Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups

Abstract

In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT’s antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high‐specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.

Clinical Perspectives of Theranostics

“…Iodine-131-meta-iodobenzylguanidine (I-131 MIBG) is a substrate of the norepinephrine transporter system and the structure is similar to norepinephrine [ 34 ]. Norepinephrine works as a neurotransmitter in the central and autonomic nervous systems.…”

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma

“…These analogs have been labeled with indium ( 111 In), gallium ( 68 Ga), yttrium ( 90 Y), and lutetium ( 177 Lu) and have been used extensively in the detection and therapy of a variety of neuroendocrine tumors [88]. A meta-analysis of studies involving advanced/ metastatic PHEO/PGL patients treated with PRRT showed that 89.8% of pooled patients had achieved disease stabilization or a partial response [31]. Menda et al treated 17 children with neuroendocrine tumors with 90 Y DOTATOC [89] including 2 patients with neuroblastoma and three with PGL.…”

“…Biochemical testing is based on the continuous production of catecholamines and their metabolites are called metanephrines [ 6 , 30 ]. Imaging procedures include anatomical and functional techniques [ 31 , 32 ]. Ga-68 DOTATATE and other diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of PHEO/PGL and an attempt has further been made to characterize the radionuclide of choice across the genotypes [ 31 , 32 ] (Fig.…”

Case Report: Primary Hypothyroidism Associated With Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma

“…Additionally, this agent has demonstrated substantial safety and efficacy based on data from 1200 patients treated for gastroenteropancreatic and bronchial NETs ( 5 ). 177 Lu-DOTATATE has also been effectively utilized in the treatment of inoperable, metastatic pheochromocytomas and paragangliomas (PPGLs) ( 6 , 7 ). 177 Lu radionuclide exerts its anti-tumor effects by emitting medium energy beta particles and has a maximal tissue penetration of 2 mm ( 8 ).…”

“…177 Lu-DOTATATE therapy is associated with several adverse effects, with nausea and vomiting being the most common adverse effects. Other adverse effects include fatigue/asthenia, abdominal pain, diarrhea, loss of appetite, musculoskeletal pain, headaches, flushing, dizziness, alopecia, cough, nephrotoxicity, hematotoxicity (leukopenia, thrombocytopenia, and lymphopenia), cardiotoxicity, hepatotoxicity, and acute hypertensive crisis ( 2 , 7 ). 177 Lu-DOTATATE therapy has also been associated with the disruption of endocrine function, although these effects are extremely rare and is often transient ( 9 ).…”