Radioligand therapy reshapes treatment outlook for rare adrenal nerve tumors

Rare tumors of the adrenal medulla and related nerve tissue called pheochromocytomas and paragangliomas, collectively PPGL, have long posed a treatment dilemma: when they spread or keep growing despite surgery, options are scarce. A new review now maps out where radioligand therapy stands today and where it is heading, arguing that targeted radioactive drugs are moving from last-resort salvage treatment toward an integral component of precision medicine for these cancers.

The review, published in EJNMMI Reports by researchers including S. Pacella and M. Maccauro, synthesizes literature on radioligand therapy in PPGL updated through August 2024. The authors searched PubMed, Scopus, and Web of Science and found the evidence base dominated by small retrospective studies and a limited number of prospective cohorts. Because of wide heterogeneity in study design, protocols, and outcome measures, a meta-analysis was not feasible, and the team explicitly notes that no formal risk-of-bias assessment was performed, so the strength of the evidence should be interpreted with caution.

PPGL arise from chromaffin cells of the adrenal medulla or from extra-adrenal sympathetic and parasympathetic paraganglia. Their estimated annual incidence is one to four cases per million, with pheochromocytomas accounting for most diagnoses. Extra-adrenal paragangliomas occur predominantly in the abdomen, while head and neck paragangliomas are the most frequent parasympathetic subtype. Clinical presentation ranges from catecholamine-related symptoms to mass-effect manifestations, and malignancy cannot be reliably predicted from histology; the presence of metastases remains the only definitive criterion of malignancy. Up to 40 percent of PPGL harbor germline mutations, which influence tumor behavior, imaging characteristics, and therapeutic responsiveness.

Radioligand therapy exploits tumor-specific molecular targets to deliver cytotoxic radiation. Two radiopharmaceuticals form the current backbone: iodine-131 labeled meta-iodobenzylguanidine, or [131I]mIBG, which targets tumors expressing norepinephrine transporters, and lutetium-177 labeled DOTATATE, a somatostatin receptor-targeted peptide receptor radionuclide therapy known as PRRT. Roughly 50 to 60 percent of paragangliomas express norepinephrine receptors on their membranes, while more than 80 percent of neuroendocrine tumors overexpress the somatostatin type 2 receptor that DOTATATE binds with high affinity. Before treatment, candidates undergo diagnostic imaging with 123I-MIBG or gallium-68 DOTA-peptide PET/CT, the latter having largely replaced scintigraphy with radiolabeled somatostatin analogs.

The two therapies differ markedly in protocol. 131I-MIBG, introduced in the 1980s, is administered with activities routinely ranging from 3.7 to 11.2 GBq per cycle, with cumulative activities up to 37 GBq and intervals of three to six months between cycles. Iodine-131 emits beta radiation with an average tissue penetration of 0.5 millimeters, and it is eliminated mainly through the urinary tract. By contrast, the 177Lu-DOTATATE protocol is nearly homogeneous, based on the regimen established for gastrointestinal neuroendocrine tumors: four cycles of 7.4 GBq each, spaced eight to ten weeks apart, with amino acid infusions of lysine and arginine given to protect the kidneys. Eligibility criteria for both include adequate performance status, bone marrow reserve, and renal function, with pregnancy and lactation as absolute contraindications.

On efficacy, the review reports that PRRT with 177Lu-DOTATATE or yttrium-90 DOTATOC consistently achieves disease control rates between 70 and 90 percent across multiple cohorts, with median progression-free survival ranging from 21 to 39 months. In a large single-center experience, PRRT achieved progression-free survival of 68 percent at five years and 53 percent at ten years, with durable disease stabilization in most patients. One study reported a median progression-free survival of 25.9 months in metastatic functioning paragangliomas, with 63.6 percent disease stabilization. PRRT appeared particularly effective in head and neck paragangliomas, where one group observed 100 percent disease stabilization and symptom improvement, and in pheochromocytomas, where higher progression-free survival was reported compared with mIBG.

Evidence for 131I-MIBG is more fragmented, reflecting variability in cumulative administered activity of 7.4 to 39.4 GBq, cycle numbers from one to twelve, and inconsistent imaging-based selection criteria. Despite this, mIBG achieves disease control rates of 60 to 70 percent in most series, with median progression-free survival of 12 to 32 months. In one systematic review, mIBG-treated patients showed a median progression-free survival of 25.4 months and lower progression-free survival than PRRT in regression models. Only a few studies directly compare the two modalities, but those that do report significantly longer progression-free survival and higher response rates with PRRT, although overall survival did not differ significantly in one analysis. The authors conclude that PRRT may offer superior disease control in patients with high somatostatin receptor expression, while mIBG remains appropriate for tumors with strong norepinephrine transporter uptake.

Safety profiles for both agents are favorable, with most adverse events mild and transient. With mIBG, nausea and vomiting dominate the first 24 hours, and temporary myelosuppression typically appears four to six weeks after therapy, more often in patients with extensive bone marrow involvement or prior chemotherapy. With PRRT, acute effects stem mainly from the amino acid infusion and include nausea, headache, and abdominal pain; transient thrombocytopenia or leukopenia occurs in 10 to 20 percent of patients, with severe grade 3 to 4 hematologic toxicity in roughly 2 to 3 percent. Rare cases of myelodysplastic syndrome and acute myeloid leukemia have been described after PRRT, at an estimated incidence below 2 percent, particularly in patients over 70, those previously treated with alkylating agents, and those with extensive marrow involvement. Renal toxicity is rare when amino acid infusion is used, and long-term marrow toxicity in PPGL remains insufficiently characterized.

Beyond the two established agents, the review highlights imaging discordance as a central challenge: some tumors are mIBG-negative yet somatostatin receptor-positive, making them strong PRRT candidates, while FDG-positive, somatostatin receptor-low lesions suggest dedifferentiation, more aggressive behavior, shorter progression-free survival, and reduced response to both conventional agents. This heterogeneity, linked in part to SDHB-related biology, underscores the need for multimodal functional imaging combining somatostatin receptor PET, mIBG scintigraphy, and FDG PET before selecting a radioligand. Guideline positioning reflects this individualized philosophy: the 2020 ESMO-EURACAN guidelines recommend an individualized approach including radioligand therapy for progressive disease without defining a preferred sequence between mIBG and PRRT, while EANM/SNMMI procedure guidelines provide operational standards, noting that PRRT use in PPGL remains off-label but supported by growing evidence.

Looking forward, the authors identify targeted alpha therapy as the most promising frontier. The leading candidate, actinium-225 labeled DOTATATE, has shown encouraging results even in patients previously treated with beta-emitter PRRT, with one recent study reporting a 66.6 percent morphologic disease control rate and high symptomatic response in patients refractory to 177Lu-PRRT, though the evidence is limited by small samples and short follow-up. Other investigational avenues include combination strategies with PARP, ATR, and DNA-PK inhibitors, which are biologically rational in SDHB-mutated tumors with defective DNA repair; pairing radioligand therapy with immune checkpoint inhibitors based on early preclinical data; and novel theranostic targets such as FAP, CXCR4, GRPR, and somatostatin receptor antagonists. Advances in voxel-based dosimetry from quantitative SPECT/CT and PET/CT may eventually allow individualized dosing that reduces marrow and renal toxicity while escalating tumor dose. The authors stress that prospective, multicenter, genotype-stratified trials remain essential to define optimal sequencing, long-term safety, and the integration of these therapies into routine clinical practice.

Subject of Research: Radioligand therapy options and future directions for pheochromocytomas and paragangliomas

Article Title: Future scenarios of radioligand therapy in pheochromocytomas and paragangliomas

Article References: Pacella, S., Elisei, F., Mattoli, M. V., Airò Farulla, L. S., Aliberti, G., Rizzo, A., & Maccauro, M. (2026). Future scenarios of radioligand therapy in pheochromocytomas and paragangliomas. EJNMMI Reports, 10(1), Article 38. https://doi.org/10.1186/s41824-026-00318-3

Image Credits: AI Generated

DOI: 10.1186/s41824-026-00318-3

Keywords: pheochromocytoma, paraganglioma, radioligand therapy, 177Lu-DOTATATE, 131I-mIBG, peptide receptor radionuclide therapy, alpha emitter therapy, somatostatin receptors, nuclear medicine, metastatic neuroendocrine tumors, theranostics, dosimetry