Prognostic value, clinical relevance, and methodological gaps of tumor burden in neuroendocrine tumors (NETs): a systematic review of phase III randomized trials of medical therapies

Background: The prognosis of neuroendocrine neoplasms (NENs) is traditionally driven by tumor grade, primary site, hormonal functionality, and disease staging; however, emerging evidence identifies tumor burden-encompassing the size, number, and anatomical spread of lesions-as an independent determinant of outcome. Despite its clinical relevance, tumor burden lacks a standardized definition across studies, with criteria ranging from liver involvement thresholds to metastatic site counts, extrahepatic spread, or surrogate biochemical markers, limiting cross-study comparability. Methods: A comprehensive search on PubMed and ClinicalTrials.gov updated until June 2025 was conducted with the objective of investigating phase III trials on medical therapeutic options (chemotherapy, targeted therapy, somatostatin analogue, peptide receptor radionuclide therapy) for advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), thoracic, and unknown primary site origin in order to highlight the definition and application of tumor burden in well-differentiated NETs. Results: After the screening process, a total of 23 completed and published phase III trials and 10 ongoing recruiting/not yet recruiting phase III trials were included in the final analysis. Our findings uncovered several critical issues regarding tumor burden staging, definition, and ethical implications. Conclusions: Harmonization of tumor burden definitions and integration into trial stratification frameworks are necessary to refine prognostic models, improve treatment evaluation in NETs, and ensure equity in care access.