Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts’ opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.

Temozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to prospectively evaluate the MGMT-promoter methylation status ability to predict outcomes to TEM-based chemotherapy in patients with NET. A single-center, prospective, observational study has been conducted at the ENETS Center-of-Excellence Outpatient Clinic of the IRCCS Policlinico Sant’Orsola-Malpighi in Bologna, Italy. Patients with advanced, gastro-entero-pancreatic or lung well-differentiated NETs candidate to TEM-based chemotherapy and with available tumor samples for MGMT-promoter methylation assessment were included. The MGMT-promoter methylation status was analyzed by using pyrosequencing. The primary endpoint was progression-free survival (PFS) by the MGMT-promoter methylation status. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival outcomes were compared by restricted mean survival time (RMST) difference. Of 26 screened patients, 22 were finally enrolled in the study. The most frequent NET primary sites were the pancreas (64%) and the lung (23%). MGMT promoter was methylated in five tumors (23%). At a median follow-up time of 47.2 months (95%CI 29.3–89.7), the median PFS was 32.8 months (95%CI 17.2–NA), while the median OS was not reached. Patients in the methylated MGMT group, when compared to those in the unmethylated MGMT group, had longer PFS (median not reached [95%CI NA–NA] vs. 30.2 months [95%CI 15.2–NA], respectively; RMST p = 0.005) and OS (median not reached [95%CI NA–NA] vs. not reached [40.1–NA], respectively; RMST p = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; p = 0.274) and DCR (100% vs. 88%; p = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade ≥3 < 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET.

Background: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. Methods: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. Results: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). Conclusions: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine tumor, commonly arising in the lung or in the gastrointestinal tract, with a frequent proportion of unknown primary origin (20%). In the metastatic setting, platinum-based or fluoropyrimidine-based chemotherapeutic regimens are as considered the first-line treatment, despite the limited duration of response. To date, the prognosis of advanced high-grade neuroendocrine carcinoma remains poor, suggesting the need to explore new treatment strategies in this orphan tumor. The evolving molecular landscape of LCNEC, not yet been completely defined, could explain the heterogeneous response to different chemotherapeutic regimens and suggest that treatment strategy could be driven by molecular features. v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, well described in melanoma, thyroid cancer, colon cancer and lung adenocarcinoma, account for approximately 2% of cases in lung LCNEC. Here, we describe the case of a patient with a BRAF V600E-mutated LCNEC of unknown primary origin who partially responded to BRAF/mitogen-activated protein kinase kinase inhibitors after standard treatment. Additionally, BRAF V600E circulating tumor DNA was used to monitor disease response. Thereafter, we reviewed the available literature about the role of targeted therapy in high-grade neuroendocrine neoplasms to provide insight for future research to identify patients with driver oncogenic mutations, who can potentially benefit from target therapy.

Pancreatic neuroendocrine neoplasms (pNENs) represent approximately 2% of all solid pancreatic tumors. The incidence of pNENs has been increasing in the last decade. The clinical manifestations of pNENs range from hormone secretion syndromes in functioning neoplasms (F-pNENs) to local infiltration or distant metastases in late-stage diagnoses or incidental findings in small non-functioning neoplasms (NF-pNENs). While surgery is the gold-standard treatment for larger and more aggressive tumors, small and low-grade tumors (G1) may be followed-up due to the indolent course of disease. Recently, endoscopic ultrasound (EUS)-guided ablative techniques, such as ethanol injection (EUS-EI) and radiofrequency ablation (EUS-RFA), have emerged as promising options for loco-regional ablations in selected cases. Despite promising safety profile and efficacy, high-quality evidence is needed to support their widespread adoption. This article reviews the current state of EUS-guided locoregional therapies, patient selection criteria, procedural details, and associated risks.