Molecular imaging and radioligand therapies in pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors of neural crest origin that exhibit wide clinical and biological heterogeneity. While surgical resection remains the only curative option, many patients have unresectable or metastatic progressive disease with uncontrolled secretion, requiring alternative management strategies. Advances in genetics have revealed germline pathogenic variants in up to 30–40% of cases, refining tumor classification and guiding the use of molecularly targeted imaging. Functional imaging modalities, such as ⁶⁸Ga or ⁶⁴Cu-DOTA-SSA (somatostatin analogs), ¹⁸F-FDOPA, ¹⁸F-FDG and ¹²³I-MIBG, exploit tumor biology, such as somatostatin receptor expression, catecholamine biosynthesis and altered glucose metabolism. These approaches not only improve diagnostic accuracy but also help in prognosis and selection to therapies. Radioligand therapies have emerged as a pivotal option in advanced PPGLs. High-specific-activity ¹³¹I-MIBG has demonstrated durable disease control, symptomatic improvement and favorable safety in multicenter studies, leading to US Food and Drug Administration approval for metastatic PPGL, although currently not commercially available. More recently, peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE has shown disease control rates of 80–100% in prospective and retrospective trials, with outcomes enhanced by standardized dosing strategies. Ongoing studies are evaluating PRRT in genetically defined subgroups and exploring synergistic combinations, including radiosensitizing approaches.

Introduction

Pheochromocytoma (PHEO) and paraganglioma (PGL), together defined as PPGLs, are rare neuroendocrine tumors (NETs) of neural crest origin originating from adrenal and extra-adrenal paraganglia cells, respectively. These are highly vascular tumors. The sympathetic derived lineage tumors from abdominal and some posterior thoracic paraganglia can be catecholamine secreting, whereas the parasympathetic counterpart in the head, neck and mediastinum generally does not produce hormones (only approx. 4% secrete catecholamines) (1). Current WHO classification avoids the terms ‘benign’ and ‘malignant’, as all PPGLs have metastatic potential; metastasis is the defining criterion of malignancy. In practice, metastatic disease is observed in roughly 10% of PHEOs and 20–40% of PGLs (2).

PPGLs are among the most strongly inherited tumors, with up to 30–40% associated with germline pathogenic variants (3, 4). Advances in genetic research have significantly expanded our understanding of their molecular landscape, with >20 genes now identified as key contributors (e.g. SDHx, VHL, RET, MEN1, NF1, FGFR1, TMEM127, MAX, FH, EPAS1/HIF2A, SUCGL2, SLC25A11, DLST, IDH2 and MDH2) (4, 5).

Molecular profiling now directly guides functional imaging through a practical cluster framework. Cluster 1 (pseudohypoxia) includes (1A) defects in the succinate dehydrogenase complex SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2) and other Krebs cycle/mitochondrial genes (FH, MDH2, SUCGL2, DLST, SLC25A11) and (1B) VHL and EPAS1/HIF2A (4, 5). These tumors are often extra-adrenal; SDHx-related disease is strongly somatostatin receptor (SSTR)-positive and shows intense uptake on ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)-PET, whereas ¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸F-FDOPA) performs best in VHL/EPAS1 (cluster 1B) and cluster 2 (kinase signaling: RET, NF1, MAX, TMEM127; occasionally HRAS), which typically present as PHEOs (including both germline and sporadic cases) (6, 7, 8). Accordingly, tracer selection should be tailored to genotype and location: SSTR-related positron emission tomography (PET)/computed tomography (CT) [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide is a high-yield first platform, especially in SDHx, parasympathetic head-and-neck PGLs and metastatic PPGLs, including sporadic patients; [¹⁸F]F-DOPA is preferred for VHL/EPAS1 and many adrenal/cluster 2 tumors; [¹⁸F]FDG complements assessing aggressive biology; and iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) is prioritized when iodine-131 [¹³¹I]MIBG therapy is being considered. This genotype-first approach improves lesion detection and aligns diagnostic imaging with their therapeutic counterpart (peptide receptor radionuclide therapy (PRRT) vs ¹³¹I-MIBG) (3, 4, 6); see Table 1.

Table 1.

Genotype and cluster-guided theranostic in PPGL.

Genetic cluster/exemplar genes	Typical phenotype	Preferred functional imaging	Secondary/adjunct	Expected avidity	Likely radioligand if needed
Cluster 1A (SDHx, esp. SDHB)	Extra-adrenal PGL; high metastatic risk	SSTR-PET/CT (68Ga/64Cu-DOTA-SSA)	18F-FDG-PET/CT (aggressiveness/heterogeneity); ± 18F-FDOPA	High SSTR, high FDG; NET often low/absent	177Lu-DOTATATE (PRRT) favored when SSTR-avid
Cluster 1B (VHL, EPAS1/HIF2A, FH)	Often adrenal PCC; lower metastatic risk than SDHB	18F-FDOPA-PET/CT	SSTR-PET/CT; 123I-MIBG SPECT/CT for avidity if therapy considered	FDOPA high, SSTR variable; NET variable	Either: 131I-MIBG if MIBG-avid; PRRT if SSTR-avid
Cluster 2 (RET, NF1, MAX, TMEM127)	Mostly adrenal PCC; catecholamine-secreting	18F-FDOPA-PET/CT	SSTR-PET/CT if MIBG-negative or for PRRT planning	FDOPA high, NET often high; SSTR variable	131I-MIBG when avid; PRRT if SSTR-avid or MIBG-non-avid

PPGL, pheochromocytoma and paraganglioma; SSTR, somatostatin receptor; SSTR-PET/CT, somatostatin receptor positron emission tomography/computed tomography; ⁶⁸Ga, gallium-68; ⁶⁴Cu, copper-64; ¹⁸F-FDG (FDG), 2-deoxy-2-(¹⁸F)fluoro-D-glucose; ¹⁸F-FDOPA (FDOPA), 6-fluoro-(¹⁸F)-L-dihydroxyphenylalanine; DOTA-SSA, DOTA-conjugated somatostatin analog (e.g. DOTATATE/DOTATOC/DOTANOC); ¹²³I-MIBG, iodine-123 metaiodobenzylguanidine; SPECT/CT, single-photon emission computed tomography/computed tomography; PRRT, peptide receptor radionuclide therapy; ¹⁷⁷Lu-DOTATATE, lutetium-177 [DOTA⁰,Tyr³]octreotate; SDHx, succinate dehydrogenase gene family (SDHA/SDHB/SDHC/SDHD/SDHAF2); SDHB, succinate dehydrogenase subunit B; VHL, von Hippel–Lindau; EPAS1/HIF2A, endothelial PAS domain protein 1/hypoxia-inducible factor-2α; FH, fumarate hydratase; RET, rearranged during transfection; NF1, neurofibromin-1; MAX, MYC-associated factor X; TMEM127, transmembrane protein 127.

Cellular targets in PPGLs

Somatostatin receptor subtypes as diagnostic and therapeutic targets in PPGLs

The expression of peptide hormone receptors, particularly SSTR, has been well characterized in NETs, including PPGLs (9). These G-protein-coupled receptors not only can mediate the inhibition of hormone secretion but also induce cell cycle arrest through activation of phosphotyrosine phosphatases (PTPs) (10). SSTR subtypes 1 through 5 have been identified in pheochromocytomas with and without metastatic disease, although surface expression varies across tumor models (9, 11). Among subtypes, SSTR2 is most consistently expressed in PPGLs (12). Notably, Elston et al. found strong expression of SSTR2A and SSTR3 in SDHB-mutated PPGLs (13), a finding that establishes these receptors as key diagnostic and therapeutic targets.

Catecholamine biosynthesis and transport as targets for functional imaging in PPGLs

Catecholamines (epinephrine, norepinephrine, and dopamine) are synthesized in the adrenal medulla and central nervous system and play critical roles in the stress response. PPGLs exploit transport and catecholamine biosynthesis machinery, making them valuable for functional imaging (14). ¹²³I/¹³¹I-MIBG localizes tumors via the norepinephrine transporter with vesicular storage through VMAT (15). By contrast, ¹⁸F-FDOPA (fluorine-18 labeled analog of L-DOPA) enters via L-type amino acid transporters (LAT1/2) and is decarboxylated by aromatic L-amino-acid decarboxylase (AADC) (16); it does not use norepinephrine transporter, making both tracers complementary for functional imaging.

Exploiting tumor metabolism reprogramming: ¹⁸F-FDG in PPGL imaging

PPGLs are metabolically active tumors, especially in their SDHx-related and/or metastatic forms. This metabolic activity is exploited using radiolabeled glucose analogs, such as ¹⁸F-FDG, which are preferentially taken up by tumor cells. ¹⁸F-FDG-PET/CT highlights glycolytic disease and is particularly informative in metastatic/SDHx-related PPGLs (17, 18, 19). In SDHx-related and other pseudohypoxic tumors, intense ¹⁸F-FDG avidity largely reflects compromised oxidative phosphorylation, activation of pseudohypoxic/hypoxia-inducible factor-related programs, and increased glucose utilization with enhanced glucose phosphorylation/hexokinase activity rather than proliferative rate per se (20). However, intense ¹⁸F-FDG avidity with absent or poor SSTR expression in metastatic (SDHx or apparently sporadic) PPGLs may indicate de-differentiated or biologically aggressive disease (18, 21, 22).

Nonetheless, in recognition of its potential therapeutic implication contemporary practice guidelines recommend [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide as first-line functional (6) imaging for many PPGL scenarios (including SDHx carriers (3)) where available, with [¹⁸F]FDG-PET/CT used adjunctively to identify interlesional heterogeneity and possible tracer mismatch relative to SSTR imaging, especially when theranostic planning is being considered (discussed ahead).

Diagnostic pathways in PPGLs: from biochemical screening to imaging selection

The diagnostic pathway in PPGLs begins with biochemical confirmation for catecholamine-secreting lesions and immediately anticipates imaging choices that will inform subsequent radioligand therapy (RLT). Biochemical screening is best performed with plasma free metanephrines obtained after at least 20 min of supine rest, or with 24-h urinary fractionated metanephrines (23). Pre-analytical rigor matters: posture, stress, acute illness, and common medications (e.g. tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, decongestants, and stimulants) can alter results. Borderline elevations can be evaluated with a clonidine suppression test when clinical suspicion remains high (24). Catecholamines themselves are less sensitive and are reserved for specific contexts (e.g. dopamine-predominant tumors).

Anatomical imaging with contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) establishes disease burden, surgical relationships, and sites that demand urgent control (8). Functional imaging should be incorporated early for whole-body staging when metastatic risk is appreciable; particularly in extra-adrenal, multifocal, hereditary patients and in with high-risk features, such as SDHB/A-associated disease, large primary tumors (>5 cm), a noradrenergic biochemical phenotype, high proliferation indices, including Ki-67 and mitotic count, or suspected metastatic spread (6, 8, 25, 26). It is also especially useful in parasympathetic head-and-neck paragangliomas, where multiplicity is common and biochemical screening can be negative (17, 25, 27). By contrast, functional imaging is not mandatory in every clearly localized adrenal pheochromocytoma with concordant biochemistry and typical cross-sectional imaging, especially in lower-risk settings such as many VHL- or RET/MEN2-associated adrenal tumors; exceptions include extra-adrenal lesions or large tumors, where whole-body staging should be added (6, 8). In asymptomatic SDHx mutation carriers, screening and follow-up remain primarily MRI- and biochemistry-based, with PET/CT considered mainly at adult initial screening rather than as routine surveillance (3). Once functional imaging is indicated, tracer selection should be individualized according to tumor biology and the intended radioligand (6). See Tables 1 and 2 and Fig. 1.

Table 2.

Radioligand therapies in PPGL: mechanisms, efficacy and safety profiles.

Radioligand	Diagnostic prerequisite	Typical regimen	Outcomes (representative)	Key toxicities/precautions	Evidence level
131I-MIBG (HSA iobenguane; FDA-approved) (64)	Demonstrable MIBG avidity on 123I-MIBG SPECT/CT; hold uptake-interfering drugs (e.g. labetalol, tricyclics, reserpine, amiodarone) when safe; thyroid blockade	Dosimetry dose → 2 therapeutic doses ≥90 days apart (500 mCi if > 62.5 kg or 8 mCi/kg if ≤ 62.5 kg; max 500 mCi each)	Pivotal phase II: RECIST ORR ∼22–23%; DCR > 90%; ≥50% antihypertensive reduction ≥6 mo in ∼25–32%; durable BP/biochemical responses	Myelosuppression, nausea, fatigue; rare therapy-related MDS/AML; inpatient radiation safety; TSH monitoring annually	FDA label + multicenter phase II; observational registry PR/SD 84.6%
131I-MIBG (LSA; low/intermediate dose; off-label in PPGL) (77, 79, 80)	MIBG-avid disease on 123I-MIBG SPECT/CT. (avoid uptake-interfering drugs when feasible; thyroid blockade)	Typical regimen low-intermediate dose: 74 MBq/kg (2 mCi/kg), often repeated; <9.25 GBq total activity. Alternative ‘very low dose’ schedule: 5.5 GBq q6 mo × 3 cycles	Meta-analyses (LSA): ORR 30% (CR 3–4%); DCR 82–87%; symptomatic improvement reported (e.g. 76% in pooled data); hormonal response reported (45% in Loh; 72% in van Hulsteijn)	Myelosuppression (rare pancytopenia); nausea/vomiting/diarrhea; pressor crisis/symptom exacerbation; hepatic dysfunction; orthostatic hypotension; rare xerostomia/parotitis, hypothyroidism; ensure α-blockade + close BP monitoring; CBC/TSH follow-up	Two meta-analyses (mostly retrospective/heterogeneous protocols); Japanese phase II
177Lu-DOTATATE (PRRT; off-label in PPGL) (84, 86, 87, 93)	SSTR-PET-positive disease (lesion uptake ≥ liver); adequate marrow/renal function; amino acid nephroprotection	Commonly 7.4 GBq × 4 q8 weeks	Meta-analyses: DCR ∼80–90%, median PFS ∼17–39 mo; prospective NIH phase II (n = 36 evaluable): 6-month PFS 86%, median PFS 20 mo; PR deepened from 14% EOT → 28% on follow-up; sporadic PFS 24.3 mo vs SDHx 12.9 mo	Transient cytopenias, nausea; catecholamine-release events ∼17–18% in functional PPGL → optimize alpha-blockade and consider intensified monitoring for high-secretion/bulky disease	Multiple retrospectives + two 2023 meta-analyses; prospective NIH phase II
225Ac-DOTATATE (alpha-PRRT; investigational) (98, 101, 105, 106)	SSTR-avid disease; typically after or instead of 177Lu in trials/series	Dosing varies by center/protocol	Small series suggest responses in refractory PGL, but data are early	Endocrine toxicities have been reported; long-term safety maturing	Pilot studies/early reports

¹³¹I-MIBG, iodine-131 metaiodobenzylguanidine; ¹²³I-MIBG, iodine-123 metaiodobenzylguanidine; HSA, high-specific-activity; SSTR-PET/CT, somatostatin receptor positron emission tomography/computed tomography; DOTA-SSA, DOTA-conjugated somatostatin analog; PRRT, peptide receptor radionuclide therapy; ¹⁷⁷Lu-DOTATATE, lutetium-177 [DOTA⁰,Tyr³]octreotate; ²²⁵Ac-DOTATATE, actinium-225 DOTATATE (alpha-PRRT); ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; PR, partial response; EOT, end of treatment; GBq, gigabecquerel; q8 wk, every 8 weeks; mo, months; SDHx, succinate dehydrogenase gene family.

Figure 1.

Nuclear imaging algorithm for pheochromocytoma/paraganglioma (PPGL) (6).

[⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide as a first-line modality and gateway to PRRT

Somatostatin receptor imaging in neuroendocrine tumors was pioneered with ¹¹¹In-pentetreotide (‘Octreoscan®’), following the seminal work of Krenning and colleagues (28). ¹¹¹In-pentetreotide is a gamma-camera/SPECT radiotracer with affinity to SSTR2 receptors but an intrinsically lower sensitivity and spatial resolution. This technical limitation, together with the higher sensitivity and more practical workflow of PET, led to its replacement in most centers by ⁶⁸Ga- or ⁶⁴Cu-labeled (DOTA-TATE/DOTA-TOC/DOTA-NOC) PET tracers, which provide superior staging accuracy when combined with CT (29, 30, 31). In the remainder of this section, comparisons refer to SSTR-PET/CT versus other contemporary PET tracers, mainly ¹⁸F-FDOPA and ¹⁸F-FDG, rather than the historical Octreoscan.

The use of SSTR2-dependent imaging was shown to have a greater diagnostic performance in SDHB/SDHx-associated PPGL (cluster 1A), achieving sensitivities of 94–100% in various prospective and retrospective trials. The study population included metastatic PPGLs in pediatric patients, head and neck, spine, sporadic, SDHA, SDHD, and SDHB mutated tumors (32, 33, 34, 35, 36, 37). Representative intraindividual examples illustrating superior lesion detection with ⁶⁸Ga-DOTATATE in metastatic PPGLs are shown in Figs 2 and 3.

Figure 2.

Metastatic SDHB: the whole-body anterior maximum intensity projection (MIP) positron emission tomography/computed tomography (PET/CT) images of ⁶⁸Ga-DOTATATE (A), ¹⁸F-FDG (B) and ¹⁸F-FDOPA (C) of a 23-year-old male with germline pathogenic variant in SDHB gene demonstrate the superiority of ⁶⁸Ga-DOTATATE-PET/CT compared to ¹⁸F-FDOPA and ¹⁸F-FDG in detecting widespread metastatic disease in bones. ¹⁸F-FDOPA is found to be negative in this patient.

Figure 3.

Metastatic sporadic: the whole-body anterior maximum intensity projection (MIP) positron emission tomography/computed tomography (PET/CT) images of ⁶⁸Ga-DOTATATE (A), ¹⁸F-FDOPA (B) and ¹⁸F-FDG (C) of a 24-year-old male without any germline pathogenic variant in any of pheochromocytoma-susceptible genes demonstrate that recurrence in right nephrectomy bed along with metastatic lesions in lungs, liver and bones with superiority of ⁶⁸Ga-DOTATATE compared to ¹⁸F-FDOPA and ¹⁸F-FDG. ¹⁸F-FDG is found to be negative in this patient.

In a limited small series of patients with tumors driven by pseudohypoxia, genes outside the SDH complex (EPAS1, HIF2A and PHD) tend to concentrate less ⁶⁸Ga-DOTATATE, with sensitivity in detection of a lesion dropping to 50% (38). With PPGL classified into various cluster groups based on genetic mutations, [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide scans have been recommended as first-line imaging modality in cluster 1A (SDHx) mutated PPGL due to high sensitivity, while also directly mapping candidacy for SSTR-targeted PRRT (6).

¹⁸F-FDOPA for cluster 1B and kinase-pathway PPGLs

¹⁸F-FDOPA was first developed for PET of the dopaminergic system and later adopted for NETs, including PPGLs (39). Tumor uptake is mediated by L-type amino acid transporters (LAT1/LAT2); intracellular aromatic L-amino-acid decarboxylase (AADC) converts FDOPA to ¹⁸F-fluorodopamine, which is then sequestered in secretory vesicles via VMAT (40). This pathway explains the high tumor-to-background contrast in many NETs. In clinical practice, ¹⁸F-FDOPA-PET/CT performs especially well in PHEOs, head-and-neck PGLs, and genotypes within cluster 1B (e.g. VHL, PHD2, EPAS1/HIF2A) and cluster 2 (kinase-pathway tumors such as RET, MEN1, NF1, FGFR1, MAX, TMEM127) (6, 14, 37, 38, 41, 42, 43, 44, 45, 46, 47). Sensitivity is lower in metastatic disease, especially SDHx-related (particularly SDHB/A), where [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide and/or ¹⁸F-FDG often outperform ¹⁸F-FDOPA (48). Furthermore, ¹⁸F-FDOPA is also found to be superior compared to [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide in FH- and IDH2-related PPGLs, which come under cluster 1A (45, 49, 50). Some centers use carbidopa premedication to raise tumor-to-background contrast, but it is not required routinely in PPGL imaging, and its use should be individualized (51).

Unlike SSTR imaging and MIBG imaging, ¹⁸F-FDOPA currently lacks an established therapeutic radionuclide pair in PPGLs. This distinction is clinically relevant because a highly ¹⁸F-FDOPA-avid phenotype does not automatically translate into a corresponding theranostic pathway (8). However, there is a therapeutic radionuclide ¹³¹I-iodophenylalanine (¹³¹I-IPA) that also targets LAT1 (18). However, it has so far been evaluated only in patients with recurrent glioblastoma in an open label, multicenter IPAX-1 trial (NCT03849105) (52). The preliminary data are encouraging and provide a rationale for investigation in other LAT1-expressing tumors, including PPGLs (18). This is particularly relevant in mutations (HIF2A, VHL, RET, MAX) where ¹⁸F-FDOPA is diagnostically superior compared to SSTR imaging (38, 43, 46, 47, 49, 50, 53).

In Fig. 3, we observe lesion-level heterogeneity in apparent sporadic metastatic PPGL. The coexistence of SSTR-only lesions and dual ¹⁸F-FDOPA/SSTR-avid lesions may reflect variable preservation of two biologic programs across metastatic sites: somatostatin receptor expression and catecholamine precursor uptake/decarboxylation/storage (54). In this framework, dual-avid lesions may represent a more differentiated chromaffin phenotype, whereas SSTR-positive/¹⁸F-FDOPA-negative lesions may retain receptor expression despite partial attenuation of catecholamine-handling machinery (12). The absence of ¹⁸F-FDG avidity in this case suggests heterogeneity within an overall well-differentiated, non-glycolytic disease phenotype rather than global dedifferentiation. Nevertheless, differences in lesion size and tracer sensitivity, particularly for osseous metastases (34), must also be considered, so this interpretation remains hypothesis-generating.

¹⁸F-FDG-PET as a biomarker of metabolic reprogramming, heterogeneity and underlying genotype

The biologic significance of [¹⁸F]FDG uptake in PPGL is genotype dependent. In SDHx-related and other pseudohypoxia-driven tumors, ¹⁸F-FDG avidity is high (55). Across metastatic PPGLs cohorts, ¹⁸F-FDG sensitivity is high, making it valuable for staging and for detecting dedifferentiated disease (17, 18, 19, 26, 33, 37, 56, 57). ¹⁸F-FDG also complements [⁶⁸Ga/⁶⁴Cu]Ga/Cu-DOTA-peptide by revealing intrapatient heterogeneity; lesions with high ¹⁸F-FDG but low SSTR uptake may respond less well to RLT (18, 19, 22, 26). Marked ¹⁸F-FDG avidity in PPGLs largely reflects intrinsic metabolic reprogramming, such as impaired oxidative phosphorylation, pseudohypoxic/HIF signaling, and increased glucose phosphorylation mediated by hexokinases, rather than proliferative rate per se (20). Accordingly, intense ¹⁸F-FDG uptake in cluster 1 disease should not automatically be interpreted as a marker of high-grade or rapidly progressive biology; indeed, strongly ¹⁸F-FDG-avid lesions may be seen even in relatively indolent hereditary head-and-neck paragangliomas, although in this study, patients did not undergo imaging with more sensitive SSTR-PET/CT or ¹⁸F-FDOPA (58).

Importantly, at times, lesion-level comparisons indicate that ¹⁸F-FDG-PET/CT can equal or exceed SSTR-PET/CT sensitivity in metastatic SDHB/A disease, so a dual-tracer approach (SSTR-PET ± FDG) is often preferred when available (18, 22, 26, 37, 59). Dual-tracer SSTR/¹⁸F-FDG imaging in pseudohypoxic PPGL should not be interpreted using the same paradigm as in gastroenteropancreatic neuroendocrine tumors, where ¹⁸F-FDG uptake more often parallels tumor grade. In PPGL, ¹⁸F-FDG-PET/CT is especially useful for whole-body staging and for recognizing lesion-level heterogeneity relative to SSTR imaging that may influence theranostic planning (18, 22, 26, 48, 59). However, intense ¹⁸F-FDG avidity with absent or poor SSTR expression in metastatic (SDHx or apparently sporadic) PPGLs may indicate de-differentiated or biologically aggressive disease (18, 19, 21, 22, 26). By contrast, the significance of ¹⁸F-FDG avidity in kinase signaling/cluster 2 tumors is less well defined, and the limited genotype-specific data available (such as small MAX series) do not yet support treating ¹⁸F-FDG uptake as a generalized biomarker of aggressive behavior in non-pseudohypoxic disease (53). Finally, in bulky lesions, intratumoral heterogeneity, including viable tumor, hypoxic zones, and central necrosis, may further complicate the biologic interpretation of ¹⁸F-FDG distribution (8).

¹²³I-MIBG imaging in diagnosis and theranostic planning

Metaiodobenzylguanidine (MIBG) is a norepinephrine analog taken up via the norepinephrine transporter (NET, uptake-1) and stored in catecholamine vesicles through VMAT (54). ¹²³I-MIBG SPECT/CT is a contemporary diagnostic technique offering better image quality and lower radiation than older ¹³¹I diagnostic imaging (17). Other norepinephrine transporter-targeted PET radiopharmaceuticals, including ¹²⁴I-MIBG, ¹⁸F-metafluorobenzylguanidine (¹⁸F-MFBG) and ¹⁸F-fluorodopamine (¹⁸F-FDA), are also available in select centers, but accessibility remains limited (18). Diagnostic performance is 38% per meta-analysis by Han et al., highest in adrenal PHEOs, but falls in PGLs, particularly head-and-neck and SDHB-related metastatic disease (60, 61, 62). Consequently, the principal role of MIBG imaging today is theranostic: to confirm MIBG avidity when considering ¹³¹I-MIBG therapy. When staging or restaging metastatic PPGL, SSTR-PET/CT, ¹⁸F-FDOPA-PET/CT and ¹⁸F-FDG-PET/CT generally provide greater lesion sensitivity than ¹²³I-MIBG, whereas ¹²³I-MIBG imaging retains a theranostic role by establishing eligibility for RLT with ¹³¹I-MIBG (15, 18, 22, 60, 61, 63, 64, 65).

Pre-radioligand therapy evaluation

Because diagnosis and treatment are tightly coupled in PPGLs, the ‘pre-therapy’ evaluation is embedded in the diagnostic work-up. For ¹³¹I-MIBG, documentation of avidity, medication washouts when safe, thyroid blockade, pregnancy testing, and careful assessment of marrow reserve and renal function are prerequisites, before proceeding to therapy (63).

For PRRT with ¹⁷⁷Lu-DOTATATE, eligibility includes clear SSTR uptake commonly assessed visually using the modified Krenning score adapted to SSTR-PET (pragmatically at least liver-level intensity on SSTR-PET), adequate hematologic and renal function, and a plan for renal radioprotection with amino acid infusion (66, 67). In hormonally active tumors, alpha-adrenergic blockade (with or without beta-blockade) is optimized before any radioligand administration, and patients with bulky, highly functional disease are monitored closely during the first infusion to mitigate catecholamine surge (68). Routine corticosteroid premedication (e.g. dexamethasone as part of standard antiemetic protocols) should be avoided or used with caution in catecholamine-secreting PPGLs unless there is a specific urgent indication (such as prevention or treatment of edema-related neurologic compromise, including impending spinal cord compression), given concern for precipitating hypertensive/catecholamine crises; supportive medications should be individualized within a multidisciplinary team. Finally, germline genetic testing should be initiated early because genotype influences functional imaging phenotype and can guide patient selection for RLT over the disease course. In real-world practice, however, germline results are often not available in time to determine the initial functional imaging strategy; therefore, first-line tracer selection is frequently driven by clinical phenotype, biochemical evaluation, tumor location, and local availability, with genotype used to refine imaging and theranostic planning once results return (1, 8).

A practical limitation should also be acknowledged in hereditary or multifocal PPGL syndromes. In patients with a genetic predisposition – particularly those with head-and-neck-predominant or SDHD-associated disease, in whom multifocal primary tumors are common – functional and anatomic imaging may identify multiple avid lesions along expected paraganglial stations, but imaging alone may not always reliably distinguish regional lymph node metastases from synchronous primary paragangliomas (1, 3, 69). This distinction often requires integration of lesion topography, longitudinal growth pattern, operative findings and, when available, histopathologic correlation. In addition, imaging phenotypes and theranostic implications remain incompletely characterized for rarer molecular subgroups. Although MAX-related tumors appear predominantly ¹⁸F-FDOPA-avid in the small dedicated series available (53), comparative functional imaging data remain limited, and for MAML3 fusion-driven/Wnt-altered PPGLs, the functional imaging phenotype and theranostic relevance are still poorly defined (4, 5, 8).

Radioligand therapies for pheochromocytoma and paraganglioma

Surgery remains the first line of treatment, as it is the only curative option for localized PPGLs, while resection of the primary tumor in the metastatic setting has also been shown to improve survival (70). For patients with unresectable locally advanced or metastatic disease, multidisciplinary care incorporates external beam radiotherapy for palliation, chemotherapy, tyrosine kinase inhibitors, belzutifan and, increasingly, RLTs when tumors demonstrate the appropriate molecular avidity on diagnostic imaging. Among non-radioligand systemic options, the most mature chemotherapy data come from cyclophosphamide, vincristine and dacarbazine (CVD), for which a meta-analysis reported pooled radiographic complete, partial and stable disease rates of 4, 37, and 14%, respectively, with a pooled partial hormonal response rate of 40% (71). For antiangiogenic therapy, the randomized phase II FIRSTMAPPP trial showed a 12-month progression-free survival rate of 36% with sunitinib versus 19% with placebo (72), while the phase II Natalie Trial of cabozantinib reported an objective response rate of 25% (73). More recently, in the phase II LITESPARK-015 study, belzutifan achieved a confirmed objective response rate of 26%, a disease control rate of 85%, and a median progression-free survival of 22.3 months (74), supporting its emerging role in advanced PPGL. Contemporary guidance from the North American Neuroendocrine Tumor Society (NANETS) endorses radioligands in this setting, with selection driven by tracer uptake, expected efficacy, and marrow/renal reserve (75).

European and global professional societies similarly support individualized use of radioligand and systemic therapies. The European Society for Medical Oncology (ESMO)/EURACAN guidelines for metastatic PPGL recommend a tailored therapeutic strategy in progressive disease, incorporating RLT, chemotherapy, and localized interventions as appropriate (76). The EANM/Euro-NET molecular imaging/theranostics initiatives along with other consensus and practicing guidelines also emphasize that functional imaging should guide RLT, integrating dosimetry, patient-specific risk factors and phenotypic tumor heterogeneity (22, 25, 69).

An additional practical feature of RLT is the possibility of dosimetry, that is, patient-specific estimation of the radiation absorbed by tumor lesions and organs at risk after radioligand administration (18, 67). Because biodistribution and clearance vary across patients, the same administered activity may translate into substantially different tumor, renal, and marrow doses (67). Accordingly, dosimetry may help explain interpatient differences in efficacy and toxicity and, where available, may support individualized decisions regarding administered activity, number of cycles or treatment interval (17, 18, 22), although PPGL-specific thresholds and standardized implementation remain limited.

In essence, consensus across major professional groups supports a theranostic paradigm in PPGL care, where diagnosis and treatment are tightly linked by molecular imaging and patient-specific parameters; see Table 2. See Table 3 for clinical evidence of radioligand therapy in PPGLs, including primary studies and systematic reviews/meta-analyses.

Table 3.

Clinical evidence of radioligand therapy in PPGL (primary studies and systematic reviews/meta-analyses).

Study/radioligand	Study design	n (PPGL)	Genotype/cluster	Prior RLT exposure	Key outcomes (efficacy/safety)
Norepinephrine transporter-targeted β-therapy (131I-MIBG)
Pryma et al. (61) – HSA 131I-MIBG	Pivotal multicenter phase II, open-label, single-arm	68 treated (74 enrolled)	NR	Prior therapies common; prior RLT NR	Primary endpoint: 25% achieved ≥50% reduction in antihypertensives for ≥6 months; ORR 23.4% (RECIST); disease control (PR + SD) 92%; median OS 36.7 months
Inaki et al. (80) – single-dose 131I-MIBG	Phase II, open-label, single-arm, multicenter (Japan)	17 enrolled/16 treated	NR	Prior 131I-MIBG excluded	Biochemical response 23.5% (primary endpoint); CT/MRI ORR 5.9% (RECIST 1.1); 123I-MIBG scintigraphy response 29.4%
van Hulsteijn et al. (79) – 131I-MIBG (SR/MA)	Systematic review and meta-analysis (17 studies; mostly retrospective; heterogeneous protocols)	243 (pooled)	Heterogeneous	NR/variable	Pooled response (mostly non-RECIST): radiographic CR 3%, PR 27%, SD 52%; biochemical PR 40%, SD 21%
SSTR-targeted β-PRRT (177Lu/90Y-DOTA-peptides)
Lin et al. (87) – 177Lu-DOTATATE (NIH PPGL phase II)	Simon two-stage, single-arm phase II	36 evaluable	Reported: SDHx pathogenic variants n = 18 (SDHA 2; SDHB 15; SDHD 1); apparent sporadic n = 18 (of 36 evaluable)	Variable	6-month PFS 86%; median PFS 20 months; PR deepened from 14% at the end of treatment to 28% on follow-up; grade ≥3 catecholamine-release events 18%
Su et al. (84) – PRRT (SR/MA)	Systematic review and meta-analysis (20 studies; search through Nov 2022)	330 (pooled)	Not consistently reported	Allowed; variable prior therapies	ORR 20% (95% CI: 12–28%); DCR 90% (85–95%); clinical response 74.9%; biochemical response 69.5%; median PFS 31.79 months; median OS 74.30 months. Toxicity: Any-grade hematotoxicity 22.3%; grade 3–4 hematotoxicity 4.3%; nephrotoxicity any grade 4.3%; grade 3–4 nephrotoxicity 4/212; discontinuation 9%; 1 toxicity-related death
Targeted α-therapy (emerging)
Yadav et al. (98) – 225Ac-DOTATATE (+capecitabine)	Pilot study in metastatic PGL	9	Reported mutation status: SDHB mutation (n = 1); SDHD mutation (n = 2); negative genetic test (n = 3); unknown (n = 3)	7/9 had prior 177Lu-DOTATATE; 3/7 failed prior 177Lu-DOTATATE	Best response: PR 50%, SD 37.5% (DCR 87.5%); reported no grade 3/4 hematologic, renal or hepatic toxicity

PPGL, pheochromocytoma and paraganglioma; mPPGL, metastatic PPGL; NET, norepinephrine transporter; SSTR, somatostatin receptor; HSA, high-specific-activity; LSA, low-specific-activity; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; PR, partial response; SD, stable disease; SDHx, succinate dehydrogenase gene family; EOT, end of treatment; NR, not reported.

High-specific-activity (HSA) iobenguane I-131 (¹³¹I-MIBG): norepinephrine transporter-targeted therapy in PPGLs

¹³¹I-MIBG exploits norepinephrine transporter-mediated uptake (uptake-1) and vesicular storage to deliver targeted radiation to chromaffin-derived cells. Early nonrandomized experiences in malignant PPGLs reported symptomatic improvement (notably blood pressure control) and biochemical responses in a meaningful subset, establishing proof of concept and laying the groundwork for later HSA formulations (77, 78).

The pivotal multicenter phase II program of HSA ¹³¹I-MIBG required demonstrable MIBG avidity on diagnostic scintigraphy and implemented a dosimetric administration followed by two therapeutic doses given ≥90 days apart (18,500 MBq/500 mCi if > 62.5 kg; 296 MBq/kg/8 mCi/kg if ≤ 62.5 kg). In this study, 23.4% achieved RECIST objective responses, 92.2% achieved disease control, and 25% had a durable (≥6 months) ≥50% reduction in antihypertensive medications; toxicities were predominantly nausea/fatigue and myelosuppression with 25% patients requiring hematological supportive care, with rare therapy-related myelodysplastic syndrome (MDS) or secondary malignancies (AML/ALL), findings that led to U.S. FDA approval for unresectable, locally advanced, or metastatic PPGL (61). However, currently, the production of HSA ¹³¹I-MIBG (Azedra^®) has been discontinued (18).

In malignant PPGLs, most published experience reflects conventional low-specific-activity (LSA) ¹³¹I-MIBG; pooled evidence suggests that responses are dominated by stable disease and biochemical improvement, with a systematic review/meta-analysis of retrospective data reporting 27% partial response and 52% stable disease by tumor volume criteria and 40% partial hormonal response (79). Consistent with these pooled data, a Japanese multicenter phase II trial of fixed-dose ¹³¹I-MIBG demonstrated a 23.5% biochemical response rate (≥50% reduction in urinary catecholamines) and a 29.4% scintigraphy response, with no grade ≥4 treatment-emergent adverse events (80).

Because therapeutic delivery hinges on norepinephrine transporter biology, treatment planning integrates several steps into routine care. First, confirm avidity with ¹²³I-MIBG SPECT/CT or other norepinephrine transporter-based PET radiotracers (the modern diagnostic standard), as sensitivity varies by site and genotype, and avidity predicts therapeutic feasibility (31). Second, review medications that impair MIBG uptake (notably labetalol, reserpine, tricyclic antidepressants, some calcium channel blockers, and amiodarone) and hold them when clinically safe to optimize tumor targeting (63). Third, the administration of thyroid blockade (e.g. potassium iodide/Lugol’s solution; perchlorate in select settings) starting at least 24 h prior to ¹³¹I-MIBG administration and continuing daily for 10 days after each administered dose to minimize thyroid uptake of free radioiodine (65, 81). Finally, the administered activity and number of cycles should follow protocol-specific fixed, weight-based, or (where available) dosimetry-guided approaches, with appropriate radiation-safety precautions and close hematologic monitoring during the expected myelosuppressive window.

Post-therapy imaging also has practical value beyond radiation-safety procedures. Whole-body planar imaging, and SPECT/CT where feasible, can confirm tumor targeting, demonstrate retention within larger lesions and sometimes reveal sites of disease or interval changes that are less conspicuous on baseline diagnostic imaging, thereby complementing serial reassessment and dosimetry workflows (65, 67, 81).

PRRT with ¹⁷⁷Lu-DOTATATE: harnessing SSTR expression for therapy

Most PPGLs express SSTRs, particularly SSTR2, creating a theranostic axis in which SSTR-PET/CT selects patients for [¹⁷⁷Lu]Lu-DOTA-TATE therapy. Radiolabeled DOTATOC had been introduced in the treatment of PPGL 18 years ago (82), but has been widely replaced by [¹⁷⁷Lu]Lu-DOTA-TATE. Eligibility is typically based on lesional uptake at least as high as normal liver on SSTR-PET (modified Krenning score ≥ 2), alongside adequate marrow and renal function (7, 18, 22, 65, 66, 83).

Across retrospective series and meta-analyses, RLT with ¹⁷⁷Lu-DOTATATE yields high disease control rates (80–90%) in inoperable/metastatic PPGL, with median progression-free survival frequently reported in the range of 17–39 months and a median overall survival of 74.3 months, recognizing heterogeneity in cohorts, genotypes and prior therapies (7, 18, 84, 85, 86). Prospective data now substantiate these signals: in a Simon two-stage, single-arm phase II trial from the National Institutes of Health (four 7.4 GBq cycles; 36 evaluable), the 6-month PFS rate was 86%, the median PFS was 20 months, and partial responses deepened over time (14% at the end of treatment rising to 28% on follow-up). Outcomes differed by genotype – sporadic tumors had a longer median PFS (24.3 months) than SDHx tumors (12.9 months) – and grade ≥3 catecholamine-release events occurred in 18%, underscoring the importance of pre-emptive antihypertensive blockade and, for highly secretory/bulky disease, intensified monitoring during cycle 1 (87). Beyond radiographic disease control, clinically meaningful benefits were also reported: among patients receiving antihypertensive therapy at baseline, 40% achieved a ≥50% reduction in at least one antihypertensive medication within 12 months after completing PRRT. Patient-reported outcomes also suggested improvement over time, with RAND-36 demonstrating gains in physical functioning and other domains at 24 months of follow-up. Overall tolerability mirrors the broader digestive NET experience, although there is an increased rate of G3 myelosuppression (excluding lymphopenia) as compared to NET (15% vs 1–3%), and that G3 symptoms and signs associated with catecholamine excess can be seen despite blockade.

Because the radioligand and its renal handling can expose proximal tubules to radiation, each cycle is delivered with amino acid co-infusion for nephroprotection, now standardized in international procedure guidance (67). In hormonally active disease, alpha-adrenergic blockade (±beta-blockade) is optimized in advance and maintained through the early treatment window to mitigate hypertensive crises (18, 75), especially for those at high risk who may benefit from pre-emptive treatment in the ICU (88). Although uncommon, abrupt clinical and radiographic acceleration after PRRT has been reported, including ‘eruption’ of metastatic paraganglioma following apparent initial treatment success (19). The mechanisms underlying this phenomenon remain poorly understood; however, the proposed contributing factors include very high uptake on ¹⁸F-FDG-PET/CT scans and high Ki-67 index (15–30%) (19).

The secondary analysis of phase II ¹⁷⁷Lu-DOTATATE data from the NIH showed that patients with a ⁶⁸Ga-DOTATATE/¹⁸F-FDG-PET/CT total uptake volume ratio >2.0 had a higher median progression-free survival of 22.0 months compared to 14.3 months by that of ratio <2.0 and genetics did not change the predictive value of this ratio (59). Similarly, a retrospective study of 25 patients treated with ¹³¹I-MIBG (a median overall survival of 63 months over a median follow-up of 42 months) found ¹⁸F-FDG-derived parameters, such as high metabolic tumor volume and total lesion glycolysis, as predictive biomarkers of poor overall survival (89). Another retrospective study in 22 patients undergoing RLT with ¹⁷⁷Lu-DOTATATE (a median overall survival of 49.6 months and a median progression-free survival of 21.6 months) identified high Ki-67 (>15%) as a negative predictive factor for both progression-free and overall survival and prior PRRT also for overall survival (90). However, such predictive biomarkers need to be externally validated in larger prospective cohorts.

Because ¹⁷⁷Lu emits gamma photons suitable for post-therapy imaging, whole-body planar imaging and/or SPECT/CT can be incorporated during PRRT for treatment quality assurance and interim disease assessment (18, 67). In practice, these studies may document biodistribution, assess tracer retention in bulky lesions over successive cycles, and occasionally identify new lesions or interval progression during treatment.

In the multidisciplinary management of metastatic PPGLs, theranostic radionuclide therapies, such as ¹⁷⁷Lu-DOTATATE (PRRT) and ¹³¹I-MIBG, can be tailored based on individual tumor biology and functional imaging phenotypes, and although prospective head-to-head data are lacking, retrospective series suggest that sequential use of ¹³¹I-MIBG and PRRT or integration of both modalities in selected patients with dual tracer uptake may enhance tumor dose delivery and symptomatic/tumor control while balancing organ-specific toxicity, underscoring the need for individualized sequencing strategies guided by SSTRs and norepinephrine transporter imaging (7, 91).

Beyond standard PRRT: terbium, alpha-emitter and novel radioligand therapies

Targeted alpha therapy is an emerging modality in PPGLs, especially for patients who have experienced progression following beta-emitter PRRT with ¹⁷⁷Lu-DOTATATE. In parallel, alternative beta-emitting radionuclides are being investigated to improve dose deposition in minimal residual disease. Terbium-161 (¹⁶¹Tb) is an attractive alternative to ¹⁷⁷Lu for PRRT because in addition to emitting β⁻ particles, such as ¹⁷⁷Lu, it also emits short-range Auger and conversion electrons. These low-energy electrons may increase subcellular energy deposition and enhance tumor cell kill, especially in small lesions or micrometastases (92, 93, 94, 95).

Alpha particles deliver a high linear energy transfer (LET) over very short distances (approximately 50–100 μm), inducing more complex double-strand DNA damage as compared to beta-emitters. This mechanism has the potential to overcome resistance to radiation therapy while minimizing damage to surrounding normal tissues (96, 97). Clinical experiences with ²²⁵Ac-DOTATATE has shown promising results, with disease control rates exceeding 80% even in a small cohort of nine patients with PPGLs previously treated with ¹⁷⁷Lu-PRRT (98). The toxicity profile has been manageable, primarily involving transient cytopenias and variable nephrotoxicity (99). However, the clinical application of these therapies faces challenges related to the limited supply of actinium-225 and issues related to chelation chemistry (100). In particular, alpha recoil can release daughter radionuclides from the radiopharmaceutical, allowing their unpredictable redistribution to non-target tissues and potentially causing unintended normal-organ irradiation and toxicity (101).

Research continues into other alpha-emitting radionuclides and novel constructs. Preliminary studies with ²¹²Pb-labeled SSAs (e.g. VMT-α-NET) have demonstrated safety and early indicators of efficacy in patients with advanced NETs, including PPGLs (102, 103). Additionally, efforts are underway to develop SSTR antagonists (e.g. ⁶⁸Ga/¹⁷⁷Lu-satoreotide-tetraxetan (DOTA-JR11) and ⁶⁸Ga-NODAGA-LM3/¹⁷⁷Lu-DOTA/LM3) labeled with alpha- or beta-emitters, which may bind more receptor sites than agonists and thereby deliver higher radiation doses to tumors (104). Novel agents, such as ²²⁵Ac-MACROPATATE, have also shown enhanced efficacy in preclinical xenograft models, highlighting the potential of next-generation alpha-RLT approaches (105). Strategies combining or sequencing beta- and alpha-emitting therapies as well as combining different beta radionuclides are being explored to leverage their complementary physical properties and address tumor heterogeneity within individual patients (22, 84, 106).

Furthermore, development is underway for alpha-emitting analogs targeting the norepinephrine transporter system. [²¹¹At] meta-astatobenzylguanidine (²¹¹At-MABG) has emerged as the alpha-emitting counterpart to the standard ¹³¹I-MIBG. By substituting the beta-emitting iodine with the alpha-emitting astatine (a halogen with similar chemical properties), ²¹¹At-MABG delivers high LET radiation specifically to norepinephrine transporter-expressing tumors (107). This approach combines the established targeting mechanism of MIBG with the potent, localized cytotoxicity of alpha particles, offering a potential therapeutic avenue for patients with norepinephrine transporter positive disease who may be resistant to beta-emitters or ineligible for SSTR-targeted therapies.

Combination therapies may provide new therapeutic opportunities by leveraging complementary mechanisms of action, potentially enhancing therapeutic efficacy, overcoming resistance, and improving disease control. In PPGL specifically, a retrospective series suggests that concomitant capecitabine with ¹⁷⁷Lu-DOTATATE is feasible and active, supporting further prospective evaluation of radiosensitizing combination approaches in this population (108). Any chemo–radionuclide combination should nevertheless be approached cautiously, because additive toxicities (particularly cumulative myelosuppression) are biologically plausible and may be especially relevant in heavily pretreated PPGL populations.

There may be a role for PRRT earlier in the disease course of carefully selected, strongly SSTR-positive PPGLs, including as part of neoadjuvant or downstaging strategies aimed at facilitating local therapy. However, this concept remains investigational in PPGL, and experience from pancreatic neuroendocrine neoplasms or prostate cancer should be regarded as hypothesis-generating rather than directly transferable, given the distinct biology of PPGL. In contrast to pancreatic NETs, in which neoadjuvant ¹⁷⁷Lu-DOTATATE can sometimes produce meaningful tumor shrinkage in selected patients, the benefit of PRRT in PPGL more often manifests as durable disease stabilization than marked cytoreduction (109, 110). Beyond cytoreduction, ionizing radiation can induce an immune-mediated (vaccine-like) effect and contribute to disease control, proving a biological rationale for combinations (111, 112). This approach could also be used in combination with EBRT in the setting of oligometastatic disease as it has been shown for prostate cancer (113). Although ionizing radiation may exert immunomodulatory effects in other tumor types, many PPGLs – particularly pseudohypoxic tumors (114) – display features of an immune-cold microenvironment, including lower PD-L1/CD8 signatures and, in some series, low tumor mutational burden and weak neoantigenicity (4, 115); accordingly, whether PRRT or EBRT can reliably sensitize PPGL to immunotherapy remains uncertain. Future studies should therefore evaluate earlier PRRT, combinations with focal EBRT in oligometastatic disease, and PRRT–immunotherapy strategies cautiously and preferably in biomarker-enriched cohorts.

In parallel, theranostic development in PPGL should also explore targets beyond SSTR and NET, including PSMA, which may be expressed predominantly in tumor neovasculature in some high-risk cluster 1 tumors (116, 117); a hypoxia-related marker such as carbonic anhydrase IX (CAIX) (118), particularly in VHL-related or pseudohypoxic PPGL; ascorbic acid uptake (119); and fibroblast activated protein (FAP) (120). However, these targets remain investigational and require prospective validation before clinical integration.

Overall, these developments suggest a promising future for alpha-emitter and novel RLTs in treating PPGLs, particularly in genetically defined and treatment-resistant cases. Nonetheless, further prospective, multicenter clinical trials, improved dosimetry techniques, and increased global radionuclide production are essential to fully establish their role within standard treatment protocols.

Response assessment and endpoints in PPGL radioligand therapy trials

Response assessment after RLT in metastatic PPGL is inherently difficult because many patients, particularly those with SDHx-related disease, harbor predominantly skeletal metastases (121). Bone lesions are frequently sclerotic and lack a measurable soft tissue component on CT/MRI, rendering them non-measurable by RECIST and leaving a substantial proportion of patients without evaluable target lesions (122, 123, 124). SSTR-PET/CT is the best way to evaluate or detect bone lesions in metastatic PPGL patients (34). When PET is used longitudinally, post-therapy changes in tracer uptake related to receptor modulation or healing (‘flare’) should be interpreted in conjunction with morphologic imaging and the clinical context. Alternatives to imaging response assessment, such as serum biomarkers, can be considered, as there is some preliminary evidence that serum levels of chromogranin A, unlike for GEP-NETs, do correlate closely in PPGL with tumor response as assessment by both anatomic (CT/MRI) and SSTR-PET imaging (87).

For prospective beta- and alpha-emitter studies, time to treatment failure or more specifically time to next therapy may be more clinically meaningful than RECIST ORR, provided that ‘failure’ is prospectively defined as the need to initiate subsequent antitumor therapy due to radiographic progression, new lesions on PET, sustained clinical deterioration (e.g. worsening hypertension), or treatment-limiting toxicity (including rare therapy-related myelodysplastic syndrome). Standardization of imaging acquisition and centralized review is critical to reduce measurement bias in this rare, bone-predominant disease. The implementation of IA may help in the identification and assessment of predictors of response and toxicities.

Conclusion

PPGLs are widely regarded as a model disease for theranostic approaches. Advances in germline testing and functional imaging allow us to match treatment to tumor biology: norepinephrine transporter-dependent (¹³¹I-MIBG) or SSTR-dependent (¹⁷⁷Lu/⁹⁰Y/²²⁵Ac/²¹²Pb-DOTATATE) radioligands can deliver durable disease control in appropriately selected patients. As prospective PPGL-specific PRRT data and alpha-emitter strategies expand, integrating patient selection, dosimetry and sequencing with surgical and systemic options will continue to improve outcomes while preserving quality of life. Radioligand therapy represents one of the most rational and potentially effective therapeutic strategies for PPGLs, as it uniquely fulfills the principles of precision medicine through a theranostic approach.

Further investigation is required to rigorously delineate the tumor and patient populations that derive meaningful benefit from RLT, and to establish whether molecular imaging targets represent true predictive biomarkers, rather than merely selection or enrichment biomarkers. Theranostics should not be viewed solely as a means to increase therapeutic efficacy, but also as a strategy to reduce treatment-related toxicity in patients with PPGLs. In this context, dosimetry represents a key potential advantage of RLT over other systemic therapies, enabling treatment individualization beyond a one-size-fits-all approach. Additional determinants, including individual patient characteristics, clinical context and social factors, must be integrated into decision-making. Such complexity underscores the necessity for management within a dedicated multidisciplinary team, where therapeutic choices can be critically discussed and tailored to each patient.

Declaration of interest

DT is a cofounder, stakeholder, and the Chief Medical Officer (CMO) of SILON Therapeutics and reports receiving advisory board honoraria from Novartis. The other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.