Rethinking treatment sequence in advanced gastroenteropancreatic neuroendocrine tumours
Affiliations & Notes
Pancreas and Transplant Surgery Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, 20132, Italy
Article Info
Publication History:
Published July 2, 2026
DOI: 10.1016/S0140-6736(26)01080-9 External LinkAlso available on ScienceDirect External Link
Copyright: © 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Linked Articles
Treatment sequencing in advanced gastroenteropancreatic neuroendocrine tumours (GEP-NETs) remains a major unmet clinical need.1 Although somatostatin receptor-positive, well differentiated GEP-NETs often follow a somewhat indolent course, disease progression eventually requires treatment decisions that balance tumour control, toxicity, quality of life, and the preservation of future therapeutic options.
References
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Pavel, M ∙ Öberg, K ∙ Falconi, M ∙ et al.
Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol. 2020; 31:844-860
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Strosberg, J ∙ El-Haddad, G ∙ Wolin, E ∙ et al.
Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors
N Engl J Med. 2017; 376:125-135
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Singh, S ∙ Halperin, D ∙ Myrehaug, S ∙ et al., NETTER-2 Trial Investigators
[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study
Lancet. 2024; 403:2807-2817
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[177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial
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Facts Only
* Gastroenteropancreatic neuroendocrine neoplasms present a major unmet clinical need regarding treatment sequencing.
* Somatostatin receptor-positive, well-differentiated GEP-NETs often follow an indolent course.
* A Phase 3 trial (NETTER-2) compared [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for newly diagnosed, advanced grade 2–3, well-differentiated GEP-NETs.
* A Phase 3 trial (COMPETE) compared [177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours.
* A Phase 3 trial (RADIANT-4) compared everolimus for advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract.
* A Phase 3 trial (NETTER-1) compared [177Lu]Dotatate plus long-acting octreotide versus high-dose long-acting octreotide for midgut neuroendocrine tumours.
* The article references published data from 2020, 2021, 2022, and planned publications in 2026.
Executive Summary
Full Take
The trajectory observed across the cited literature points toward a sophisticated decision-making landscape where prognostic indolence must interact with the risks and benefits of targeted therapies like peptide receptor radionuclide therapy (PRRT) and mTOR inhibitors (everolimus). The shift in focus from single endpoints to sequencing—balancing immediate control against long-term preservation of options—suggests a move away from monolithic treatment protocols toward personalized trajectories for GEP-NET management. A key tension exists between managing the progression inherent in advanced disease and mitigating systemic toxicity while maintaining patient quality of life, especially when considering options like [177Lu]ligand therapy versus targeted hormonal blockade or mTOR inhibition. The pattern suggests that clinical practice must evolve to integrate outcomes from trials investigating different combinations of radionuclide delivery and endocrine modulation across various anatomical sites (midgut vs. pancreatic). This evolution implies a recognition that the optimal sequence is context-dependent, potentially influenced by tumor differentiation grade and functional status.
Bridge Questions: How do long-term follow-up data inform the sequencing decisions when initial responses vary? What are the established thresholds for accepting toxicity versus survival benefits in indolent disease states? What mechanisms drive the differential response to PRRT versus systemic agents in these heterogeneous tumors?