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Coriat et al. clarify data about their recently published article on gastroenteropancreatic neuroendocrine carcinomas, specifically as related to the management of grade 3 neuroendocrine tumors.
We thank Fazio and Milione  for their comment on our position paper recently published in The Oncologist . As highlighted in our paper, evidence‐based medicine in response to chemotherapy is lacking, and the choice of the best therapeutic option remains a challenge. Fazio and Milione described in their letter that the main primary localization of a well‐differentiated grade 3 neuroendocrine tumor (NET G‐3) is the pancreas. They identified in their retrospective cohort that the incidence of pancreatic NET G‐3 is 42% of all NET G‐3 (10 out of 24). Similarly, in our position paper, we stressed that the main localizations of NET G‐3 are the pancreas, the stomach, and the colon.
In addition, we factually reported that there is no validated phase III study on NET G‐3 and there are no prospective data ongoing on the targeted therapy efficacy. Furthermore, we agree with their comment that in “low” NET G‐3, the proven efficacy of targeted therapy should be evaluated and that in some cases such therapy, either everolimus or sunitinib, should be considered. Fazio and Milione believe that somatostatin receptor‐targeted treatments might have a therapeutic efficacy in NET G‐3. In 2016, the NETTER‐1 phase III study validated the efficacy of the 177Lu‐DOTA0‐Tyr3‐Octreotate (Lutathera, Advanced Accelerator Applications, Saint‐Genis‐Pouilly, France) in patients with inoperable, progressive, somatostatin receptor‐positive midgut grade 1–2 neuroendocrine tumor. The NETTER‐1 study presented as an inclusion criterion patients with a Ki‐67 level below 20. No data on the “aggressive” grade 2 NET subgroup treated in the NETTER‐1 study that helped to propose 177Lu‐DOTA0‐Tyr3‐Octreotate in NET G‐3 have been published. Moreover, it has been reported that patients with pancreatic tumors had higher rates of positive somatostatin receptor scintigraphy (46%), lower rates of Ki‐67 (70% with Ki‐67 <55%), and longer overall survival. Such data pave the way for an evaluation in NET G‐3 with a Ki‐67 below 55% of the efficacy of the 177Lu‐DOTA0‐Tyr3‐Octreotate (Lutathera). Finally, the 2016 European Neuroendocrine Tumor Society (ENETS) guidelines state that chemotherapy as first‐line treatment with a temozolomide plus capecitabine or streptozotocin plus 5‐fluorouracil regimen  appears as the recommended option in NET G‐3.
As stressed by Milione et al. in a recent review, there is a clinicopathologic heterogeneity of NET G‐3 that deserves specific clinical trials . Cell differentiation and Ki‐67 level appear as the key points in the management of NET G‐3 with a Ki‐67 cut‐off.
Romain Coriat Department of Gastroenterology, Cochin Teaching Hospital, Assistance Publique‐Hôpitax de Paris, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Benoît Terris Department of Pathology, Cochin Teaching Hospital, Assistance Publique‐Hôpitax de Paris, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Thomas Walter Gastroenterology Department, Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Oncologie Digestive, Lyon, France Universite de Lyon, Universite Claude Bernard Lyon 1, Villeurbanne, Lyon, France
Romain Coriat: Merck, Novartis, Pfizer, Celgene, Roche (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.