Controversies in NEN: An ENETS position statement on the treatment of patients with Grade 3 well-differentiated neuroendocrine tumours of the gastro-enteropancreatic tract.

Grade 3 neuroendocrine tumours (NET G3) represent approximately 20% of high-grade neuroendocrine neoplasms, and the recent identification of this entity has given rise to many unanswered questions relating to clinical management. The prognosis for these patients is worse than for those with Grade 1-2 well-differentiated NET, but better than for those with Grade 3 poorly differentiated neuroendocrine carcinoma. This consensus statement aims to address some uncertainties and explore unmet needs in the management of patients with NET G3. Firstly, the role of surgery in localised disease will be discussed as well as the dilemma in relation to the use of neo-adjuvant and/or adjuvant treatment in this setting. Treatment of oligometastatic digestive NET G3 will also be examined, including the positioning of surgery and ablative therapy. In the advanced setting, traditionally, chemotherapy in the form of temozolomide/capecitabine or 5-fluorouracil-based therapies, rather than platinum/etoposide, is considered a first-line treatment option, with second-line therapy dependent on what was used first-line. More recently, following the results of the NETTER-2 trial, Peptide Receptor Radionuclide Therapy with Lu-DOTATATE may be an option for selected patients with somatostatin receptor positive NET G3. There is limited data on the use of immunotherapy and targeted therapy in this disease group to date, and some available evidence will be presented. The role for re-biopsy to guide treatment decision-making in patients with digestive NET G3 and whether NET G3 outside of the digestive tract should be treated similarly will also be scrutinised. Prospective studies with translational end-points are required to enable a better understanding of this diagnosis and to facilitate more optimal treatment discoveries.