Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.

Background: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [¹⁷⁷Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of ¹⁷⁷Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). Results: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7–not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8–28.1) in pancreatic, and 17.6 months (14.4–33.1) in bronchopulmonary NENs. [¹⁷⁷Lu]Lu-DOTATATE exhibited scant severe toxicity. Conclusion: This study confirms the efficacy and safety of [¹⁷⁷Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Peptide receptor radionuclide therapy (PRRT) has become a cornerstone in the management of neuroendocrine tumors (NETs), yet optimal sequencing and patient selection remain unsettled. This study aimed to develop and internally validate the NEPTUNE score to predict progression-free survival (PFS) in advanced NETs patients receiving [¹⁷⁷Lu]Lu-DOTATATE. Real-world data from the nationwide SEPTRALU registry and the Jules Bordet Institute included patients with advanced NETs treated with [¹⁷⁷Lu]Lu-DOTATATE. Predictors of PFS were identified using an accelerated failure time model and combined into the NEPTUNE score. Internal validation was performed using bootstrap resampling. This tool was subsequently transformed into a nomogram and an interactive web-based calculator to enhance its integration into routine clinical practice. The cohort comprised 647 patients with diverse NET subtypes: pancreatic (39%), midgut (30%), bronchopulmonary (9%), pheochromocytoma/paraganglioma (3%), other gastroenteropancreatic (11%), and other non-gastroenteropancreatic (8%). The NEPTUNE score incorporates ten routinely available variables: ECOG performance status, PRRT line, Ki67 index, number of metastatic sites, primary tumor site, sex, Krenning grade, surgical resection of metastases, presence of liver metastases, and time from advanced tumor diagnosis to PRRT. The score demonstrated strong performance, with an Integrated Brier Score (IBS) of 0.201 and a bias-corrected C-index of 0.702, indicating good calibration and discrimination. The NEPTUNE score is a promising tool for predicting individual PFS in patients with advanced NETs treated with [¹⁷⁷Lu]Lu-DOTATATE. By integrating readily available clinical variables, it may support clinical decision-making. However, external validation is required before broader clinical implementation.