6 Adrenal functional imaging - which marker for URRENT PINION which indication?
Rudolf A. Wernera,b, Philipp E. Hartrampfª, Andreas Schirbela and Stefanie Hahner℃
Purpose of review
In recent years, a broad spectrum of molecular image biomarkers for assessment of adrenal functional imaging have penetrated the clinical arena. Those include positron emission tomography and single photon emission computed tomography radiotracers, which either target glucose transporter, CYP11B enzymes, C-X-C motif chemokine receptor 4, norepinephrine transporter or somatostatin receptors. We will provide an overview of key radiopharmaceuticals and determine their most relevant clinical applications, thereby providing a roadmap for the right image biomarker at the right time for the right patient.
Recent findings
Numerous radiotracers for assessment of adrenal incidentalomas ([18F]FDG; [123I]IMTO/IMAZA), ACC ([123I]IMTO/IMAZA; [18F]FDG; [68Ga]PentixaFor), pheochromocytomas and paragangliomas ([123|]mIBG; [18F]flubrobenguane; [18F]AF78; [68Ga]DOTATOC/-TATE), or primary aldosteronism ([1]C]MTO, [68Ga] PentixaFor) are currently available and have been extensively investigated in recent years. In addition, the field is currently evolving from adrenal functional imaging to a patient-centered adrenal theranostics approach, as some of those radiotracers can also be labeled with ß-emitters for therapeutic purposes.
Summary
The herein reviewed functional image biomarkers may not only allow to increase diagnostic accuracy for adrenal gland diseases but may also enable for achieving substantial antitumor effects in patients with adrenocortical carcinoma, pheochromocytoma or paraganglioma.
Keywords
adrenocortical carcinoma, paraganglioma, PET, pheochromocytoma, SPECT
INTRODUCTION
There is an increasing demand for noninvasive bio- markers for staging, restaging, or treatment monitor- ing in patients affected with adrenal gland diseases. In addition, the more widespread use of conventional imaging techniques including computed tomogra- phy or magnetic resonance imaging (MRI) led to an increasing discovery of incidentalomas [1] and func- tional imaging modalities may then allow to further characterize those ambiguous findings, e.g., to segre- gate between nonadrenocortical lesions or adreno- cortical primary or secondary tumors [2]. In this regard, various radiotracers for positron emission tomography (PET) and single photon emission com- puted tomography (SPECT) have penetrated the clin- ical arena in recent years [3]. In addition, those agents can also be used in a therapeutic scenario, by using the identical compound not only for diagnosis, but also for therapy (theranostics) [4""]. In the present review, we aimed to provide an overview of the most relevant PET or SPECT agents used in clinical routine, thereby
providing a roadmap to identify the right molecular image biomarker for the right patient at the right time. In addition, the (sub)cellular target structure for every radiotracer will also be highlighted and the concept of theranostics for adrenal gland tumors will also be introduced.
Table 1 and Fig. 1 provide an overview of key radiopharmaceuticals and their respective target on a cellular level.
ªDepartment of Nuclear Medicine, University Hospital, University of Würzburg, Germany, bThe Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA and “Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital, University of Würzburg, Germany
Correspondence to Rudolf A. Werner, MD, University Hospital Würzburg, Department of Nuclear Medicine, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. Tel: +49 931 201 35906; fax: +49 931 201 635 001; e-mail: werner_r1@ukw.de
Curr Opin Urol 2022, 32:585-593
DOI:10.1097/MOU.0000000000001040
KEY POINTS
· Numerous radiotracers have been applied for adrenal functional imaging.
· Those include single photon emission computed tomography and positron emission tomography agents for adrenal incidentalomas, pheochromocytomas and paragangliomas or primary aldosteronism.
· The field is currently evolving from functional imaging to adrenal theranostics, as some of these diagnostic agents can also be labeled with respective ß-emitters for therapeutic purposes.
Glucose transporter - [18F] fluorodeoxyglucose
Adrenocortical carcinomas
Also considered the workhorse in nuclear oncology, [18F]fluorodeoxyglucose (FDG) is interacting with the glucose transporter and its accumulation in disease sites is based on the assumption that tumor sites are characterized by an increased glucose con- sumption [5]. As such, [18F]FDG has been applied in patients affected with adrenocortical carcinoma
(ACC) [6]. Size of the adrenal masses may be of importance, as with decreasing diameter of the lesion, uptake substantially declined (only 15% of the lesions with ≤5 mm positive vs. 58% positivity for lesions with 5-10 mm) [7]. This finding may be most likely explained by the partial volume effect, which is characterized by less uptake in small sites of disease due to the limited spatial resolution of installed PET devices [8].
Adrenal incidentalomas
Adrenal incidentalomas have also been extensively investigated using [18F]FDG. A substantially high sensitivity and specificity was demonstrated in large meta-analyses for identification of malignant adre- nal lesions [9]. However, high-quality data system- atically investigating the role of in patients with adrenal incidentaloma are scarce and regarded as insufficient to make strong recommendations [2,10]. Both qualitative and quantitative interpreta- tions of [18F]FDG PET imaging have been studied. In two prospective studies performing a quantification on [18F]FDG PET an optimal adrenal-to-liver ratio of >1.45 and 1.5 was reported to reliably distinguish malignant from benign adrenal lesions (with surgi- cal specimen serving as gold standard) [11,12].
| Tracer | Target | Adrenal disease | Radiotracer has been applied for |
|---|---|---|---|
| SPECT: | |||
| [1231]/[13][]metaiodobenzyl-guanidine | Norepinephrine transporter | ACC, PHEO, PARA | I /T |
| [123[]/[13]]]iodometomidate | CYP11B enzymes | ACC, adrenal incidentalomas | I /T |
| [ 123I]/[131I]MAZA | CYP11B enzymes | ACC, adrenal incidentalomas | I/T |
| PET: | |||
| [ 124I]metaiodobenzylguanidine | Norepinephrine transporter | PHEO, PARA | I |
| [18F]flubrobenguane, [18F]AF78 | Norepinephrine transporter | PHEO, PARA | I |
| [18F]fluorodeoxyglucose | Glucose metabolism | ACC, adrenal incidentalomas | I |
| [68Ga]PentixaFor [68Ga]DOTATATE/-DOTATOC | Membrane bound G-protein-coupled receptors (CXCR4, somatostatin receptors) | ACC, PA ACC, PHEO, PARA | I / T |
| [1]C]MTO, [18F]FETO, [18F]-CETO, [18F]FAMTO | CYP11B enzymes | ACC, PA, adrenal incidentalomas | I |
Radiopharmaceuticals had been used either for imaging [I] or therapy [T] in a theranostic setting. Applied adrenal disease is also displayed. ACC=adrenocortical carcinoma, PA=primary aldosteronism, PHEO=pheochromocytomas, PARA=paragangliomas. IMAZA=(R)-1-[1-(4-[123|]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide. DOTATOC/DOTATATE=1,4,7,10-tetraazacyclododecane-N,N’,N”,N’“-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide/-octreotate ([68Ga] DOTATOC/-TATE). CXCR4=C-X-C motif chemokine receptor 4. MTO=metomidate. [18F]FETO=2-[18F]fluoroethyl-etomidate and the para-fluorinated aromatic (R)- MTO derivative ([18F]FAMTO). [18F]CETO=para-chloro-2-[18F]fluoroethyl-etomidate.
DOTATATE/ DOTATOC
PentixaFor
FDG
CXCR4
SSTR
·
₿/Y
B/Y
a
GLUT
a
Adrenal Gland
Hexokinase
accumulation of FDG-6 phosphate
IMTO/ IMAZA
steroid hormone synthesis
mIBG/ Flubrobenguane/ AF78
Created with BioRender.com
CYP11B enzymes - [123|]lodometomidate/ (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H- imidazole-5-carboxylic acid azetidinylamide Etomidate and metomidate are potent inhibitors of the enzymes CYP11B1 (11-hydroxylase) and CYP11B2 (aldosterone synthase), which are cru- cially involved in the regulation of cortisol and aldosterone synthesis in the adrenal gland [13]. Considering the high adrenal selectivity for those molecular targets, both enzymes have been reported to be useful for molecular imaging [14]. Dating back to the late 90’s, Bergström and colleagues verified the high affinity for CYP11B1 and CYP11B2 of eto- midate (ETO) and metomidate (MTO) and their specific binding to adrenocortical tissue [15]. Thus, C11-labeled MTO and the respective ethyl ester ETO were studied in monkeys and humans, showing that this radiotracer may be useful to differentiate between adrenocortical lesions from nonadreno- cortical lesions [15,16]. In patients, adrenal gland metastases, nonadrenal masses and pheochromocy- tomas demonstrated no uptake on [11C]MTO PET
[17], whereas adrenocortical tumors exhibited sub- stantial radiotracer accumulation.
The potential of this radiotracer for noninvasive subtyping in primary aldosteronism was evaluated by different studies. Whereas higher tracer uptake was detected in patients with unilateral aldosterone- producing adenoma, no lateralization was detected in patients with bilateral disease [18]. In contrast, [11C]MTO PET was not superior when compared with computed tomography and adrenal venous sampling in another study [19].
When compared to carbon-11, fluorine-18 radiochemistry has multiple advantages, including its longer half-life and higher positron yield, thereby allowing for radiotracer supply of distant PET sites without regular access to a cyclotron facility [20,21]. Initial preclinical experiments with the 11ß-hydrox- ylase inhibitors 2-[18F]fluoroethyl-etomidate ([18F] FETO) [22], the para-fluorinated aromatic (R)-MTO derivative ([18F]FAMTO) [23], and para-chloro-2- [18F]fluoroethyl-etomidate ([18F]CETO) [24] showed promising results with a remarkable selectivity
towards aldosterone-producing enzymes, including 11ß-hydroxylase/aldosterone synthase (CYP11B1/ B2). Those studies, however, have been primarily conducted in a preclinical environment and thus, human prospective studies are underway to demon- strate the superior diagnostic performance of CYP11B1/B2-targeting radiotracers in the clinic [25].
PET is mainly restricted to university hospitals [26], and thus, the use of scintigraphy would allow for a broader application of functional molecular imaging of the adrenal gland. For instance, the compound [123I]iodometomidate (IMTO), which binds to CYP11B1/2, achieved successful inhibition of those enzymes in cell culture experiments. Imag- ing studies in mice revealed excellent image quality [27-29]. In this translational approach, the accu- mulation of the radiotracer was detected only in adrenocortical tissue [28]. In patients, planar [123]] IMTO scintigraphy and SPECT/computed tomogra- phy provided images with high contrast to assess adrenal masses of more or equal to 2 cm [30]. The FAMIAN study (EudraCT number: 2012-003604- 13) aimed to investigate indeterminate adrenal neo- plasms with combined [18F]FDG PET and [123]]IMTO scintigraphy and first results will be provided shortly [31].
[123I]IMTO can also be used for treatment of patients affected with ACC using the therapeutic equivalent [13]]]IMTO. The latter radiotracer was used in 11 subjects with advanced ACC, based on substantial elevated accumulation of [123I]IMTO on SPECT. Controlled disease was achieved in 6/11 subjects, with one patient even exhibiting a 50% reduction in target lesions when compared to base- line scan. Among responders, median progression- free survival was 14 months [32].
Despite its high image quality, the use of [123]] IMTO is limited as it can be inactivated relatively quickly and thus, the metabolically more stable derivative [123I]IMAZA had been developed. Rela- tive to [123I]IMTO, [123I]IMAZA revealed elevated binding to adrenocortical tissue in patients, along with better image contrast for the novel agent [33]. Analyses of sensitivity and specificity for adrenal mass characterization are pending. However, of 69 patients with ACC, approximately 50% showed relevant IMAZA uptake in tumorous lesions. In addition, 13 patients underwent [131IJIMAZA treat- ment in a theranostic setting, and posttherapeutic dosimetry revealed high doses of up to 256 Gy in sites of disease. Five patients achieved disease stabilization, and median overall survival was 14.1 months for the entire cohort [4""]. Figure 2 illustrates a case of an ACC patient treated with [131]]IMAZA, demonstrating partial response on follow-up imaging.
C-X-C motif chemokine receptor 4 - [68Ga] PentixaFor
Primarily developed for hematologic malignancies, [68Ga]PentixaFor targets the G-protein coupled receptor CXCR4, which is overexpressed in various malignancies, including ACC [34]. As such, a recent bicentric investigation analyzed more than 770 [68 Ga]PentixaFor PET/computed tomographies of 690 patients affected with various malignancies, which then allowed to determine the most relevant clinical application for this pan-tumor agent [35”]. Among others, metastatic sites of ACC exhibited the highest target-to-background ratios, thereby indi- cating that this disease has a high CXCR4 expression in disease sites along with negligible uptake in back- ground tissue yielding excellent contrast. As such, [68Ga]PentixaFor may serve as an excellent radio- tracer to determine disease extent in patients with ACC (Fig. 3) [35”]. Spearheaded by Blümel et al. 30 patients scheduled for dual-imaging with [68Ga]Pen- tixaFor and [18F]FDG showed that in-vivo assess- ment of CXCR4 provides a more accurate read-out in selected cases [36]. Of note, [68Ga]PentixaFor has been rationally designed by also providing a thera- nostic twin labeled with ß-emitters, which can then be used for therapeutic purposes ([177Lu]/[9ºY]Pen- tixaTher). This therapeutic agent, however, has been mainly applied to patients with hematologic malig- nancies such as T-cell lymphoma, but not to solid tumor entities including ACC [37"",38]. This is due to the fact that this therapeutic strategy also includes targeting the stem cell niche leading to bone marrow ablation, thereby paving the way for hematopoietic stem cell transplantation [38]. Such myeloablative effect would not be desired for ACC, as [177 Lu]/[90Y]PentixaTher should then achieve rel- evant antitumor effect, but not bone marrow abla- tion. As such, a theranostic approach using CXCR4- directed ß-emitters would require stem cell support, e.g., by conducting therapy with radiolabeled CXCR4 followed by autologous stem cell transplan- tation. In this regard, the use of [177Lu]/[9ºY]Pentix- aTher may be limited to patients that have no further other available treatment options [37""]. Nonetheless, a recent work by Blümel et al. reported on 70% of ACC patients, which were suitable for [177 Lu]/[9ºY]PentixaTher treatment [36]. In addi- tion, [68Ga]PentixaFor PET/computed tomography may also allow to determine presence or absence of the target to initiate nonradiolabeled anti-CXCR4 directed drugs once those are available [37""], e.g. at the time of increased CXCR4 expression.
Beyond its use in oncology, [68Ga]PentixaFor has also been tested in the context of primary aldos- teronism, which may differentiate between unilat- eral aldosterone producing adenoma (APA, leading
(a)
(b)
(f)
(c)
(g)
(d)
(h)
(e)
(i)
to surgery) vs. idiopathic bilateral adrenal hyper- plasia, which is treated with mineralocorticoid receptor-targeted inhibition [39]. Based on the observation of high CXCR4 expression in aldoster- one-producing tissue, nine subjects with APA were enrolled, which exhibited substantially higher radiotracer accumulation on the site identified as source of aldosterone excess [40]. This observation was corroborated by a prospective study including 36 patients. Accuracy of [68Ga]Pentixafor was more than 90% in distinguishing APA from non-APA lesions [41]. Large prospective studies are currently underway and will further clarify the clinical rele- vance of this tracer for the diagnostic evaluation of primary aldosteronism.
[68Ga]Pentixafor has also been recently applied to differentiate between adrenocorticotropic hor- mone-producing (ACTH) pituitary adenoma and ACTH-independent Cushing syndrome. For the lat- ter subtype, an increased uptake in adrenal lesions were found, while there was no substantial radio- tracer accumulation in the pituitary fossa [42”].
Norepinephrine transporter - [123]] metaiodobenzylguanidine (mIBG), [18F] flubrobenguane and [18F]AF78
The norepinephrine transporter-directed SPECT agent mIBG is used in various clinical settings, including cardiac innervation, Parkinson’s disease
15
SUV
0
or neuroblastoma [43-45]. Of note, sympathome- dullary tissue shows high retention of mIBG and thus, [1231]/[13]]]mIBG scintigraphy for imaging of pheochromocytomas and paragangliomas has been used for decades. Sensitivities and specificities ranged between 80% and 100% [46-51].
[131I]mIBG can also be used in a therapeutic setting and a recently published multicenter phase 2 study reported on 68 patients with advanced pheochromocytoma or paraganglioma receiving minimum one cycle of [13]I]mIBG. Interestingly, 25% of patients had sustained reductions in anti- hypertensive medication, and 92% achieved a par- tial response or stable disease within 12 months. The median overall survival was indicated as up to 36.7 months [52]. Recent developments have led
to [124I]-labeled mIBG, thereby allowing to use mIBG also for PET. Such a cross-modality use of mIBG has several advantages. First, the similar bio- distribution to [123I]mIBG may allow to translate established concepts for imaging interpretation from SPECT to PET. Moreover, [124I]mIBG-PET would most likely inherit all advantages of mIBG scintigraphy, but would even achieve higher sensi- tivity and also allow for better and reliable quanti- fication, mainly due to the inherent advantages of PET technology [53-55]. With the long half-life of I- 124 (4.2 days), it would also be possible to evaluate pharmacokinetics using imaging and blood tests at various time points [56,57], e.g., to determine the appropriate amount of activity for mIBG therapy. The first results of [124I]mIBG-PET/computed
tomography were recently published. In 43 patients with suspected malignant pheochromocytoma or with known metastases, PET/computed tomogra- phy showed sensitivity, specificity, and positive and negative predictive value of 86%, 100%, 100%, and 88%, respectively [58""].
In the context of pheochromocytoma and para- ganglioma imaging, results of a novel, fluorine-18 labeled PET radiotracer, which has comparable affin- ity to the norepinephrine transporter and mIBG [59], has been recently published [60]. An initial study with 23 patients scheduled for N-[3-bromo- 4-(3-[18F]fluoropropoxy)-benzyl]-guanidine ([18F] flubrobenguane) showed an excellent tracer-to- background ratio as well as superior diagnostic cer- tainty on positive lesions for [18F]flubrobenguane hybrid imaging compared to computed tomogra- phy or MRI alone [32]. The authors concluded that the novel PET radiotracer [18F]flubrobenguane has the potential to change the diagnostic landscape in suspected pheochromocytomas and paragan- gliomas by combining the advantages of PET imaging with preferred properties of mIBG [61""]. In addition, a recent fluorine 18-labeled PET agent (AF78) demonstrated comparable NET affinity as mIBG and thus, may also be used for tumors originating from chromaffin cells of the adrenal medulla [62].
Somatostatin receptor (SSTR) - 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N’,N”,N”- tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide/- octreotate ([68Ga]DOTATOC/-TATE)
Somatostatin receptor (SSTR)-targeting [68Ga] DOTATOC/-TATE is primarily employed in patients diagnosed with neuroendocrine tumors of the gas- trointestinal tract [63] but has also been used in the context of ACC. SSTR, however, may be a less promising target for this disease, as only two sub- jects were identified as candidates for treatment using the theranostic twin [177 Lu]DOTATOC/-TATE, exhibiting controlled disease of four and 12 months, respectively [64]. Further clinically more relevant applications include pheochromocytomas or para- ganglioma. Investigating a mixed cohort, a direct comparison with the reference PET probe [18F]FDG showed that higher uptake values along with lower background activity can be achieved with the SSTR-directed PET radiotracer [65]. Not surpris- ingly, this triggered further studies using the ther- apeutic counterpart [177Lu]DOTATOC/-TATE, demonstrating disease control in all subjects and overall survival of more than 49 months in patients with pheochromocytomas and paraganglioma [66].
CONCLUSION
Over the last decades, numerous radiotracers have been applied for adrenal functional imaging. Those include SPECT or PET agents for assessment of adrenal incidentalomas ([18F]FDG; [123I]IMTO/IMAZA), ACC ([123I]IMTO/IMAZA; [18F]FDG; [68Ga]PentixaFor), pheochromocytomas and paragangliomas ([123I] mIBG; [18F]flubrobenguane; [18F]AF78; [68Ga]DOTA- TOC/-TATE), or primary aldosteronism ([11C]MTO, [68Ga]PentixaFor). Of note, the field is currently evolving from functional imaging to adrenal theranos- tics, as some of these diagnostic agents can also be labeled with respective ß-emitters. In this regard, future studies evaluating the impact of adrenal func- tional imaging on therapeutic management and larger studies on the use of theranostic radiotracers, preferably in a prospective setting by comparing with guideline-compatible treatment, are warranted.
Acknowledgements
None.
Financial support and sponsorship
This review work was supported by the Deutsche For- schungsgemeinschaft (DFG) (project number 314061271 - TRR 205; AL 203/11-1; 507803309; 453989101) and IZKF Würzburg (Grant No. F-365, A.S., S.H.).
Conflicts of interest
A.S. and S.H. filed a patent application WO/2014/ 048568 for IMAZA. All other authors declare no poten- tial conflicts of interest.
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