Background: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. Patients and Methods: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014. Results: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo [‘median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. Conclusion: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival.

This ENETS guidance paper, developed by a multidisciplinary working group, provides an update on the previous colorectal guidance paper in a different format. Guided by key clinical questions practical advice on the diagnosis and management of neuroendocrine tumours (NET) of the caecum, colon, and rectum is provided. Although covered in one guidance paper colorectal NET comprises a heterogeneous group of neoplasms. The most common rectal NET are often small G1 tumours that can be treated by adequate endoscopic resection techniques. Evidence from prospective clinical trials on the treatment of metastatic colorectal NET is limited and discussion of patients in experienced multidisciplinary tumour boards strongly recommended. Neuroendocrine carcinomas (NEC) and mixed neuroendocrine non‐neuroendocrine neoplasms (MiNEN) are discussed in a separate guidance paper.

Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers. We retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed. The median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities. STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response.

Background: The incidence and prevalence of neuroendocrine neoplasms (NEN) are rising. In view of continuously improving imaging techniques, more than half of the patients present with distant metastases at initial diagnosis. An advanced disease stage negatively correlates with the 5-year survival rate. In stage IV disease, bone metastases (BM) are frequent, yet knowledge concerning their clinical or prognostic relevance is rare. This study presents a single-center experience on the frequency and management of BM in patients with gastroenteropancreatic NEN and lung carcinoids. Methods: Between 2000 and June 2015, 327 of 677 patients treated in the European Neuroendocrine Tumor Society (ENETS) center in Marburg (Germany) presented with distant metastases (48.3%), including 85 patients (12.6%) with BM. Data of both groups were analyzed using descriptive statistics. Overall survival was assessed by Kaplan-Meier curves and compared by log-rank test. Results: Median age in the BM group was 54.9 years, the small intestine and the pancreas being the most common primaries. 83.5% of the tumors were well and moderately differentiated (G1/G2). Nearly half of the patients with BM were symptomatic and suffered either from pain (42.4%) or had fractures (11.7%). Bisphosphonates were employed in almost two-thirds of the patients, radiation therapy in 25.9%. Overall survival was significantly inferior in patients with BM than in those with other distant metastases (p = 0.01; 49.0 vs. 100.8 months). Conclusion: BM appear to have a significant clinical and prognostic impact. Further studies are needed to evaluate therapeutic approaches directed to the treatment of BM in particular for asymptomatic patients.

Background: According to the latest WHO classification, neuroendocrine neoplasm (NEN) G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Gastrointestinal neuroendocrine carcinoma (NEC) is a rare and highly aggressive malignancy and despite responsiveness to chemotherapy, overall survival is poor. In the last 3-4 years, the heterogeneity of the NEN G3 group has become evident. Summary: In addition to the proliferative activity, the tumour differentiation seems to play a major role, further dividing the NEN G3 group into neuroendocrine tumour (NET) G3 and NEC. NET G3 often arise in the pancreas, and their median proliferation rate is lower and prognosis is better as compared to NEC. However, NET G3 show a limited response to platinum-based chemotherapy. Lack of specific data for NET G3 hampers clear therapeutic recommendations. Cisplatin combined with etoposide is the established standard regimen for advanced gastrointestinal NEC. Substituting carboplatin for cisplatin or irinotecan for etoposide is considered alternative first-line regimen. There is no standard second-line treatment; options are discussed within this review. Key Points: (1) In NEN G3, the distinction between NET G3 and NEC G3 is clinically and prognostically meaningful. (2) Platinum-based chemotherapy remains the recommended first-line treatment in metastasized NEC patients. (3) There is no established standard for NET G3; treatments established for NET G2 such as temozolomide-based chemotherapy or peptide receptor radiotherapy may be considered. (4) Specific trials for NET G3 are necessary. (5) New therapies for NEC are urgently needed. Checkpoint inhibitors should be evaluated.