FET and
11C-MET are also substrates for LAT2 transporters, which is also expressed in normal cells [
14,
35]. The low kidney uptake PET tracer
anti-1-amino-3-
18F-fluorocyclobutane-1-carboxylic acid (
18F-FACBC) has recently been meta-analyzed for its accuracy in prostate cancer recurrence detection. However, the specificity of
18F-FACBC is lower than
11C-choline PET and even T2-weighted MRI [
36]. Therefore,
18F-FAMT probably the most versatile oncologic PET radiotracer currently available.
However, there a few limitations in this study and also in
18F-FAMT itself. First, all studies were from a single institution, which was potentially affected by publication bias despite the authors of each study belonging to various departments and evaluating different types of tumors. Even though studies by Watanabe et al. and Tian et al. focused on musculoskeletal tumors, they were separated by more than a decade, eliminating the possibility of overlapping patients [
12,
23]. A study of various tumors by Inoue et al., however, included two patients with chondrosarcoma and schwannoma that might also be involved in the Watanabe et al. study, since these studies were from the same period [
5,
12]. Unfortunately, this is difficult to confirm. Second, not all types of malignancies were evaluated; in particular, lymphoma, melanoma, pancreas and thyroid cancer, which are tumor types for which
18F-FDG PET is recommended to improve diagnostic accuracy [
3]. Tumors in the pelvic area and abdomen were also poorly represented in this study.
Another drawback of the current
18F-FAMT studies is the absence of dynamic PET data. Currently
18F-FAMT PET scan is performed at 40–60 min post injection. However, phases as early as 5–15 min post injection might show higher tumor detection accuracy for any amino acid PET tracer considering the two-way-directional characteristic of amino acid uptake by their transporters [
37]. A dynamic
18F-FAMT PET study in an animal tumor model showed that tumor-to-muscle uptake ratio is highest at 20 min and remains high at 60 min [
38]. However, clinical dynamic PET studies are necessary to obtain optimal scan times.
Our current findings emphasize the need for prospective multicenter studies to overcome limitations of the single center report. This can only be achieved when the
18F-FAMT synthesis method is optimized and becomes widely used. The current
18F-FAMT radiofluorination method yields a low radioactivity that is only enough for PET scans for a mere three to four patients in each radiosynthesis [
39]. Recently, a modified method of
18F-FAMT synthesis allows production to achieve high radioactivity for routine use [
40]. However, a more practical approach is warranted. The twenty years of anticipation might soon be realized with the recent rapid development of fluorination methods. Of particular interest are the so-called late-stage fluorination methods which allow optimized synthesis of previously inaccessible PET radiotracers [
41]. These novel radiofluorination approaches which make possible large-scale synthesis allow reconsideration of promising but underutilized radiotracers, like
18F-FAMT. Hence, revisiting the diagnostic performance of
18F-FAMT is a major step in the quest for an ideal general oncology PET tracer. Once these impediments are resolved, which we foresee shortly, the future may bring increased clinical impact of
18F-FAMT in oncology.