Abstract
Opinion statementTreatment recommendations for advanced gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are based on uncontrolled, mainly retrospective data. Chemotherapy can offer palliative relief, but long-lasting complete responses or cures are rare. The European Neuroendocrine Tumour Society (ENETS) and European Society for Medical Oncology (ESMO) recommend platinum-based chemotherapy as first-line treatment. This has been the golden standard since the late 1980s and has been evaluated in mostly retrospective clinical studies. However, progression is inevitable for most patients. Unfortunately, data on effective second-line treatment options are scant, and ENETS and ESMO recommendations propose fluorouracil- or temozolomide-based chemotherapy schedules. As such, there is a huge unmet need for improved care. Improved knowledge on GEP-NEC biology may provide a pathway towards more effective interventions including chemotherapy, targeted gene therapy, peptide receptor radionuclide therapy, as well as immune checkpoint inhibitors. The review summarises this current state of the art as well as the most promising developments for systemic therapy in GEP-NEC patients.
Highlights
Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are highly aggressive cancers associated with poor prognosis and fast disease progression
Small-cell NEC-like tumours were characterised by the bi-allelic inactivation of both TP53 and RB1 [30, 31], whereas the genomics of large-cell NEC were more complex and heterogeneous having a ‘carcinoma-like’ signature, with similar profiles to those observed in carcinomas without neuroendocrine differentiation occurring in the corresponding location [30, 31]
Anti-BRAF therapy has shown to be efficient across different cancers harbouring BRAF V600E mutations [82–85]
Summary
Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are highly aggressive cancers associated with poor prognosis and fast disease progression. Since 2017, the World Health Organization (WHO) classifications [7, 8] recognise poorly differentiated high-grade NEC as a distinct entity from high-grade neuroendocrine tumours (NET) [9] This is reflected in treatment recommendations where first-line platinum-based chemotherapy is reserved for NECs and not for high-grade NETs [10, 11]. A decade later, demand for improved prognostic and diagnostic criteria led to the WHO 2010 classification [8] based on the Ki-67 proliferation index, mitotic index, and tumour cell morphology This introduced the term ‘NEN’ as an umbrella term for well and poorly differentiated tumours of neuroendocrine cell origin [19]. Small-cell NEC-like tumours were characterised by the bi-allelic inactivation of both TP53 and RB1 [30, 31], whereas the genomics of large-cell NEC were more complex and heterogeneous having a ‘carcinoma-like’ signature, with similar profiles to those observed in carcinomas without neuroendocrine differentiation occurring in the corresponding location [30, 31]. It should not delay the initial patient management as early treatment onset is thought to be crucial to avoid rapid patient deterioration
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