Editorial: Diagnosis, treatment and prognosis of neuroendocrine neoplasms with a focus on peptide receptor radionuclide therapy (PRRT)

Abstract

Neuroendocrine neoplasms (NENs) arising from neuroendocrine cells can develop throughout the body from pituitary to thyroid and paraganglion or the gastroenteropancreatic (GEP) and bronchopulmonary (BP) tract (1). Focusing on the latter two origins, they can be classified by the Ki-67 proliferation index and mitotic count into distinct grades of differentiation (grade 1, grade 2 and grade 3 for GEP; typical, atypical, large-cell/ small-cell lung carcinoma for BP) or by their morphology in well-differentiated neuroendocrine tumours (NET)s or poorly differentiated neuroendocrine carcinomas (NEC)s (2,3). Molecular and biological profiles may characterize them further in the future (4). Regarding the symptoms, NENs can be functional, due to their hormonal secretion along with the respective clinical syndrome or produce only symptoms by local growth or metastatic disease. Well-differentiated NENs present a rather indolent history, so that survival of patients with NENs depends not only on their biological behavior but also on the efficacy of sequential antiproliferative treatments along with comparative or combination studies.The majority of well-differentiated NENs present positive uptake on somatostatin receptor (SSTR) imaging (SRI) and positive immunohistochemical staining for the SSTR2a and SSTR5 (5). In this context, besides surgical removal, somatostatin analogues (SSAs) are considered essential in NEN treatment, thanks to their both symptomatic and antiproliferative action (6,7,8). Additionally, a number of targeted molecular treatments such as mTOR inhibitors, like everolimus, and tyrosine kinase inhibitors (TKIs), like sunitinib, cabozantinib or surufatinib, can be used prior to classic cytotoxic treatment, like the combinations temozolomide/ capecitabine or streptozotocin/ 5-fluorouracil, for the management of advanced NETs (9), while for the NEC treatment carboplatin/ etoposide or cisplatin/ irinotecan can be applied (10).In this Research Topic, we have focused on 'Diagnosis, Treatment and Prognosis of Neuroendocrine Neoplasms with a focus on peptide receptor radionuclide therapy (PRRT) that after the NETTER-1 has been characterized as a revolutionary treatment (11,12,13) that can achieve disease control in well-differentiated advanced NENs but can additionally lead to symptom control in functioning NENs (14,15). Of note, PRRT holds a benefit over its comparators such as SSAs, sunitinib (16) or everolimus, whereas more data will be available with the COMPOSE trial (NCT04919226) (17).Several radionuclides have been tested in radiolabeled SSA therapy, such as 111 In-DTPA 0octreotide, 90 Y-DOTA 0 -Tyr 3 -octreotide ( 90 Y-DOTATOC) and 177 Lu-DOTA 0 -Tyr 3 -octreotate ( 177 Lu-DOTATATE) (12). 177 Lu-DOTATATE efficacy was initially tested in patients with advanced midgut NETs at disease progression on SSA treatment in the NETTER-1 study, where 4 cycles of the treatment offered a significantly longer progression free survival (PFS) in comparison to the control group receiving 60 mg Octreotide LAR monthly (12). Comparable efficacy in the PFS showed this treatment, when applied as first-line therapy in patients with welldifferentiated grade 2 or 3 tumors in the NETTER-2 study (13). On top, a repetition of PRRT treatment can be considered in patients with disease progression at least one year after initial treatment (2). In this issue, the study of Mathew et al., adds more evidence for this important treatment demonstrating that patients with metastatic pancreatic NENs receiving more than four cycles of PRRT showed improved overall survival, with the best responses documented in patients with low-grade tumors and without bone metastases (18). So far, several factors have been considered as possible effectors of PRRT efficacy. Tumor derived inflammatory biomarkers, the commercially available NETest and the PRRT Predictive Quotient (PPQ), the PET-based molecular tumor volume and the chromogranin A levels have been used as predictiv