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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2024 Apr 23;109(9):2366–2388. doi: 10.1210/clinem/dgae252

Approach to the Patient: Concept and Application of Targeted Radiotherapy in the Paraganglioma Patient

Karel Pacak 1,✉,, David Taieb 2, Frank I Lin 3, Abhishek Jha 4,✉,
PMCID: PMC11319006  PMID: 38652045

Abstract

Paragangliomas can metastasize, posing potential challenges both in symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and 177Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians’ knowledge of the stepwise approach to treat these patients with paraganglioma-targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. Perspectives in radiotherapies of paraganglioma patients are outlined since they hold promising approaches in the near future that can improve patient outcomes.

Keywords: pheochromocytoma, paraganglioma, neuroendocrine tumor, radiotherapy, positron emission tomography, scintigraphy, Lutathera®, 68Ga-DOTATATE, 123/131I-metaiodobenzylguanidine, α-emitter, 18F-FDG, 18F-FDOPA

A Patient's Presentation

A 25-year-old African American woman initially experienced episodes of severe headaches, palpitations, night sweats, and dizziness approximately twice a week. These episodes were not related to any specific trigger and occurred either when walking or resting or waking up from sleep. The patient presented to her primary physician and was asked to cut back on intake of caffeinated and energy drinks. During the subsequent course of 4 years, she developed easy fatigability and dizziness accompanied by abdominal fullness. This was then followed by symptoms and signs of constipation, face flushing, sweating, and anxiety attacks. She again presented to her physician in January 2015, when she was also found to have recent onset of diabetes mellitus and computed tomography (CT) of the abdomen revealed a 17-cm centrally necrotic right retroperitoneal, most likely an adrenal tumor with inferior vena cava (IVC) compression and intracaval tumor thrombus extending into the right atrium. Of note, the patient did not have any specific paraganglioma workup prior to planned surgery. Subsequently, the patient underwent radical resection of a right retroperitoneal/adrenal tumor with en bloc IVC resection without reconstruction, right partial hepatectomy, and tumor thrombectomy with pericardial defect repair associated with episodes of hemodynamic instability during the surgery. Histopathological examination confirmed a 17.5 × 17 × 10 cm metastatic intra-adrenal paraganglioma (also called pheochromocytoma) with liver involvement (multiple nodules present within liver capsule and one lesion 0.5 × 0.4 × 0.4 cm within the liver), lymphovascular invasion, and positive IVC margin. About 1 month after surgery, she experienced shortness of breath, palpitations, and hypertension (150/100 mm Hg), presented to a hospital, and was found to have pleural effusion for which chest tubes were placed. Three months after her initial surgery, chest CT scan showed a 5 mm pleural-based pulmonary nodule in the left lower lobe. Around that time 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy (single photon emission computed tomography [SPECT] or SPECT/CT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/CT (PET/CT) were negative. Due to her elevated blood pressure, the patient was put on various α-adrenoceptor and calcium channel blockers. Subsequent repeated whole-body CT scans demonstrated multiple right and left lung nodules, and approximately 1.5 years after her surgery, multiple liver metastatic lesions, the largest one measuring 1.6 cm, were found. At that time, repeated 123I-MIBG scintigraphy showed multiple liver and bone metastatic lesions and she was considered for treatment with targeted radiotherapy using 131I-MIBG. Furthermore, 2 to 3 months after the surgery, biochemical evaluation for intra-adrenal paraganglioma revealed an elevated plasma normetanephrine (NMN) of 186 pg/mL (upper reference limit, 148 pg/mL) and normal plasma metanephrine (MN) of less than 25 pg/mL (upper reference limit, 57 pg/mL). Chromogranin A was 30 ng/mL (upper reference limit, 15 ng/mL). During a course of 1.5 years after the operation, plasma NMN gradually increased to 175, 268, 325, 331, and 660 pg/mL. Due to increasing plasma NMN levels and multiple organ and bone metastatic lesions detected on various scans, the patient underwent 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) PET/CT (18 months after the surgery) that showed very avid metastatic disease diffusely involving the lungs, liver, and bones. Two months later, 123I-MIBG scintigraphy also showed multiple liver and lung lesions, with the uptake in the lung lesions being more prominent compared to prior 123I-MIBG examinations. A new focal uptake in the right femoral neck region was also noted and considered a metastatic lesion. The patient was scheduled for 131I-MIBG–targeted radiotherapy. Genetic testing was negative for Ambry PGLNext 14-gene panel that included SDHA-D, SDHAF2, TMEM127, FH, RET, MAX, KIF1B, MEN1, VHL, NF1, and EGLN1. Despite being scheduled for systemic radiotherapy with 131I-MIBG, the patient opted to start lanreotide treatment given subcutaneously every 6 weeks. In 2018 to 2019, repeated 68Ga-DOTATATE PET/CT and 123I-MIBG scintigraphy as well as plasma NMN showed progression of metastatic disease in the liver, lungs, and bones, and lanreotide treatment was stopped. Subsequently, the patient was referred to the National Institutes of Health (NIH) for further evaluation of her progressive metastatic pheochromocytoma under the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD) protocol (NCT00004847) and 177Lu-DOTATATE treatment protocol at the National Cancer Institute (NCI) (NCT03206060).

At the NIH, the patient did not present with any major complaints, admitting to being very active and performing exercises on a regular basis. Her blood pressure was 96/56 mm Hg, heart rate 87 beats per minute, temperature 37.50 °C, oxygen saturation 99%, and body mass index of 26.7. Biochemical evaluation revealed elevated plasma NMN of 1762 pg/mL (upper reference limit, 112 pg/mL) and plasma MN of 89 pg/mL (upper reference limit, 61 pg/mL). Plasma chromogranin A was 2120 ng/mL (upper reference limit, 93 ng/mL). Functional imaging with 68Ga-DOTATATE, 18F-FDOPA, and 18F-FDG PET/CT showed widespread metastatic lesions in the lungs, liver, and bones (Fig. 1). Various treatment options were considered and discussed with the patient, including temozolomide; cyclophosphamide, vincristine, and dacarbazine (CVD) regimen chemotherapy; or systemic targeted radiotherapy. It was suggested to the patient that if 68Ga-DOTATATE and 123I-MIBG uptake in metastatic lesions were comparable, a high-specific-activity 131MIBG (Azedra®) would be preferrable compared to low-specific-activity 131MIBG as the former was the Food and Drug Administration (FDA)–approved treatment for metastatic pheochromocytoma/paraganglioma and clinical factors favored it (good bone marrow reserve due to her younger age and not having undergone any prior cytotoxic therapies). If 123I-MIBG uptake would be less than 68Ga-DOTATATE uptake, then probably 177Lu-DOTATATE (Lutathera) would be pursued over the commercially available high-specific-activity 131MIBG (Azedra®). Careful reading of the patient's functional imaging scans found that the tracer avidity of the multifocal metastases was greater on 68Ga-DOTATATE PET/CT than 123I-MIBG scintigraphy (Fig. 1). Taking chemotherapy vs systemic targeted radiotherapy into very careful consideration including previously published treatment outcomes, toxicity profiles, and the patient's wishes, the patient was deemed to be a good candidate for systemic targeted radiotherapy using 177Lu-DOTATATE (Lutathera®) rather than 131I-MIBG (either low-specific-activity or high-specific-activity (Azedra®) treatment.

Figure 1.

Figure 1.

Baseline functional imaging of the patient to choose targeted radiotherapy (177Lu-DOTATATE vs 131I-MIBG). The anterior (A) and posterior (B) whole-body planar images of 123I-MIBG (A, B) single photon emission computed tomography/computed tomography (SPECT/CT) and whole-body anterior maximum intensity projection images of 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT, C), 18F-FDOPA PET/CT (D), and 18F-FDG PET/CT (E) of a 33-year-old female patient. In this patient genetic testing did not reveal any germline pathogenic variant in paraganglioma susceptibility genes, with a history of a previously resected 17.5 × 17 × 10 cm right pheochromocytoma, demonstrating widespread metastatic lesions in the lungs, liver, and bones. 123I-MIBG SPECT/CT also demonstrates multiple lesions in the lungs, liver, and bones. However, 68Ga-DOTATATE PET/CT demonstrates more lesions in the lungs, liver, and bones and has a higher tumor-to-liver ratio compared to 123I-MIBG SPECT/CT. Of note, contrast recovery, sensitivity, and spatial resolution of PET/CT imaging is superior to SPECT/CT imaging and therefore, small lesions on PET/CT scans may not be visible on SPECT/CT scans despite adequate uptake. Additionally, compared to 68Ga-DOTATATE PET/CT, the 18F-FDOPA PET/CT demonstrates only a few lesions in lungs and liver and does not demonstrate any lesions in bones, whereas the 18F-FDG PET/CT demonstrates only a few lung lesions and does not demonstrate any liver or bone lesions. Furthermore, interpretation of 18F-FDG PET/CT is limited by patient movement of the arms causing attenuation artifacts and therefore, repeat imaging of the lower chest was acquired.

The treatment with 177Lu-DOTATATE (Lutathera®) was started in August 2019 and the patient received the first 4 cycles, which ended in February 2020 (Fig. 2). Her heart rate and blood pressure remained within normal limits before, during, and immediately after 177Lu-DOTATATE administrations. She was given a small dose of 0.5 mg of doxazosin daily, which was continued throughout her therapy. Her NMN levels (upper reference limit, 112 pg/mL) just before, 24 hours post therapy, and 48 hours post therapy for each of the 177Lu-DOTATATE cycles were 1787, 2529, and 2540 pg/mL for the first cycle; 2744, 2067, and 2280 pg/mL for the second cycle; 1519, 1922, and 1681 pg/mL for the third cycle; and 1133, 1329, and 1091 for the fourth cycle, respectively. Per RECIST 1.1, the patient achieved the best response of a 49.3% reduction in the diametric sum of target lesions after 29 months of initiation of 177Lu-DOTATATE (Lutathera) therapy and therefore, she was classified to achieve partial response (PR). The patient did not experience any grade 3/4 severe adverse events. She has not progressed at the end of follow-up at 48 months (censured to last date of follow-up in July 2023) (Fig. 3).

Figure 2.

Figure 2.

Baseline 68Ga-DOTATATE PET/CT imaging of the patient and 24-hour post 177Lu-DOTATATE therapy scans. The pretherapy baseline anterior maximum intensity projection whole-body image of 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) (A) demonstrates widespread metastatic lesions in the lungs, liver, and bones. The 24-hour post-therapy anterior (B, D, F, H) and posterior (C, E, G, I) whole-body planar single photon emission computed tomography/computed tomography (SPECT/CT) images after 200 mCi (7.4 GBq) of 177Lu-DOTATATE (B-I) performed 2 (B, C), 4 (D, E), 6 (F, G), and 8 (H, I) months after baseline (pretherapy) 68Ga-DOTATATE PET/CT shows good uptake in most of the metastatic lesions. Of note, contrast recovery, sensitivity, and spatial resolution of PET/CT imaging is superior to SPECT/CT imaging and therefore, small lesions on PET/CT scans may not be visible on SPECT/CT scans despite adequate uptake.

Figure 3.

Figure 3.

Baseline and follow-up 68Ga-DOTATATE and 18F-FDG PET/CT imaging after 177Lu-DOTATATE therapy. The anterior maximum intensity projection whole-body images of 68Ga-DOTATATE (top panel, A-G) positron emission tomography/computed tomography (PET/CT) and 18F-FDG PET/CT (bottom panel, H-N) at various time points (baseline or pretherapy [A, H]) and whole-body post-therapy scans (B-G and I-N) after 3 (B, I), 10 (C, J), 26 (D, K), 32 (E, L), 38 (F, M), and 44 (G, N) months of first cycle (August 2019) of 177Lu-DOTATATE therapy (200 mCi [7.4 GBq], 4 cycles given 2 months apart August 2019, October 2019, December 2019, and February 2020) demonstrating widespread metastatic lesions in lungs, liver, and bones. Compared to the baseline 68Ga-DOTATATE PET/CT scan, the baseline 18F-FDG PET/CT demonstrates a few lung lesions and does not demonstrate any liver or bone lesions. The smaller bone, lung, and liver lesions that are seen on baseline 68Ga-DOTATATE PET/CT are no longer visible on subsequent follow-up 68Ga-DOTATATE PET/CT scans. Similarly, a few lung lesions that are seen on baseline 18F-FDG PET/CT are no longer visible on subsequent follow-up 18F-FDG PET/CT scans. Per RECIST 1.1, the patient partially responded and achieved a maximum reduction of 49.3% in diametric sizes of target lesions after 29 months of the first cycle of 177Lu-DOTATATE therapy. The patient has not progressed at the end of last follow-up at 48 months and did not experience any persistent adverse events related to therapy.

Paraganglioma as an Endocrine Tumor

In contrast to the previous definition and view that paraganglioma (either extra-adrenal or intra-adrenal/so-called pheochromocytoma/) is a benign tumor, the most updated 2022 World Health Organization Classification of Tumors of Endocrine Organs defines this tumor as potentially metastatic due to its ability to metastasize even years after complete resection of the primary mass (1). Thus, this tumor is now viewed as malignant and since chromaffin cells from which these tumors arise are not present in bones and lymph nodes, metastatic paraganglioma is defined specifically by lesions present in bones and/or lymph nodes. Nevertheless, in clinical practice, although most metastatic lesions are indeed present in bones and lymph nodes (2, 3), those lesions can often present in other organs like the liver and lungs (4). Thus, patients with vital organ lesions and synchronous metastases are usually characterized as having short-term survival/prognosis compared to those with only, for example, bone lesions, characterized as having a long-term survival/prognosis (4, 5).

Paragangliomas are considered the most hereditary tumor among all endocrine and nonendocrine neoplasms and are divided into two major groups related to their genetic background: sporadic and hereditary (6). Susceptibility genes related to hereditary tumors are present in up to 40% of patients and are currently divided into 3 clinically relevant clusters (7, 8). Among them, cluster 1 represents the most locally aggressive and metastatic tumors that are mainly related to pathogenic variants in the succinate dehydrogenase subunit (SDHx) gene family (for details, see review by Pacak (6)). Knowledge of the genetic makeup of these tumors is important in tumor behavior as it dictates functional imaging signature/phenotype (eg, PET) (9), tumor localization and metastatic behavior (10-13), specific biochemical phenotype of a tumor and by extension cardiovascular consequences, clinical outcomes, candidacy for effective systemic radiotherapy and chemotherapy treatment, as well as respective responses and patient survival during and following systemic treatment (14-16).

However, when considering paraganglioma as a tumor with metastatic potential, genetics are not the only risk factor that is closely linked to the development of metastatic lesions (3, 17). In fact, only about half of metastatic paraganglioma patients have a known genetic defect, although relatively new genetic abnormalities have been recently described such as TERT structural rearrangements, long intragenic noncoding RNA profiles, ATRX, and NOP10 (18-22). Therefore, there are other risk factors that play an important role in the metastasis of these tumors that in our view currently include the developmental origin (sympathetic vs parasympathetic tumors) (23), the size of the primary tumor, the biochemical profile including high norepinephrine and dopamine as well as 3-methoxytyramine levels (4, 5, 24-27), the location of a tumor (eg, intra-adrenal paragangliomas have a lower metastatic potential), the immune landscape (28-30), the patient's age (4, 5, 31), and the overall metabolic profile (28, 32-34) as revealed by very recent radiomics and machine learning studies (5, 35).

When compared to other cancers, paragangliomas—defined as particularly exceptional and unique tumors—are well-suited for “theranostics” due to the unique expression of cell membrane receptors/transporters, which are a prerequisite for the use of systemic radiotherapies (10, 11, 36-44). However, although radiotherapy fundamentals are met in paraganglioma, as described next, those fundamentals must be allied to clinical variables that result in the proper selection of systemic radiotherapy, otherwise the result would be suboptimal care with often poor or inadequate tumor responses and poor overall patient survival (45-47).

Radiotherapeutic Targets in Paraganglioma

In 1900, Dr Paul Ehrlich introduced the concept of the “magic bullet,” which envisioned drugs with the ability to precisely target and eliminate disease without harming healthy tissue (48-50), which laid the foundation not only of modern hematology and immunology but also for modern chemotherapy and targeted therapies. Today, the “magic bullet” concept continues to influence the development of molecule-driven treatments for diseases like cancer, now known as personalized, targeted, or precision medicine (48-50), initially applied to thyroid cancer with radioiodine therapy (51).

Theranostics, a term coined by John Funkhouser, is a portmanteau combining diagnostics and therapeutics (52). It involves the use of radiopharmaceuticals targeting the same cell membrane receptor or transporter expressed on tumor cells, enabling both diagnosis and therapy to be achieved (Fig. 4). Three radiotheranostic targets are currently identified for paragangliomas (Fig. 5) (10, 11, 37, 46). The first target involves the norepinephrine transporter (NET), where a theranostic pair (123I-MIBG for imaging and 131I-MIBG for therapy) binds, gets internalized, and is transported to secretory granules via vesicular monoamine transporters (VMATs). The second target is the somatostatin receptor (SSTR), specifically the type 2 subtype, which is expressed in paragangliomas (38). Hence, they can be imaged and treated using radiolabeled SSTR analogues (eg, 68Ga/64Cu-DOTA-TATE/TOC for imaging and 177Lu/90Y/225Ac-DOTA-TATE/TOC for therapy). The last target is the L-type amino acid transporter (LAT) (53), which can be targeted by 18F-fluorodopa (18F-FDOPA) for imaging and 131I-iodophenylalanine (131I-IPA) for therapy. However, 18F-FDOPA is available in only a few centers worldwide, and so far, 131I-IPA has been used only in the treatment of primary brain tumors in a phase I/II multi-center clinical trial (NCT03849105).

Figure 4.

Figure 4.

Theranostic concept and application. Theranostics, a branch of precision medicine, involves the combination of diagnostics and therapeutics that share a same specific molecular target on tumor cells. Diagnostic and therapeutic radiopharmaceuticals that share the same target (cellular structure or biologic process)—called theranostic pairs—exemplify this approach. For instance, 68Ga-DOTATATE, an imaging radiopharmaceutical, and 177Lu-DOTATATE, a therapeutic radiopharmaceutical, form a theranostic pair, as shown here. A radiopharmaceutical consists of 3 main building blocks: i) a radionuclide (therapeutic radionuclides: β-Lutetium-177 [177Lu], Iodine-131 [131I], Yttrium-90 [90Y], Copper-67 [67Cu], Terbium-161 [161Tb] and α-Actinium-225 [225Ac], Lead-212 [212Pb], Astatine-211 [211At], Bismuth-213 [213Bi], or diagnostic radionuclides: positron emission tomography (PET)—Copper-64 [64Cu], Gallium-68 [68Ga], Fluorine-18 [18F], Iodine-124 [124I], and single photon emission computed tomography [SPECT]—Indium-111 [111In], Iodine-123 [123I]); ii) a targeting molecule (or vector or ligand) that recognizes and binds specifically onto cancer cells similar to a key and lock system (“-TATE” for somatostatin receptor (SSTR), “-guanidine” for norepinephrine transporter (NET), and “-phenylalanine” for L-type amino acid transporter 1 (LAT1); and iii) a linker (or chelator) that joins the radionuclide and vector (eg, “DOTA” between radionuclide and “-TATE”, “metaiodobenzyl” between radionuclide and “-guanidine”, and no linker is required between radionuclide and “-phenylalanine”, as they are bound by a covalent bond). The various theranostic targets in paragangliomas are SSTR, NET, and LAT1.

Figure 5.

Figure 5.

Various specific theranostic targets in paragangliomas. The cell membrane of paragangliomas expresses 3 specific receptors/transporter systems that can be used for the diagnosis and therapy (theranostic) of these tumors. First, somatostatin receptors (SSTRs), particularly the SSTR2 subtype, are expressed in paragangliomas. SSTRs can be targeted using radiolabeled SSTR-analogues (agonist or antagonist) for imaging (68Ga/64Cu-DOTATATE/TOC) or therapy (177Lu/90Y/225Ac-DOTATATE). SSTR-based theranostic agents bind to SSTR2, which gets internalized (agonists only) into an endosome. Furthermore, SSTR-based gamma probes can be used for radioguided surgery. Norepinephrine transporter (NET) is the second targeting method whereby the MIBG theranostic pair (123I-MIBG, a single photon emission computed tomography [SPECT] is used for imaging and 131I-MIBG [low-specific-activity or high-specific-activity] for therapy). 124I-MIBG, 18F-metafluorobenzylguanidine (18F-MFBG) and 18F-fluorodopamine (18F-FDA) are positron emission tomography (PET)-based imaging radiopharmaceuticals that also target NET but are sparsely available, which get internalized and transported to secretory granules via vesicular monoamine transporters (VMAT). The third targeting method involves the use of 18F-fluorodopa (18F-FDOPA), which targets the cells via the L-type amino acid transporter system (LAT), specifically type 1 (LAT1), found in paragangliomas, especially the pheochromocytoma (intra-adrenal paraganglioma). Once inside the tumor cells, 18F-FDOPA undergoes decarboxylation by L-aromatic amino acid decarboxylase (AADC) to form 18F-FDA. These compounds are then internalized and transported to neurosecretory vesicles via VMAT. LAT1-based theranostic radiopharmaceuticals or pairs are not widely available clinically. Moreover, 123/131I-iodophenylalanine (123/131I-IPA, a theranostic pair that targets LAT1) has currently not been used in neuroendocrine tumors including paragangliomas, whereas 18F-FDOPA (diagnostic radiopharmaceutical) targeting LAT1 is used in a few centers worldwide for imaging neuroendocrine tumors including paragangliomas.

Current Radiopharmaceuticals Available for Systemic Radiotherapy

The basic principle of using targeted radiation for cancer treatment is to deliver cytotoxic ionizing radiation causing single-strand and double-strand breaks in the DNA of a tumor cell, and subsequent cell death, while limiting damage to healthy tissues. Although healthy tissue also suffers from radiation-induced DNA damage, it is felt that the impaired ability of tumors to repair DNA damage compared to healthy tissue leads to a therapeutic window that is exploited with targeted radiotherapies.

Currently, therapeutic radionuclides delivering radiation come in 2 flavors: i) β particles, which are negatively charged electrons and are emitted spontaneously from atomic nuclei during a nuclear transformation of certain radioisotopes (eg, Lutetium-177 [177Lu], Iodine-131 [131I], Yttrium-90 [90Y], Copper-67 [67Cu], and Terbium-161 [161Tb]), and ii) α particles, which are heavier helium nuclei (mass number of 4 and charge of +2), are also emitted spontaneously from the nucleus of other radionuclides (eg, Actinium-225 [225Ac], Lead-212 [212Pb], Astatine-211 [211At], Bismuth-213 [213Bi], and Radium-223 [223Ra]), and are highly potent. Their physical properties are summarized in Tables 1 and 2, and Fig. 6 (54-62).

Table 1.

Physical properties of various α-emitting and β-emitting radionuclides

Radiopharmaceutical Half-life Mean energy of emitted particle, MeV Mean linear energy transfer, KeV/μm Maximum path length, mm Gamma radiation for posttherapy imaging, KeV
β Emitters (β)
Iodine-131 (131I) 8.0 d 0.182 ∼ 0.2 3.6 364 (81% abundance)
637 (7% abundance)
284 (6% abundance)
Lutetitum-177 (177Lu) 6.6 d 0.133 ∼ 0.2 1.8 113 (6% abundance)
208 (11% abundance)
Yttrium-90 (90Y) 2.7 d 0.933 ∼ 0.2 11.3 No
Copper-67 (67Cu) 2.6 d 0.141 ∼ 0.2 2.0 185 (49% abundance)
93 (16% abundance)
91 (7% abundance)
Terbium-161 (161Tb)
(β and Auger electrons)
6.9 d 0.154 ∼ 0.2 (β)
∼ 20 (Auger)
3 (β) < 0.002 (Auger) 75 (10% abundance)
α Emitters (α)
Radium-223 (223Ra) 11.4 d 5.6 ∼ 80 <0.1 84, 95, 270
Actinium-225 (225Ac) 9.9 d 6.8
(27 in total)
∼ 100 <0.1 218,
440 (from 213Bi daughter)
Lead-212 (212Pb)a 10.6 h 7.8 ∼ 100 <0.1 440
Astatine-211 (211At) 7.2 h 6.8 ∼ 100 <0.1 85 (x-ray)b
Bismuth-213 (213Bi)a 46 min 8.3 ∼ 100 <0.1 440

Abbreviations: d, days; h, hours; KeV, kilo electron-volt; MeV, mega electron-volt; μm, micrometer; mm, millimeter; min, minutes.

a Emits β particle; however, considered as α therapy because of its α-emitting daughter.

b X-ray radiation, whereas others are gamma radiation.

Table 2.

Physical and biological properties of various α-emitting and β-emitting radionuclides

Characteristic β emitters (β) α emitters (α)
Radionuclide type Energetic electron (e) 4He2+ (helium nucleus)a
Mean particle energyb, MeV 0.1-0.9 5.6-8.3
Maximum path lengthb, mm 2-11 < 0.1
Linear energy transferb, KeV/μm ∼0.2 ∼80-100
RBE 1 20
Affinity and specificity for target Low High
Hypoxic tumors Effective Less effective
Bystander effect Yes Yes
Tumor cross-fire Low Low
Daughter products with extra emissions No Yes (225Ac, 213Bi, 211At)

Abbreviations: 225Ac, Actinium-225; 211At, Astatine-211; 213Bi, Bismuth-213; KeV, kilo electron volt; MeV, mega electron volt; μm, micrometer; mm, millimeter; RBE, relative biological effectiveness.

a Mass number of 4 and charge of +2.

b Values obtained from summarizing the individual values of various β-and α-emitting radionuclides listed in Table 1.

Figure 6.

Figure 6.

Physical properties of both α- and β-therapeutic radionuclides. This schematic figure compares various β-particle and α-particle emitters and illustrates some of their key physical properties. In the context of theranostic application for paragangliomas, which express 3 specific targets (somatostatin receptor [SSTR], norepinephrine transporter [NET], and L-type amino acid transporter 1 [LAT1]), SSTR- and NET-based theranostics are widely available for clinical use and are depicted in green, whereas LAT1-based diagnostic radiopharmaceutical (18F-FDOPA) is available in only a few centers worldwide. The LAT1-based therapeutic radiopharmaceutical, 131I-iodophenylalanine (131I-IPA), currently being studied in primary brain tumors (NCT03849105), has not been used so far but can potentially be used in LAT-1–expressing paragangliomas. Therapeutic radionuclides can be classified as β-emitters: Iodine-131 (131I), Terbium-161 (161Tb), Yttrium-90 (90Y), Copper-67 (67Cu), and Lutetitium-177 (177Lu), as depicted in the upper right quadrant, as well as α-emitters: Actinium-225 (225Ac), Lead-212 (212Pb), Bismuth-213 (213Bi), Astatine-211 (211At), as depicted in the lower right quadrant. Among these, 131I and 211At are NET-based radionuclides (depicted in purple), while the rest are SSTR-based radionuclides (depicted in orange). β-Emitting radionuclides have lower mean particle energy (in the range of 0.1-0.9 MeV) and longer, more meandering path lengths (2-11 mm, depicted as waves), compared to α-emitting radionuclides (54, 55). The linear energy transfer (LET), which measures the ionizing density (ie, molecular damage of a particle per unit length for β-emitters) is low (0.2 keV/μm), making them sparsely ionizing along their path lengths (54). Relative biological effectiveness (RBE), defined as the ratio of biological effectiveness or damage done by a given type of radiation per unit of energy deposited in biological tissues, is low for β-emitters (56). α-Emitting radionuclides have a high particle energy (5.6-8.3 MeV) and a very short linear path length (< 0.1 mm, equivalent to the thickness of a few cell widths), and higher RBE, compared to β-emitting radionuclides. Because of this short therapeutic range, α particles are more likely to accumulate intracellularly and cause damage to a cell nucleus. Compared to β particles, the LET is very high for α particles (80-100 keV/μm) throughout their range and 3 times greater at the end of the path range (the Bragg peak) (54, 55). As a result, fewer particles are required to achieve a similar absorbed dose compared to β particles. Higher LET results in more double-strand breaks and has indirect effects on tumors such as increased cell division time, being relatively independent of cell cycle phase, and reduced enzymatic repair mechanisms, which make DNA and cell damage less likely to be repaired (54-59). Because of their physical characteristics, α-emitting radionuclides are generally considered to be more cytotoxic (∼500 times) to tumor cells compared to β-emitters (60, 61). This is due to the many physical differences, such as a higher LET, more compacted path of energy deposition, higher RBE, and a greater theoretical tolerance for hypoxic environments as the DNA-damaging capabilities of α-emitters rely less on having intermediary reactive oxygen species than do β particles. The shorter range of most α-emitters (microns vs millimeters in β-emitters) appear to be suitable for disseminated disease, small neoplasms, elimination of micrometastases and single tumor cells, and also suggests less collateral damage to surrounding nontumor tissue, although it might be at the cost of slightly decreased efficacy from less cross-fire effect (Table 2). However, in a preclinical mice study with α-targeted radiotherapy (213Bi-DOTATATE) bearing tumors of different sizes (50 and 200 mm3) using 2 different tumor models (H69 and CA20948, human small cell lung carcinoma and rat pancreatic tumor cell lines, respectively), 213Bi-DOTATATE demonstrated a great therapeutic effect both in small and larger tumor lesions, suggesting that α-targeted radiotherapy has a role even in larger tumors (62). However, this needs to be further proven in clinical studies. In summary, compared to α particles, β particles have a longer maximum path length (20-100 times), lower mean energy (by a factor of 10-50), and lower linear energy transfer (LET) (by 400-500 times). β particles induce damage through single-strand breaks, while α particles cause double-strand breaks, which are more challenging to repair. Both β- and α-particles indirectly cause DNA damage by releasing reactive oxygen species or free radicals. β particles have a wavy path and often traverse through tumor cells without causing DNA damage, while α particles have a linear path and traverse fewer tumor cells (1–10) compared to β particles. The shorter path length of α particles results in minimal radiation exposure to healthy tissues surrounding tumors compared to β particles, thus limiting adverse effects. The length and thickness of radiation in the figure represent the relative path length and mean energy of the respective radionuclides in α- or β-groups.

Efficacy and Safety of Targeted Radiotherapies in Paragangliomas

Two kinds of targeted radiotherapies have been attempted so far in metastatic paragangliomas. They either target NET (131I-MIBG) or SSTR (177Lu/90Y/225Ac-DOTA-TATE/TOC, commonly called peptide receptor radionuclide therapy [PRRT]).

131I-MIBG comes in 2 forms: low-specific- and high-specific-activity. Low-specific-activity 131I-MIBG preparations (0.555-1.85 MBq/mg) typically contain approximately 1/2000 131I-MIBG molecules labeled with 131I, whereas most MIBG molecules are labeled with 131I in preparations of high-specific-activity 131I-MIBG (92.5 GBq/mg) (46). To date, 2 meta-analyses have been reported in patients who have undergone low-specific-activity 131I-MIBG therapy consisting of studies that are mainly retrospective and heterogeneous in terms of baseline patient characteristics and use of treatment protocols (63, 64). Both the meta-analyses by Loh et al and van-Hulsteijn et al have an equal objective response rate (30% each) and disease control rates (87% vs 82%), respectively (Table 3).

Table 3.

Performance of various radiopharmaceuticals in metastatic or inoperable pheochromocytoma/paraganglioma

Radiopharmaceutical Author, y of publication, and reference No. of patients (studies)a No. of cycles Objective response rate (studies)a Disease control rate (studies)a Progression-free survival (studies)a Overall survival (studies)a
Meta-analysis
131I-MIBG (LSA) Loh et al 1997 (63)b 116 (24) 1-11 30.0%
(CR = 4%)
87% NR Responders: 29 (range: 9-110)
Nonresponders: 18 (range: 3-75)
131I-MIBG (LSA) van-Hulsteijn et al 2014 (64) 243 (17) 1-12 30.0%
(CR = 3%)
82.0% 23-28 mo (2)c 45%-64% (2), range for 5-y survival rated
177Lu/90Y-DOTATATE Taieb et al 2019 (10) 179 (13) 1-11 NR 89.6% 17-39 mo (7)c 49.6-68.0 mo (3)c
177Lu/90Y-DOTATATE Satapathy et al 2019 (65) 201 (12) 1-10 25.0% 84.0% 10-91 mo (4),c
37.1 (2), mean mo
54.5 (4), mean mo
177Lu/90Y-DOTATATE Su et al 2023 (66) 330 (20) 1-11 20% 90% 31.8 mo (13) 74.3 mo (11)
177Lu/90Y-DOTATATE
177Lu
90Y
Marretta et al 2023 (67) 213 (12)
149 (10)
64 (3)
1-10
1-5
1-10
NR
NR
NR
81%
83% (10)
76% (2)
NR
NR
NR
NR
NR
NR
Seminal studies
131I-MIBG (HSA) Pryma et al 2019 (68)e 68 1-2 23.4% 92.2% NR 36.7 mo
131I-MIBG (LSA) Yoshinaga et al 2021 (69) 11 (10 paraganglioma, 1 medullary thyroid carcinoma) 2-3 27.3% 81.8% NR NR
225Ac-DOTATATE Yadav et al 2022 (70)f 9 2-9 50% 87.5% NR NR
177Lu-DOTATATE
 Sporadic
SDHx
Lin et al 2023
(interim analysis) (71)g
36
18
18
4 13.9%
11.1%
16.7%
86.1%
100%
72.2%
19.1 mean mo
22.7 mean mo
15.4 mean mo
NR
NR
NR

Duration of progression-free survival and overall survival are mentioned as medians in months, unless otherwise specified.

Abbreviations: CR, complete response; HSA, high-specific-activity; LSA, low-specific-activity; NR, not reported; SDHx, succinate dehydrogenase subunit gene.

a Values in parentheses are number of studies.

b Response criteria used was World Health Organization criteria.

c Range described in few studies. Different response criteria (World Health Organization (8 studies), RECIST (4, out of which 1 was 1.1 version), Eastern Cooperative Oncology Group (1 study), and International Neuroblastoma Response Criteria (1 study) were used.

d Five-year survival rate.

e Best objective response within 12 months of initiation of high-specific-activity 131I-MIBG therapy.

f Concomitant radiosensitizer, capecitabine, was also given with 225Ac-DOTATATE α-targeted therapy.

g Response rates were calculated at 6 months following initiation of 177Lu-DOTATATE therapy.

The study conducted by Loh et al (63), comprising 116 pooled patients (mean dose 5.8 GBq, 1-11 cycles with a cumulative dose range of 3.6-85.9 GBq) treated at 24 centers, reported a tumor response in 30% (complete response, 4%; PR, 26%; stable disease, 57%, and progressive disease, 13%) by World Health Organization (WHO) criteria (see Table 3) along with an initial symptomatic improvement in 76% and hormonal response in 45% of pooled patients. Survival data were available for 89 patients who were followed for a median of 29 months (range, 9-110 months) and 18 months (range, 3-75 months) in responders (n = 40) and nonresponders (n = 49), respectively. The median overall survival rates reported in responder and nonresponder groups were 22 months (range, 12-40 months) and 13 months (range, 2-34 months), respectively. Death rates reported were 33% and 45% in responders and nonresponders, respectively. Safety data were available for 47 patients who reported 52 adverse events that are summarized in Table 4. Notably, 2 patients reported pancytopenia and 1 of these patients, having widespread bone metastases, succumbed to the disease within 3 weeks of therapy.

Table 4.

Targeted radiotherapy: schedules and adverse events reported in paraganglioma patients

Radiopharmaceutical Schedule Adverse events
131I-MIBG (LSA)
(13, 46, 64)
High-dose (>444 MBq/kg) Studies or review articles reported the following:
  • Hematotoxicity:

    • Neutropenia (grade 3/4): 87% (required growth factors);

    • Thrombocytopenia (grade 3/4): 83.0% (required platelet transfusion);

    • Myelodysplastic syndrome: 4%

  • Hypothyroidism: 11.0-20.0%

  • Hypogonadism: 6.8%

  • Pulmonary: acute respiratory distress syndrome, bronchiolitis obliterans

  • Cardiac: hypertension, rarely hypertensive crisis (despite α-adrenoceptor blockade)

  • Hepatotoxicity: rarely

  • Renal failure: rarely

  • Constitutional symptoms, ie, nausea and vomiting

131I-MIBG (LSA) (13, 46, 63) Low-intermediate dose (74 MBq/kg, often repeated, < 9.25 GBq total dose) Meta-analysis by Loh et al published in 1997 reported 52 adverse events in 45 patients (grade not specified, percentages mentioned are proportion of adverse events to total events reported:
  • Myelosuppression: 36.5%, pancytopenia in 3.8% (2 events, 1 patient with widespread bone metastases died 3 wk later due to pancytopenia),

  • Pressor crisis or exacerbation of headache, palpitations or diaphoresis (1 patient required phentolamine): 17.3%

  • Orthostatic hypotension: 3.8%

  • Hepatic dysfunction (liver failure, hyperbilirubinemia, transaminitis): 7.7%

  • Parotitis with xerostomia: 1.9%

  • Hypothyroidism: 1.9%

  • Nausea or vomiting or diarrhea: 25.0%

    Other studies or review articles reported the following:

  • Myelodysplasia: 7%

  • Hypothyroidism: 11.0%-20.0%

  • Hypogonadism

  • Myelotoxicity grade 3-4: <19%

  • Constitutional symptoms are common

131I-MIBG (HSA) (68) High-dose (∼18.5 GBq usually × 2) Reported in 68 patients (prospective evaluation):
  • Hematotoxicity:

    • any grade: 90%

    • grade 3/4: 72% (25% required hematological supportive care, packed RBCs, platelet transfusions, granulocyte colony-stimulating factor, or erythropoietin)

    • Myelodysplastic syndrome: 4%

  • Pulmonary embolism: 3%

  • Hypothyroidism: 3.4% (data from package insert)

  • Worsening of hypertension within 24 hours: 11%

  • Nephrotoxicity (kidney failure or acute renal injury): 7%

  • Constitutional symptoms, ie, nausea all grades: 76%

  • Secondary malignancies: acute myeloid leukemia (1.5%), acute lymphocytic leukemia (1.5%)

131I-MIBG (LSA) (69) 5.5 GBq every 6 mo × 3 cycles Reported in 11 patients (prospective evaluation; 10 paraganglioma, 1 medullary thyroid carcinoma):
  • Early side effects (all were temporary except pleural effusion):

    • Nausea: 81.8%

    • Loss of appetite: 36.4%

    • Hypertension, orthostatic hypotension, bradycardia, taste abnormality: 9%

    • Pleural effusion: 9%

Late side effects:
  • Hematotoxicity (no one required blood transfusion):

    • Anemia, grade 2: 27.3%; anemia, grade 3: 9%

    • Leukopenia, grade 2: 45.5%; leukopenia, grade 3: 9%

    • Thrombocytopenia, grade 1: 9%

177Lu/90Y-DOTATATE (65, 66) Typically, 7.4 GBq × 4 (46) 274/330 patients in most recent meta-analysis by Su et al published in 2023 reported adverse events:
  • Hematotoxicity (reported in 270 patients):

    • any grade, 22.3% (95% CI, 12.5%-33.5%)

    • grade 3/4, 4.3% (95% CI, 0.2%-11.4%)

    • Myelodysplastic syndrome in 1 patient after receiving a cumulative dose of 44.4 GBq and died 4.5 years later from myelodysplastic syndrome–related complications

  • Nephrotoxicity (reported in 212 patients):

    • any grade, 1.9% (95% CI, 0.0%-6.2%)

    • grade 3/4, 1.9% (95% CI, not reported)

  • Treatment discontinuation due to disease progression or upper renal dose limits in 9.0% (95% CI, 0.5%-22.3%):

    • due to recurrent thrombocytopenia in 3 patients

    • due to nephrotoxicity after completing third PRRT cycle (cumulative dose 11.1 GBq) in 1 patient

45/201 patients in meta-analysis by Satapathy et al reported hematotoxicity or nephrotoxicity:
  • Hematotoxicity (grade 3/4):

    • Neutropenia, 3.0% (95% CI, 0.0%-13.0%)

    • Lymphopenia, 11.0% (95% CI, 4.0%-24.0%)

    • Thrombocytopenia, 9.0% (95% CI, 3.0%-21.0%)

    • Myelodysplastic syndrome in 1 patient likely prior chemotherapy related

  • Nephrotoxicity: 4.0% (95% CI, 1.0%-14.0%)

  • Discontinuation of therapy reported in 4.9% (5/102) patients

177Lu-DOTATATE (71) 7.4 GBq every 8 wk × 4 cycles Interim analysis reported in 36 patients (prospective evaluation):
  • Hematotoxicity: 5%-10% range

  • Catecholamine-related symptoms (flushing, hypertension, and tachycardia) starting as early as 177Lu-DOTATATE therapy and lasting for days

  • Serum catecholamine levels surge rapidly (on average peaked at 24 h post-administration, median increase: 60%, maximum increase 10× baseline, approximately returned to baseline by 28th day)

  • A few patients with baseline severe hypertension, heart rate went >160 beats per minute and systolic blood pressure as high as 260 mm Hg, and required ICU admission for monitoring and intravenous antihypertensives

225Ac-DOTATATE (70)
(used capecitabine as a radiosensitizer)
Mean cumulative dose of 42.4 ± 27 MBq × 3 (range, 2-9 MBq) Reported in 9 patients
  • Hematotoxicity:

    • Thrombocytopenia (grade 1): 22.2%

  • Grade 1/2 nausea, stomach discomfort, and diarrhea: 33.3%

  • No grade 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity

Abbreviations: GBq, giga becquerel; HSA, high-specific-activity; ICU, intensive care unit; LSA, low-specific-activity; MBq, mega becquerel; RBCs, red blood cells.

A meta-analysis by van Hulsteijn et al (64) of 17 studies comprising 243 pooled patients who underwent 131I-MIBG therapy showed a complete response, PR, and stable disease in 3% (95% CI, 6%-15%), 27% (95% CI, 19%-37%), and 52% (95% CI, 41%-62%) of pooled patients, respectively, after a follow-up duration of 24 to 62 months by various criteria (WHO [8 studies], RECIST [4, out of which 1 was 1.1 version], Eastern Cooperative Oncology Group [ECOG, 1 study], and International Neuroblastoma Response Criteria [INRC, 1 study]) and hormonal response in 72% of pooled patients (64). One group received an injected dose of approximately 18.5GBq (72, 73), whereas most of the other studies injected a dose of approximately 7.4 GBq (74-77). One group used a much higher activity (up to 666 MBq/kg) in conjunction with stem cell support (10). In the only direct comparison of very low (5.55 GBq) vs low/intermediate (9.25-12.95 GBq) activity, low/intermediate activity had more rapid onset of efficacy at the expense of increased acute and chronic toxicity (78), whereas others have suggested improved response with a higher administered 131I-MIBG dose of greater compared to lower than 18.5 GBq (72). The activity of greater than or equal to 444 MBq/kg low-specific-activity 131I-MIBG can have higher toxicity, particularly pulmonary (79) and therefore, doses greater than 296 MBq/kg are not recommended (46). One of the main drawbacks of conventional MIBG preparations is that more than 99% of the MIBG molecules are not labeled with 131I, therefore, possibly competing for NET binding sites and disrupting the norepinephrine reuptake mechanism. This could possibly lead to increased side effects especially with high-dose (>444 MBq/kg) administrations due to decreased absorbed dose (10, 79, 80). Hematotoxicity was the most significant toxicity, especially thrombocytopenia (80). Grade 3/4 thrombocytopenia and leukopenia were observed in 83% to 87% of patients, requiring platelet transfusion and growth factors (>444 MBq/kg), whereas low-dose administrations (5.5 GBq for adult patients) were well tolerated (10, 79, 80). Myelodysplastic syndrome and acute leukemias have been reported in patients treated with large amounts of 131I-MIBG (and with prior chemotherapies), with an incidence of 4% of myelodysplastic syndrome with high-dose administrations (10, 79, 80). Other adverse events are summarized in Table 4.

Recently, high-specific-activity 131I-MIBG consisting almost entirely of 131I-MIBG (∼92.5 GBq/mg) was developed (68). The primary end point was reached in 25% of patients, defined as a reduction in baseline antihypertensive medication lasting 6 months or longer (68). Per RECIST 1.0, an objective response of 92% patients (PR, 23% and stable disease, 69%) within 12 months and median overall survival of 36.7 months from the first treatment was reported (68). Therapeutic response evolved over time as the PR increased to 23% at 12 months from 6% at 3 months in patients receiving at least 1 therapeutic dose (see Table 3) (68). Grade 3/4 hematotoxicity was reported in 72% of patients (68). Other severe adverse events are described in Table 4 (68).

The use of PRRT for patients with pheochromocytoma and paraganglioma who have high tumor SSTR expression has mainly been reported in retrospective small case series, and the protocols varied in all these studies. To date, 4 meta-analyses (Taieb et al and Satapathy et al in 2019 as well as Su et al and Marretta et al in 2023) based on PRRT (177Lu/90Y-DOTAT-TATE/TOC) therapy have been reported (10, 65-67). The reported number of pooled patients ranged from 179 to 330 without any complete response. The reported PR ranged from 20% to 25% and stable disease from 59% to 70%, giving an objective response rate range of 20% to 25% and disease control rate range of 81% to 90% (see Table 3) (10, 65-67). Survival rates have been reported by only 3 meta-analyses (10, 65, 66). The reported progression-free survival rates were 17 to 39 months in 7 studies by Taieb et al, 10 to 91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al, and a median of 31.8 months in 13 studies by Su et al, whereas overall survival rates were 49.6 to 68.0 months in 3 studies by Taieb et al, a mean of 54.5 months in 4 studies by Satapathy et al, and a median of 74.3 months in 11 studies by Su et al (see Table 3) (10, 65, 66). Su et al (66) reports pooled adverse events data in 274 of 330 patients that mention a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient (see Table 4). Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n = 3) or nephrotoxicity (n = 1).

Efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating 177Lu-DOTATATE in paraganglioma patients conducted at the NIH (NCT03206060) in 36 patients have been reported (n = 18, apparently sporadic cohort and n = 18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex [SDHA = 2, SDHB = 15, SDHD = 1], SDHx cohort) after 177Lu-DOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles (71). The progression-free survival at 6 months since initiation of 177Lu-DOTATATE was 19.1 months (22.7 months in the apparently sporadic cohort and 15.4 months in the SDHx cohort), and overall survival was not reached in both cohorts (71). Per RECIST 1.1, overall, 86.1% patients showed PR (13.9%) or stable disease (72.2%). In the sporadic cohort, PR was observed in 11.1% and stable disease in 88.9% patients, whereas those in the SDHx cohort were 16.7% and 55.5%, respectively, at the end of 6 months (71). Catecholamine-related symptoms, such as flushing, hypertension, and tachycardia, often began during the 177Lu-DOTATATE infusion and lasted for days to weeks after therapy. Serum catecholamine levels surged quickly, likely contributing to the increase in symptoms, peaking at around 24 hours post administration (with a median increase of 60% and a maximum increase of 10× the baseline level) (71). In some patients with severe baseline hypertension, systolic blood pressure rose as high as 260 mm Hg, with a heart rate exceeding 160 beats per minute, necessitating intensive care unit admission for monitoring and intravenous antihypertensive treatment (71). Despite these acute increases and associated symptoms, catecholamine levels in most patients returned to baseline levels by the 28th day (71).

Overall, the efficacy rates are similar of both targeted radiotherapies (131I-MIBG and PRRT) and are safe except the higher dosed 131I-MIBG (high-specific-activity or low-specific-activity), which show higher hematotoxicity warranting hematologic supportive care. The efficacy and adverse events data of the aforementioned studies along with other seminal studies in targeted radiotherapies are summarized in Tables 3 and 4.

Clinical Stepwise Strategies for Choosing Proper Radiopharmaceutical for a Paraganglioma Patient

When evaluating a patient with metastatic paraganglioma, the first step is to assess whether systemic therapy is warranted based on various factors: tumor burden and its progression or stability; catecholamines/metanephrines production and plasma/urine concentrations, and their organ-related complications (hypertensive emergency, myocardial infarction, arrhythmia, and ischemic or hemorrhagic stroke); and tumor location (eg, mass effect on surrounding structures, neurologic consequences from vertebral metastases) (13, 45, 81-83). This assessment is crucial because a few paraganglioma patients have indolent disease and are asymptomatic and therefore can be safely monitored with active surveillance and medical management of catecholamine excess (recommendation No. 25 (13)).

If the patient is a potential candidate for systemic therapy, especially targeted radiotherapy (slow-to-moderate progression together with moderate-to-high tumor burden, recommendation No. 25 (13)), the next step is to evaluate SSTR (68Ga/64Cu-DOTA-TATE/TOC) PET/CT and NET (123I-MIBG) expression on scans to determine the extent and intensity of uptake (recommendation No. 28 (13)). It is critical to ensure that the tumors express SSTR or NET on a whole-body level. This is achieved by comparing the uptake on SSTR PET/CT and 123I-MIBG scans initially with anatomic imaging (CT and/or magnetic resonance imaging) and subsequently with 18F-fluorodeoxyglucose (18F-FDG) PET/CT (45, 46). Along with it, other important factors need to be taken into consideration, including insurance coverage (45). These can be broadly categorized as clinical (patient-based) or tumoral (tumor-based) as described next.

The choice between 177Lu-DOTATATE and 131I-MIBG for targeted radiotherapy is clear when one scan shows superior uptake compared to the other (Fig. 7) (45). However, when the uptake and extent of disease on both scans are similar (Fig. 8), then the aforementioned factors guide the selection (45).

Figure 7.

Figure 7.

Variable expression of somatostatin receptor and norepinephrine transporter imaging. Panel (A) demonstrates superior detection of tumors by whole-body anterior maximum intensity projection (MIP) of 68Ga-DOTATATE positron emission tomography–computed tomography (PET/CT) (A) compared to 123I-MIBG (B and C, anterior and posterior planar images, respectively) single photon emission computed tomography/computed tomography (SPECT/CT) of a 65-year-old man with germline pathogenic variant in succinate dehydrogenase subunit D (SDHD) showing multiple metastatic lesions in bilateral neck, lungs, mediastinum, and bones. The planar images of 123I-MIBG SPECT/CT are found to be negative, thus favoring 177Lu-DOTATATE therapy. Panel (B) demonstrates inferior detection of tumors by 68Ga-DOTATATE PET/CT (D, anterior MIP) compared to 123I-MIBG SPECT/CT (E and F, anterior and posterior whole-body planar images, respectively) in a 64-year-old man without any germline pathogenic variant in paraganglioma susceptibility genes, revealing a recurrent tumor in the left adrenalectomy bed along with retroperitoneal lesions, multiple scattered bony metastatic disease including cervical bone metastasis, and a left supraclavicular lymph node favoring 131I-MIBG therapy. Of note, contrast recovery, sensitivity, and spatial resolution of PET/CT imaging is superior to SPECT/CT imaging and therefore small lesions on PET/CT scans may not be visible on SPECT/CT scans despite adequate uptake.

Figure 8.

Figure 8.

Similar expression of somatostatin receptor and norepinephrine transporter imaging. The whole-body anterior maximum intensity projection (MIP) image of 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) (A) and whole-body anterior (B) and posterior (C) planar images of 123I-MIBG single photon emission computed tomography/computed tomography (SPECT/CT) demonstrate a similar pattern of tumor detection by both 68Ga-DOTATATE PET/CT and 123I-MIBG SPECT/CT in a 72-year-old man without any germline pathogenic variant in any of the paraganglioma susceptibility genes revealing multiple bilateral lung, liver, and bone lesions. Therefore, selection of targeted radiotherapy with 177Lu-DOTATATE or 131I-MIBG depends on clinical and tumor characteristics. While interpreting the scans, it is important to consider the inherent differences between SPECT imaging (123I-MIBG) and PET (68Ga-DOTATATE) imaging as contrast recovery, sensitivity, and spatial resolution are far superior for PET imaging. Therefore, a few of the small lesions seen on 68Ga-DOTATATE MIP may not be visible on planar images of 123I-MIBG scintigraphy despite adequate MIBG uptake. This should not be confused for greater uptake or a higher likelihood of response to therapy. To mitigate the effect of comparing planar SPECT and PET MIP images, we have included an 18F-fluorodopamine (18F-FDA, anterior MIP, D) PET/CT image. This compound also targets the norepinephrine transporter, similar to 123I-MIBG. Additionally, 124I-MIBG and 18F-metafluorobenzylguanidine (18F-MFBG) are other PET-based radiopharmaceuticals that targets norepinephrine transporter. However, none of these are widely available for imaging.

Insurance coverage is an important factor to consider, as reimbursement for both 131I-MIBG (high-specific-activity or low-specific-activity) and 177Lu-DOTATATE can vary across and sometimes within countries. In the United States, high-specific-activity 131I-MIBG (Azedra) is currently the only FDA-approved radiopharmaceutical specifically for inoperable/metastatic pheochromocytoma/paraganglioma patients, although low-specific-activity 131I-MIBG therapy has often been reimbursed or supported by third-party payers. 177Lu-DOTATATE is approved by the FDA only for gastroenteropancreatic neuroendocrine tumors and is not approved for paraganglioma, although National Comprehensive Cancer Network guidelines also include it as an option for paragangliomas. Of note, Lantheus Holdings, Inc. in 2023 expressed to discontinue the production of Azedra® since the first quarter of 2024 and production was continued until then to ensure the availability of doses only for existing patients.

Additional important patient characteristics to be considered are age, bone marrow reserve, renal function, prior therapies—chemotherapy with alkylating agents or radiotherapies, and catecholamine/metanephrine levels (45). 177Lu-DOTATATE or low-specific-activity 131I-MIBG (low-intermediate dose) should be considered in patients with marginally limited bone marrow reserve (older patient or patient with prior alkylating chemotherapies or radiotherapies) whereas in patients with good bone marrow reserve (younger patients, patients without any history of prior extended alkylating chemotherapies or radiotherapies to the spine or pelvic bone marrow, and patients with fewer bone metastases), high-dose 131I-MIBG (high-specific-activity or low-specific-activity) can be considered. In patients with elevated catecholamines and/or metanephrines, high-specific-activity 131I-MIBG might be favored over low-specific-activity 131I-MIBG and 177Lu-DOTATATE, as it is generally not associated with catecholamine crises; however, caution should be exercised for high-specific-activity administrations as well (see Table 4) (45). There is no major preference between 131I-MIBG (high-specific-activity or low-specific-activity based on meta-analysis studies) and 177Lu-DOTATATE in patients with impaired renal functional and/or underlying risk factors for nephropathy/nephrotoxicity (see Table 4). Furthermore, low-dose targeted radiotherapy or dosimetry can be used to personalize therapy in patients with suboptimal bone marrow reserve or with a lower renal functional reserve or underlying renal disorders (45).

Important tumor-based characteristics to be considered are tumor size, location, growth rate, and tumor heterogeneity and differentiation. 177Lu-DOTATATE, 131I-MIBG, and α-emitter–based targeted therapies are better suited for smaller tumors (<2.0-3.0 cm), whereas for patients with large-sized tumors (>3.0 cm), 90Y-DOTA-TATE/TOC should be considered, if available, as path length and maximum emitted energy for 90Y is greater compared to 177Lu and 131I (see Table 1) (84, 85) or α-emitter, based on mouse models (62). Further, in patients with variable-sized tumors, combinations of 131I-MIBG and 90Y-DOTATOC can be attempted, which is currently being evaluated in neuroendocrine tumors including paragangliomas (NCT03044977) (45, 85). The sequence and optimal combination may be decided on tumor burden, location, and avidity on respective scans (45). In the event of uptake in some but not all lesions of both tracers, the choice of tracer is influenced by whether the lesions being visualized are located in visceral organs, bones, or lymph nodes, as lesions in visceral organs are likely associated with a higher risk of worse outcomes for patients, and therefore should take precedence. In such cases, disease control may potentially be achieved by combining these therapeutic agents, with the first therapy agent being the radiopharmaceutical demonstrating the highest focal uptake in the highest number of visceral organ lesions. In cases where tumor heterogeneity results in a mismatch between 123I-MIBG– and 68Ga-DOTATATE–avid lesions, the feasibility of targeted radiotherapy in a sequential order or with a combined regimen (“cocktail”) can be considered, even though this approach has not yet been rigorously tested (45, 85). Additionally, external beam radiation can be used to target any progressive lesions lacking uptake in either 123I-MIBG or 68Ga-DOTATATE scans (Fig. 9) (86). Note that all rapidly progressive lesions showing positivity on 123I-MIBG scintigraphy or SSTR PET/CT scans should be treated either by external beam radiation (especially when mass effect is present) or any therapy ranging from systemic chemotherapy to high-dose targeted radiotherapies or optimized PRRT or α-targeted radiotherapies.

Figure 9.

Figure 9.

Local therapy before targeted radiotherapy with 177Lu-DOTATATE. This figure shows whole-body anterior maximum intensity projection (A, B) and axial (C, D; fused) positron emission tomography/computed tomography (PET/CT) images of 68Ga-DOTATATE (A, C) and 18F-FDG (B, D), respectively, as well as an axial image of contrast-enhanced CT (CE-CT, E) of a 53-year-old woman with a germline pathogenic variant in the succinate dehydrogenase subunit A (SDHA) gene with multiple metastatic liver lesions (up to 6 cm in size), bilateral lung lesions, multiple metastatic neck, mediastinal, retroperitoneal lymph nodes, and a left coracoid process and a left inferior pubic ramus bone metastases. Imaging with 123I-MIBG scintigraphy (not shown) demonstrated uptake only in the left coracoid process and left inferior pubic ramus bone metastases, thus ruling out targeted radiotherapy with 131I-MIBG. Furthermore, 68Ga-DOTATATE (C, fused axial PET/CT) lacked uptake in 4 liver lesions including a large liver lesion located in the left hepatic lobe (green arrowhead) and 3 more liver lesions (arrows) that were all seen on 18F-FDG (D); the larger 2 are also appreciated on CE-CT (green arrowhead and green arrow on E, axial). She was initially recommended for CVD chemotherapy due to 18F-FDG detecting more lesions compared to 68Ga-DOTATATE and hence, a possibility of dedifferentiation. However, the patient refused to undergo chemotherapy. Therefore, she underwent embolization of liver lesions in anticipation of starting targeted radiotherapy with 177Lu-DOTATATE. She subsequently received external beam radiotherapy to the pubic bone before starting 177Lu-DOTATATE therapy. Thereafter, she underwent 2 cycles of 200 mCi of 177Lu-DOTATATE without any complications or associated adverse events. However, she showed progression on imaging after 2 cycles and hence 177Lu-DOTATATE therapy was discontinued. Following the progression of her disease, she was recommended to undergo CVD chemotherapy. Subsequently, she received 6 cycles of CVD chemotherapy but progressed due to an increasing number and size of liver lesions. Later she underwent liver embolization and liver trisegmentectomy to control liver disease as the bulk of her disease was in the liver. However, she later succumbed to her disease.

Important tumor locations that need some considerations are metastases in lung/liver, peritoneum/mesentery, brain, or spine compressing the spinal cord or its nerve roots. Peritoneal/mesenteric metastases can cause intestinal immobility or obstruction/ischemia. Caution should be exercised in using targeted radiotherapy as 177Lu-DOTATATE seems to be ineffective in reducing the size of a mesenteric or peritoneal metastases (87-89). However, in a retrospective study in neuroendocrine tumors by Strosberg et al (88), 6% (5/81, out of which 2/5 succumbed to progressive peritoneal or mesenteric disease) of patients (22% high-risk category) experienced at least one episode of bowel obstruction within 3 months with peritoneal or mesenteric disease 177Lu-DOTATATE whereas in another multicentric retrospective study, an improvement in baseline mesenteric mass-related symptoms occurred in almost half of patients with relatively fewer major gastrointestinal complications during therapy (bowel obstruction, 2%) and long-term major gastrointestinal complications in 12% patients (obstruction, 6%; ischemia, 2%, and perforation, 2%) (88, 89). A postinfusion trial of corticosteroids can be considered in patients at high risk of these complications (88). Paragangliomas rarely metastasize to brain parenchyma. However, spinal bone metastases compressing the spinal cord or its nerve roots can frequently occur (90). In such cases, 177Lu-DOTATATE may be considered (except for rapidly growing lesions) as it was found to reduce tumor volume, thereby reducing pain and spinal compression (91). Nevertheless, 177Lu-DOTATATE–induced damage can cause initial/temporary edema, which may lead to increased compression of nearby vital structures and potentially worsen neurological symptoms and signs (92). In situations involving brain metastases or in patients at risk of spinal cord or nerve compression, prophylactic corticosteroid therapy can be considered to prevent or reduce radiation-induced edema (92). Note that any corticosteroid therapy given in patients with biochemically positive paraganglioma must be accompanied by the prior administration of adrenoceptor blockade since corticosteroids increase secretion of catecholamines (16, 93).

β-Targeted radiotherapy should be used only in slow-to-moderate tumor growth with moderate-to-high tumor burden (recommendation No. 27 (13)). In patients with rapid tumor growth or high tumor burden, chemotherapy, such as with temozolomide, CVD, or tyrosine kinase inhibitors, should be considered (recommendation No. 26 (13)) apart from high-dose β-targeted radiotherapy, optimized PRRT, or α-targeted radiotherapy.

If there is multifocal nonavid 123I-MIBG/68Ga-DOTATATE disease and high avidity is observed only on 18F-FDG PET/CT scan, the tumors in these patients are likely less differentiated, and hence are better served with other systemic treatment options, at present most commonly cytotoxic chemotherapy.

It is recommended to use adrenoceptor blockade with any systemic/local therapies, including targeted radiotherapy in patients with metastatic paragangliomas, to prevent catecholamine-induced cardiovascular complications associated with released catecholamines during tumor destruction due to systemic therapy, particularly when 177Lu-DOTATATE and low-specific-activity 131I-MIBG therapy are used (6, 81-83, 94). A schematic algorithm has been provided to show the stepwise workflow to choose the appropriate targeted radiotherapy in paraganglioma patients (Fig. 10).

Figure 10.

Figure 10.

Schematic algorithm showing stepwise workflow in selecting patients for appropriate targeted radiotherapies. This schematic figure shows a stepwise workflow in selecting patients for appropriate targeted radiotherapies. *The “high-dose” 131I-MIBG therapy is available both in high-specific-activity (Azedra® [Lantheus], discontinued in first quarter of 2024) as well as low-specific-activity forms, whereas “intermediate-dose” and low-dose 131I-MIBG is available only in a low-specific-activity form. **In cases with very elevated metanephrines/catecholamines, high-specific-activity 131I-MIBG (high-dose) therapy is preferred due to catecholamine crises not being reported with its use. In patients with normal or mildly elevated levels, low-specific-activity 123I-MIBG (intermediate-dose or low-dose) or 177Lu-DOTATATE should be considered. However, we suggest caution be exercised in all patients irrespective of their catecholamines/metanephrines levels. ***When it comes to location of metastases, uptake and tumor burden of visceral metastases (lungs and liver) rather than metastases in bones and lymph nodes on scans should be considered. ****212Pb-DOTAMTATE was accorded FDA approval in 2024 under breakthrough therapy designation for peptide receptor radionuclide therapy (PRRT)-naive gastroenteropancreatic neuroendocrine tumors. Selection of targeted radiotherapies should be personalized and made in a stepwise decision-making process on the basis of 123I-MIBG scintigraphy, 68Ga-DOTATATE PET/CT, and 18F-FDG PET/CT results. The choice between 177Lu-DOTATATE and 131I-MIBG is straightforward when one scan shows superior uptake compared to the other, provided there is no or inferior uptake on 18F-FDG. If 123I-MIBG is superior in uptake and/or number of tumors showing 123I-MIBG uptake compared to 68Ga-DOTATATE (and 18F-FDG), 131I-MIBG therapy is chosen whereas 177Lu-DOTATATE therapy is chosen if 68Ga-DOTATATE is superior in uptake and/or number of tumors showing 68Ga-DOTATATE uptake compared to 123I-MIBG (and 18F-FDG). In cases where 18F-FDG is superior compared to 123I-MIBG and 68Ga-DOTATATE in uptake and/or number of tumors showing 18F-FDG uptake: i) Standard of care therapies: chemotherapy (cyclophosphamide, vincristine, and dacarbazine [CVD], temozolomide, and tyrosine kinase inhibitors [TKIs]), and ii) Experimental therapies: a) α-targeted radiotherapy (212Pb-DOTAMTATE/VMT-α-NET, 225Ac-DOTATATE, and 211At-MABG) or b) Optimizing targeted radiotherapy (potentiating by using chemo-PRRT or PARP inhibitors [PARPi]; increasing absorbed dose in tumors by using dosimetry, intra-arterial injection, SSTR antagonist, or using Evans blue modification; overcoming radioresistance by using α-targeted radiotherapy or combination of radionuclides; and SSTR upregulation by using epigenetic drugs). When the uptake in these two scans (123I-MIBG scintigraphy and 68Ga-DOTATATE PET/CT) is similar and there is no or inferior uptake on 18F-FDG, factors related to the patient (including age, bone marrow reserve, prior cytotoxic therapies, and catecholamines/metanephrines secretion) and the tumor (tumor burden, tumor growth, location and size of tumors, tumor heterogeneity, and Ki-67 index) should be taken into consideration. In patients with good or preserved bone marrow reserve (young age, no prior cytotoxic therapies or external radiotherapies to pelvic bone), high-dose 131I-MIBG (high-specific-activity or low-specific-activity) or intermediate-dose 131I-MIBG (low-specific-activity) is favored whereas in patients with compromised bone marrow reserve (older patients and those who have received prior cytotoxic therapies or external beam radiation), low-dose 131I-MIBG (low-specific-activity) or 177Lu-DOTATATE is favored. A few special scenarios include the following: i) In patients with large tumors (>5.0 cm), 90Y-based targeted radiotherapy (or α-based targeted radiotherapy based on preclinical studies) can be considered; ii) patients who progress on 131I-MIBG or 177Lu-DOTATATE (β-based targeted radiotherapy) can undergo α-based targeted radiotherapies; iii) patients with variable tumor sizes can undergo either “cocktail” or “sequential” targeted radiotherapies with combinations of 90Y and 177Lu or 131I, provided they show uptake both on 68Ga-DOTATATE and/or 123I-MIBG; and iv) patients with mismatched expression on 123I-MIBG and 68Ga-DOTATATE can undergo either “cocktail” or “sequential” targeted radiotherapies with combinations of 131I and 90Y or 177Lu. Figure created using Biorender.com.

Predictive Biomarkers of Targeted Radiotherapies

There have been a few studies of targeted radiotherapies in which predictive factors were identified in metastatic paragangliomas. In one such study by Vyakaranam et al (86), 22 patients received dosimetry-guided 177Lu-DOTATATE until 23 Grays to the kidneys or 2 Grays to bone marrow was reached, achieved a median overall survival of 49.6 months (range, 8.2-139 months) and a median progression-free survival of 21.6 months (range, 6.7-138 months). The authors identified high Ki-67 (>15%) as a negative predictive factor both for progression-free and overall survival and prior PRRT also for overall survival (86).

The interim analysis of an open-label, single-arm phase 2 study evaluating 177Lu-DOTATATE in paraganglioma patients, conducted at the NIH (NCT03206060) in 36 patients, calculated the total uptake volume (akin to total lesion glucose for 18F-FDG scan) obtained by multiplying tumor volumes of every tumor with their respective mean standardized uptake value (SUVmean) for all tumors identified in baseline 68Ga-DOTATATE and 18F-FDG PET/CT scans, respectively (95). The researchers found out that the ratio of the total uptake volumes of 68Ga-DOTATATE to 18F-FDG PET/CT scans greater than 2.0 had a higher median progression-free survival compared to that of less than 2.0 (22.0 vs 14.3 months) (95). Factoring in the genetics did not change the predictive value of this ratio (95). This shows that the tumor uptake volume ratio of 68Ga-DOTATATE to 18F-FDG PET/CT reflects underlying tumor biology and can be used as a predictive marker of treatment efficacy of 177Lu-DOTATATE (95). Similarly, combining interpretation of dual 68Ga-DOTATATE to 18F-FDG PET/CT imaging (so-called “NETPET” score) and recently discordant tumor volume on 18F-FDG PET/CT scan not observed on 68Ga-DOTATATE PET/CT scan has been found to be predictive/prognostic in neuroendocrine tumors (96-98). These findings are supported by a report of 2 patients who had marked rapid progression of metastatic paraganglioma following initial partial response to PRRT and subsequently succumbed to their disease (99). Both these patients had very high uptake on their 18F-FDG PET/CT scans as well as Ki-67 index (15% for one patient and 20%-30% for the other) (99). Furthermore, certain pathogenic variants (SDHA) may not be ideally suitable for targeted radiotherapy (17).

Similarly, 18F-FDG–based parameters have been found to be predictive biomarkers of overall survival in patients who have undergone 131I-MIBG therapy (100). A retrospective analysis of 25 patients who underwent 131I-MIBG therapy with a median follow-up of 42 months (range, 2-136 months) reported a median overall survival of 63 months (100). A high metabolic tumor volume (total tumor volume) and total lesion glucose (similar to total uptake volume, sum of product of all tumor volumes with their respective SUVmean) on 18F-FDG scans were found to be associated with poor overall survival (100).

The effects of 177Lu-DOTATATE on catecholamine levels and endocrine functions in the immediate period after administration have been recently published and described (101). In general, a noticeable increase in catecholamine levels is seen within 24 hours of 177Lu-DOTATATE administration, although this increase could likely be as early as during 177Lu-DOTATATE infusion and immediately after it is ended. While catecholamines may start decreasing around 48 hours after 177Lu-DOTATATE administration, it is unknown for how long this state of “temporarily treatment-induced” elevated catecholamine levels persist, but it is a phenomenon that can be seen often in patients treated with 177Lu-DOTATATE. In the presented patient, her normetanephrine (upper reference limit, 112 pg/mL) levels just before, 24-hour post-therapy, and 48-hour post-therapy for each of the 177Lu-DOTATATE cycles were 1787, 2529, and 2540 pg/mL for the first cycle; 2744, 2067, 2280 pg/mL for the second cycle; 1519, 1922, and 1681 pg/mL for the third cycle; and 1133, 1329, and 1091 pg/mL for the fourth cycle, respectively. It remains to be investigated whether there is any correlation among, for example, genetic background of these tumors, the size, the catecholamine type, age/sex, location of metastatic lesions, and the degree of catecholamine increase and its course in patients after 177Lu-DOTATATE administration, including their eventual clinical response. Nevertheless, as mentioned earlier, those with high tumor burden and catecholamines levels being on several antihypertensives (often difficult to control hypertension/tachyarrhythmia) are considered high-risk patients.

Furthermore, there are other identified predictive biomarkers in neuroendocrine tumors, like inflammation-based index and PRRT predictive quotient, which is a “circulating transcript assay” biomarker (102). This assay involves evaluating the expression of genes related to growth factor expression and metabolism, which was found to predict PRRT response in 97% of cases (103). Therefore, for patients identified as nonresponders based on the predictive biomarker, a strategy to optimize targeted radiotherapies or explore other therapies may be considered (102). It is important to note that this approach has not yet been validated in paragangliomas for the prediction of targeted radiotherapy response.

Local Radiotherapy for Paraganglioma

Although not the case here, some patients may present with locally aggressive or inoperable paraganglioma. Those locally aggressive paragangliomas are often found outside the head and neck region and, if hereditary, they are likely to be associated with SDHx pathogenic variants (104, 105).

Another very important group of patients who should be thoughtfully considered for local therapy are those who present with head and neck paraganglioma. Head and neck paragangliomas represent approximately 3% to 5% of all paragangliomas, and based on their anatomic location, are divided into 3 main categories, carotid, vagal, and jugulotympanic paragangliomas (for review, see (106)).

Although head and neck paragangliomas are much less often metastatic (∼10%) than other paragangliomas (23), these tumors do not produce any epinephrine; norepinephrine is produced only in less than 5% of patients, and dopamine in approximately 30% of patients (107). Therefore, patients with these tumors do not present with any symptoms and signs of catecholamines excess (note that although dopamine is produced in ∼30% of these patients, it is usually converted to 3-methoxytyramine, and neither is associated with any symptoms or signs) (107). As a result of this, these tumors usually advance locally and, since they originate along the lower cranial nerves and associated blood vessels, they tend to rapidly compress and infiltrate these key neurovascular structures and may also erode bone structures, often becoming inoperable (108). This is especially important for surgically challenging vagal paragangliomas (109, 110). Although up to approximately 25% to 55% of these tumors will not grow further after their initial discovery with a median follow-up of 51 months, favoring the “wait and scan” strategy, the major proportion of these will grow and ultimately need surgery or local or systemic radiotherapy or chemotherapy (111, 112). Furthermore, most head and neck paragangliomas are hereditary and associated with SDHx pathogenic variants that favor recurrence, multiplicity, and metastatic behavior (23, 107).

Since surgery for most vagal and some jugulotympanic head and neck paragangliomas is associated with cranial nerve deficits, local and now well-defined and established radiotherapeutic approaches are highly considered and often preferred. This is further supported by the newest clinical consensus guidelines focusing on SDHB and SDHD paragangliomas, including head and neck tumors (12, 13). Experts in these tumors strongly recommend, despite overall moderate quality of evidence in practically all recommendations, (a) a thorough examination of the cranial nerves and laryngoscopy before and after radiotherapy for patients with head and neck paragangliomas and (b) therapeutic radiation as a treatment for patients with radiologically progressive or symptomatic tumors (recommendation Nos. 10 and 15, respectively (12)). Older patients with multiple comorbidities or highly complex tumors that would require high-risk surgery leading to cranial nerve palsies (eg, vagus nerve involvement and contralateral lower cranial neuropathies) should be strong candidates for primary therapeutic radiation (recommendation No. 15 (12)). Furthermore, (c) therapeutic radiation should be considered on postsurgical residual and recurrent head and neck paragangliomas (recommendation No. 16 (12)). Stereotactic radiosurgery has been recommended as the primary or complementary treatment for surgical resection of small tumors (ie, maximum diameter <3 cm), and conventional radiotherapy could be recommended for patients with larger tumors (recommendation No. 17, high quality of evidence (12)). Furthermore, since also some non–head and neck paragangliomas cannot be completely surgically resected or behave as locally aggressive or recur less than 6 months after surgery, experts also suggest considering therapeutic radiation for patients with symptomatic or progressive chest, abdomen, or pelvis paragangliomas (recommendation No. 18, low quality of evidence (12)).

Currently external beam radiotherapy related to head and neck paragangliomas is either stereotactic radiosurgery (SRS) delivering a large dose of radiation on a single day, or stereotactic body radiation therapy delivering radiation over multiple days (fractionated treatment schedule), and intensity-modulated radiation therapy (IMRT) using smaller daily doses over several weeks. The newly developed proton beam radiation or radiosurgery is another promising therapeutic modality for these tumors (113). These therapeutic modalities can be modified using hypofractionated doses, especially for those patients with contralateral lower cranial neuropathies or multifocal/bilateral paragangliomas wrapping around cranial nerves since lower radiation doses result in lower cranial nerve damage (for review, see (106)).

SRS uses either Gamma Knife (multiple radiation beams delivered simultaneously to a tumor using static images taken in advance of treatment and therefore not updated in real-time and cannot take into account movement during normal breathing) or CyberKnife (a single high-energy photon beam delivered from various angles to a tumor that can move with normal breathing since this technology uses real-time imagining), both suitable for small to medium size paragangliomas (usually with a maximum diameter < 3 cm or volume < 4 cm3) (114-117). For both modalities, usually 1 to 5 fractions are used. Compared to IMRT, SRS can deliver larger irradiation doses with extremely precise, submillimeter accuracy of a target lesion, therefore minimizing irradiation damage to tumor surrounding structures and having very a low risk of irradiation-induced malignancy. Most studies using these radiation modalities include jugular and less frequently vagal paragangliomas. Overall, they show tumor growth stabilization of 88% to 100% (in 20% or less tumor shrinkage was noted) over 5 years or more (118-120). A long-term series of jugular paragangliomas treated with SRS showed a 7-year progression-free survival of 97% in patients with grade 1 and 2 toxicities in 7.7% of patients (121). Efficacy of IMRT for head and neck paragangliomas described in several studies or reviews also showed a high tumor control rate of approximately 93% (122). The most recent study using proton beam therapy for 17 patients with glomus jugulare paraganglioma showed tumor stabilization/regression in all patients with limited toxicity (nausea, headache, alopecia, dermatitis, otitis, hearing loss) (113). The advantage of this therapy is that there is no tumor size limit and thus all tumors may be irradiated.

These data suggest that irradiating head and neck paragangliomas, especially nowadays using very precise techniques with minimal damage to adjacent tissues, provides an excellent alternative to surgery, especially in patients with vagal and jugulotympanic paragangliomas. Nevertheless, it should be noted that data related to long-term effects of external beam radiation on head and neck paragangliomas (usually beyond 5 years) are still limited. There are also no data related to irradiation outcomes of hereditary and nonhereditary tumors, the use of (neo)adjuvant radiotherapy, and long-term comorbidities. Furthermore, in head and neck paraganglioma patients who have progressed (clinically or radiographically) despite surgery or local radiotherapy, a trial of cold somatostatin analogues (octreotide, lanreotide) for 68Ga-DOTATATE–positive paraganglioma should be attempted before systemic radiotherapy/chemotherapy, due to its low side effect profile (123, 124) (Fig. 11). Currently a phase 2 clinical trial evaluating lanreotide in unresectable or metastatic pheochromocytoma/paraganglioma is ongoing (LAMPARA, NCT03946527).

Figure 11.

Figure 11.

Successful long-term control of a pterygopalatine fossa paraganglioma using cold somatostatin analogue. This figure displays baseline and follow-up imaging of a 42-year-old woman with an unresectable pterygopalatine fossa paraganglioma associated with a germline pathogenic variant in the succinate dehydrogenase subunit B (SDHB) gene at the NIH. Five years ago, she presented with headaches and blurred vision, leading to the discovery of an enhancing left pterygopalatine fossa mass on magnetic resonance imaging (MRI). Surgical debulking of the mass was only partially successful due to significant bleeding, resulting in 15% to 20% mass resection. Histopathological analysis revealed a paraganglioma. Over the following 2 years, she remained asymptomatic, and surveillance MRIs indicated stable disease. However, she later experienced severe headaches and migraines, accompanied by an increase in the mass's size on MRI. She underwent external beam radiation therapy (5040 cGy), which initially improved her symptoms. However, 8 months after radiotherapy, despite the mass maintaining its size on MRI, she developed intermittent, dull, left retrobulbar pain, blurred vision, and headaches. She subsequently presented to the NIH for evaluation and an optimal management plan. Panel A (A-D) displays baseline imaging at the NIH with sagittal (A) and axial (B) contrast-enhanced T1-weighted MRI (CE-MRI) showing a heterogeneously enhancing irregularly shaped mass (dotted boundary, A and arrow, B) in the left pterygopalatine fossa extending into the left orbit, pterygopalatine canal, and middle cranial fossa. Further, displacement of the globe, optic nerve, and extraocular muscles by the mass, and extension of the mass into the left middle cranial fossa and left cavernous sinus via erosion of the sphenoid bone. The whole-body planar anterior (C) image of 123I-MIBG single photon emission computed tomography/computed tomography (SPECT/CT) of the patient was negative, ruling out targeted radiotherapy with 131I-MIBG. However, the whole-body maximal intensity projection (MIP) 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scan shows high uptake of 68Ga-DOTATATE by the lesion without any evidence of metastasis. The therapeutic options available to her were either chemotherapy or targeted radiotherapy with 177Lu-DOTATATE. However, 177Lu-DOTATATE was not available in the United States for paraganglioma patients at that time. Therefore, she was left with the only option of chemotherapy for symptomatic control and possibly reduction in the size of the tumor. Based on the 68Ga-DOTATATE positivity, it was decided to give her a trial of a cold somatostatin analogue due to its safety profile and limited toxicity. She started on monthly intramuscular injections of 20 mg octreotide. Panel B (E-Y) consists of baseline (E, axial CE-MRI; L, fused axial fused 68Ga-DOTATATE PET/CT; and S, axial fused 18F-FDG PET/CT) and follow-up imaging with CE-MRI (F-K, axial), 68Ga-DOTATATE (M-R, axial fused PET/CT), and 18F-FDG (T-Y, axial fused PET/CT) after 6, 12, 18, 29, 36, and 82 months of octreotide administrations, demonstrating a lack of growth (F-K) on MRI and stable maximum standardized uptake values (SUVmax) of the mass on 68Ga-DOTATATE (M-R) and 18F-FDG (T-Y). Clinically, the patient has reported dramatic improvement in the stabbing eye sensation and accompanying headaches. This case has been published as a case report (123). Furthermore, this case supports recommendation numbers 20 and 21 (15). R20. We recommend local or systemic therapy for symptomatic patients in whom surgery is not possible. R21. We suggest selecting on an individual and personalized basis the currently most appropriate local therapy based on tumor localization/behavior, institutional expertise, patient's general condition, and the patient’s preference) (16).

Back to the Patient

This patient so far has responded well to the 177Lu-DOTATATE therapy and is receiving follow-up every 6 months at the NIH. She is currently on active surveillance and continues to be monitored for any adverse events. If she progresses, she can undergo either retreatment with 177Lu-DOTATATE (Fig. 12) or targeted α radiotherapy with 225Ac/212Pb-based PRRT. Moreover, she could also consider other systemic chemotherapies (eg, CVD, temozolomide, tyrosine kinase inhibitors, or enrollment in a phase 2 trial investigating olaparib, a poly adenosine diphosphate ribose polymerase [PARP] inhibitor [PARPi, NCT04394858]).

Figure 12.

Figure 12.

Retreatment with 177Lu-DOTATATE in a metastatic pheochromocytoma patient. The figure shows a 57-year-old man with a history of resection of a 13-cm right pheochromocytoma with widespread metastatic lesions in the lungs, liver, and bones who underwent 8 cycles of 177Lu-DOTATATE. The patient tested negative for any germline pathogenic variant in paraganglioma susceptibility genes. Panel A shows pretherapy, post-therapy, and follow-up imaging scans at various time points after 4 cycles of 177Lu-DOTATATE therapy. The whole-body pretherapy (baseline) anterior maximum intensity projection (MIP) image of 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) (A), 24- or 48-hour post-therapy whole-body anterior planar single photon emission computed tomography/computed tomography (SPECT/CT) images after 4 cycles of 200 mCi (7.4 GBq) of 177Lu-DOTATATE (B-E) performed 3 months (B), 5 months (C), 7 months (D), and 8 months (E) after baseline (pretherapy) 68Ga-DOTATATE PET/CT scan (A) shows good uptake in most of the metastatic lesions. The follow-up 68Ga-DOTATATE PET/CT (F-K) scans were performed at 7 months (F), 13 months (G), 18 months (H), 25 months (I), 30 months (J), and 35 months (K) after cycle 1 of 177Lu-DOTATATE therapy. Per RECIST 1.1, the patient partially responded to initial 4 cycles of 177Lu-DOTATATE and achieved a progression-free survival of 38 months (in March 2021) and a maximum reduction of 39.3% in diametric sum of target lesions per RECIST 1.1 after 35 months. Of note, the patient achieved an approximately 30% reduction in the diametric sum of target lesions per RECIST 1.1 after 18 months, showing that antitumoral effects take time to achieve and are sustained for a long-time duration. There were no adverse events or complications reported. The patient progressed due to development of new and growth of multiple nontarget lesions. Subsequently, the patient decided to enroll in the retreatment arm of 177Lu-DOTATATE clinical trial at the NIH over chemotherapy due to negligible side effects and improved quality of life during and follow-up after 4 cycles of 177Lu-DOTATATE therapy. Panel B shows pretherapy, post-therapy, and follow-up imaging scans at various time points after repeating 4 cycles (cycles 5-8) of 177Lu-DOTATATE therapy. For retreatment 177Lu-DOTATATE arm, the pretherapy baseline MIP image of 68Ga-DOTATATE PET/CT (L), 24- or 48-hour post-therapy anterior planar SPECT/CT images after 200 mCi (7.4 GBq) of 177Lu-DOTATATE (M, N, P, Q) performed 4 months (M), 6 months (N), 8 months (P), and 10 months (Q) after baseline (pretherapy) 68Ga-DOTATATE PET/CT (L) scan. The 68Ga-DOTATATE PET/CT (L) scan showed good uptake in most of the metastatic lesions. The follow-up 68Ga-DOTATATE PET/CT (O and R-V) was performed 3 months (O), 7 months (R), 13 months (S), 19 months (T), 24 months (U), and 29 months (V) after cycle 5 of 177Lu-DOTATATE therapy, and the numbers in parentheses (42, 46, 52, 58, 63, and 68) are months after cycle 1 of 177Lu-DOTATATE therapy. The patient was classified as stable disease per RECIST 1.1 after retreatment with 177Lu-DOTATATE (cycles 5-8) and achieved a progression-free survival of 27 months and a 16.4% maximal reduction in the diametric sum of target lesions per RECIST 1.1 after 10 months of cycle 5 of 177Lu-DOTATATE begun. There were no adverse events or complications reported. The patient progressed due to development of new and growth of multiple nontarget lesions.

Perspectives and Conclusions

The field of theranostics is seeing exciting times with the evaluation of novel radiopharmaceuticals, identification of targets, approaches, and optimization of existing targeted radiotherapies.

Recently, a study in 9 patients of metastatic paragangliomas (7 patients received prior 177Lu-DOTATATE and 3 out of 7 patients failed prior 177Lu-DOTATATE) treated with 225Ac-DOTATATE (α-particle–based radiotherapy targeting SSTRs) and concomitant capecitabine showed a high partial response of 50% (compared to < 25% with β-particle–targeted radiotherapies) and stable disease in 37.5% with a disease control rate of 87.5%, without any grade 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity (70) demonstrating that α-particle–based targeted radiotherapy is safe and effective in metastatic paragangliomas, and offers an alternative to patients refractory to 177Lu-DOTATATE. More recently, data from a phase 1 trial using 212Pb-DOTAMTATE as an in vivo generator of α-particles has shown an objective response rate of 80% in neuroendocrine tumors (no paragangliomas) and no serious treatment-emergent adverse events (125). Based on this study, 212Pb-DOTAMTATE was accorded FDA approval under breakthrough therapy designation for PRRT-naive gastroenteropancreatic neuroendocrine tumors in 2024. 211At-meta-astatobenzylguanidine (211At-MABG, an α-emitter targeting NET), has biologic properties comparable with 131I-MIBG (126). In preclinical studies, powerful antitumor effects and tolerable toxicity have been demonstrated in nude mice bearing PCC xenograft tumors (127, 128). Recently, a clinical trial is ongoing in Japan to fill in the lack of in-human investigations (126).

SSTR antagonists (68Ga/177Lu-DOTA-NODAGA-LM3 or 68Ga/177Lu-DOTA-LM3)-based theranostics are characterized by a strong binding capacity to SSTR but without cellular internalization, and suggest a higher efficacy than SSTR agonists that undergo cellular internalization and have weaker SSTR binding (129). The therapeutic efficacy of antagonist-based SSTR currently suffers from higher hematotoxicity and needs to be further optimized (129). Furthermore, radiolabeling α-emitters with SSTR may provide a joint benefit from the biophysical properties of both offering potential therapeutic advantages even in patients refractory to treatment with conventional PRRT as well as in patients having multiple liver metastases, and in poorly differentiated patients (129).

131I-IPA (LAT-1–based therapeutic radiopharmaceutical) is currently being investigated in a multicentric, open-label phase 1/2 clinical trial (NCT03849105) in patients with recurrent glioblastoma multiforme, and the results of this study would make a stronger case for the treatment of LAT-1–expressing paragangliomas evaluated by 18F-FDOPA.

Furthermore, there is a small subset of patients who are less likely to respond to current targeted radiotherapies. It is important to preidentify and predict these patients (using methods such as 18F-FDG, Ki-67 index, molecular, or liquid biomarkers) so that efforts can be made to optimize targeted radiotherapies and improve patients’ outcomes (102). Such strategies include but are not limited to potentiating effects of targeted radiotherapy (chemo-PRRT, PARPi), increasing absorbed tumor dose (tumor dosimetry, intra-arterial administrations [especially in patients having high liver tumor burden and poor bone marrow reserve], Evans blue dye modification of PRRT, SSTR antagonists), overcoming radioresistance and hypoxic tumors (α-particle–based radiotherapy, combination of radioisotopes targeting different tumor sizes), and SSTR upregulation (valproic acid, a histone deacetylase inhibitor [HDACi], and 5-aza2'-deoxycytidine [5-aza-dC], a DNA methyltransferase inhibitor [DNMTi] 5-aza2'-deoxycytidine [5-aza-dC]) (102).

Last but not the least, radiomics and artificial intelligence–based algorithms have been applied in paragangliomas but are still at a nascent stage. However, they have tremendous potential to predict response and toxicity, thereby assisting in tailoring of targeted radiotherapies to the patients (9).

Currently, 131I-MIBG and PRRT (90Y/177Lu-DOTA-TATE/TOC) are two targeted radiotherapies that have demonstrated safety and efficacy with acceptable toxicity in metastatic paragangliomas. The decision-making process for selecting targeted radiotherapies should be personalized. Due to the absence of randomized controlled studies comparing these two targeted radiotherapies, we recommend a stepwise approach based on the results of 123I-MIBG scintigraphy and SSTR PET/CT. Priority should be given to the agent with the highest uptake, focusing primarily on the uptake of visceral metastases (lungs and liver) rather than in bones and lymph nodes as well as tumors showing growth. If the uptake in these two scans is similar, factors related to the patient and the tumor, as well as relevant risk factors (including age, bone marrow reserve, prior cytotoxic therapies, catecholamine/metanephrine secretion, tumor burden, tumor growth, location and size of tumors, avidity of visceral metastases, and tumor heterogeneity) and predictive factors (high Ki-67 index and high 18F-FDG tumor uptake) should be taken into consideration. Additionally, other practical considerations related to treatment facility availability, insurance coverage, and clinical experience can affect the selection process. Further, multicentric randomized controlled trials comparing PRRT and 131I-MIBG therapy in progressive inoperable/metastatic paraganglioma patients should be planned to help us make informed, evidence-based decisions.

Finally, no theranostic agent can succeed in the clinic unless it receives support from regulatory and reimbursement agencies. These two agencies will need to coordinate their “requirements” to ensure that safety, efficacy, and payment processes are streamlined without major delays, enabling patients to benefit from these scientific innovations (130). Otherwise, we may see similar situations to what happened with the fate of Azedra®.

Acknowledgments

The authors want to thank Alan Hoofring from the Arts Department, NIH, for the assistance with Figures 4 through 6. Figure 10 was created using Biorender.com

Abbreviations

CR, complete response; 18F-FDOPA

18F-fluorodopa

68Ga-DOTATATE

68Ga-DOTA(0)-Tyr(3)-octreotate

131I-IPA

131I-iodophenylalanine

123I-MIBG

123I-metaiodobenzylguanidine

18F-FDG

18F-fluorodeoxyglucose

CT

computed tomography

CVD

cyclophosphamide, vincristine, and dacarbazine

FDA

Food and Drug Administration

IMRT

intensity-modulated radiation therapy

IVC

inferior vena cava

LAT

L-type amino acid transporter

MN

metanephrine

NET

norepinephrine transporter

NIH

National Institutes of Health

NMN

normetanephrine

PARP

poly adenosine diphosphate ribose polymerase

PET

positron emission tomography

PR

partial response

PRRT

peptide receptor radionuclide therapy

SD, stable disease; SDHx

succinate dehydrogenase subunit gene

SPECT, single photon emission computed tomography; SRS

stereotactic radiosurgery

SSTR

somatostatin receptor

SUVmean

mean standardized uptake value

Contributor Information

Karel Pacak, Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892-1109, USA.

David Taieb, Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, 13385 Marseille, France.

Frank I Lin, Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Abhishek Jha, Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892-1109, USA.

Funding

This work was supported by the National Institutes of Health (NIH; grant No. Z1AHD008735 to K.P.) and the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosures

K.P., D.T., F.I.L., and A.J. have nothing to disclose. They declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. The authors’ (K.P., F.I.L., and A.J.) contribution to the work was done as part of the authors’ official duties as NIH employees and is a work of the United States government. Therefore, copyright may not be established in the United States, 17 U.S.C. § 105. If the publisher intends to disseminate the work outside the United States, the publisher may secure copyright to the extent authorized under the domestic laws of the relevant country, subject to a paid-up, nonexclusive, irrevocable worldwide license to the United States in such copyrighted work to reproduce, prepare derivative works, distribute copies to the public and perform publicly and display publicly the work, and to permit others to do so.

Data Availability

Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors on reasonable request.


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