Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms derived from neuroendocrine cells, most commonly located in gastrointestinal tract, pancreas, bronchopulmonary system, thymus, and adrenal or extra-adrenal paraganglionic tissue (pheochromocytomas and paragangliomas) [1]. According to the 2022 World Health Organization (WHO) classification, NETs are defined as well-differentiated epithelial neoplasms stratified into three grades (G1–G3) based on mitotic count and Ki-67 index, with location-specific cut-offs. By contrast, neuroendocrine carcinomas (NECs) are poorly differentiated neoplasms classified as grade 3 and subdivided into small-cell and large-cell types [2].

From a functional perspective, NETs are classified as functioning or non-functioning depending on the presence of hormone-related symptoms. Functioning NETs can cause distinct clinical syndromes with a significant impact on quality of life, whereas non-functioning tumors are often diagnosed in advanced stages due to mass effect or metastatic disease [3].

Management of NETs is complex due to their biological heterogeneity, variable clinical behavior, and differences in grade, site, and disease extent [4]. Surgical resection remains the treatment of choice in localized stages, as it offers the potential for long-term disease control. However, many patients are diagnosed with unresectable or metastatic disease, requiring systemic therapy and individualized management [5]. Given the diversity of clinical scenarios, treatment decisions should ideally be guided by a multidisciplinary tumor board with expertise in neuroendocrine neoplasms.

Somatostatin analogs (SSAs) are the standard first-line treatment for well-differentiated NETs with somatostatin receptor (SSTR) expression, providing anti-proliferative effects and control of hormone-related symptoms in functioning tumors [6, 7]. The high prevalence of SSTR expression—reported in more than 80% of NETs—also enables molecular imaging and supports the use of peptide receptor radionuclide therapy (PRRT) as a targeted option [8–12].

PRRT with [177Lu]Lu-DOTA-TATE has emerged as a cornerstone treatment for patients with SSTR-positive NETs. The pivotal NETTER-1 trial demonstrated a significant improvement in progression-free survival (PFS) and objective response rate (ORR) in patients with progressive mid-gut NETs previously treated with somatostatin analogs [8]. More recently, the NETTER-2 trial extended these findings by showing the benefit of PRRT in the first-line setting for grade 2–3 gastroenteropancreatic NETs (GEP-NETs), with improvements in both PFS and ORR [9]. Additional randomized evidence is becoming available from the phase III COMPETE trial—comparing [177Lu]Lu-edotreotide with everolimus in G1–G2 GEP-NETs—and from the OCCLURANDOM trial—comparing [177Lu]Lu-DOTA-TATE with sunitinib in G1–G3 pancreatic NETs—further consolidating the therapeutic role of PRRT across different clinical scenarios [10, 11].

Beyond randomized trials, large real-world series have reinforced and expanded the evidence base for PRRT. The Erasmus MC experience not only confirmed durable disease control and long-term safety but also provided valuable data in bronchopulmonary and thymic NETs, clinical settings not addressed in randomized studies [12]. Similarly, the SEPTRALU registry captured a broad spectrum of NETs in routine practice—including GEP, pulmonary, and rarer entities, such as pheochromocytomas and paragangliomas—thereby extending the applicability of PRRT beyond the classical GEP-NET population [13]. More recently, a phase II study by Lin et al. prospectively demonstrated meaningful antitumor activity of [177Lu]Lu-DOTA-TATE in progressive metastatic pheochromocytomas and paragangliomas [14].

Appropriate patient selection is critical to maximize the benefit of PRRT. Confirmation of SSTR expression by functional imaging—most commonly [68Ga]Ga-DOTA PET/CT or scintigraphy—is mandatory before treatment. In selected scenarios, particularly in higher-grade tumors, aggressive clinical behavior, or discordance between morphological and functional imaging, [18F]-FDG-PET provides complementary prognostic information and may support risk stratification, without constituting an exclusion criterion for PRRT [15, 16].

Despite the expanding evidence base, clinical practice remains heterogeneous with respect to candidate selection, imaging workflows, therapeutic sequencing, response evaluation, and follow-up. Importantly, this heterogeneity largely reflects differences in real-world workflows and clinical decision-making rather than a lack of efficacy data supporting PRRT. To address these gaps, the Galician Multidisciplinary Group on Neuroendocrine and Endocrine Tumors (GGNET) convened a Delphi panel to develop pragmatic, multidisciplinary, practice-oriented recommendations for PRRT in well-differentiated, SSTR-positive NETs—covering patient selection, treatment delivery with [177Lu]Lu-DOTA-TATE and post-treatment follow-up. The resulting statements and the algorithms are intended to harmonize practice across centers and support decision-making in routine care.

This Delphi consensus was conceived as a real-world, practice-oriented document. Rather than redefining PRRT indications or addressing investigational strategies, its primary objective was to provide operational guidance along the standard PRRT pathway—in areas where international guidelines appropriately remain non-prescriptive and where variability in daily practice persists.