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High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

There is an increased risk of second primary cancers (SPCs) after neuroendocrine tumor (NET) diagnosis. The clinical significance of SPCs in this population is unknown. The purpose of this study was to evaluate the association between SPCs after NET diagnosis and survival. We performed a population-based, retrospective cohort study of NET patients (gastrointestinal, pancreatic, or lung primary) from 2000 to 2016 using the Surveillance, Epidemiology, and End Results database. Cox regression models assessed the association between SPCs and NET-specific (NET-SS), cancer-specific (CSS), and overall survival (OS). Of 58,553 NET patients, 7.9% experienced an SPC. SPCs were associated with worse OS (hazard ratio (HR) 2.14, 95% CI 1.94-2.36) and CSS (HR 2.31, 95% CI 2.06-2.59) with no difference in NET-SS (HR 1.04, 95% CI 0.87-1.23). Stratified analyses by histologic grade showed similar results for well and moderately differentiated NETs, but no difference in OS or CSS for poorly differentiated NETs (P > 0.05). In stratified analyses by NET site, SPCs were associated with worse OS (HR 3.41, 95% CI 3.01-3.87) and CSS (HR 4.96, 95% CI 4.28-5.74) in gastrointestinal NETs and worse OS (HR 1.25, 95% CI 1.03-1.52) with no difference in CSS (HR 1.08, 95% CI 0.85-1.36) in lung NETs. SPCs were not associated with a difference in OS or CSS in pancreatic NETs (P > 0.05). In conclusion, SPCs after NETs were associated with inferior OS and CSS compared to no SPC but were not associated with NET-SS. These data highlight the need for long-term follow-up in NETs to include the detection of SPCs to ensure early diagnosis and timely management.

Liver metastases are common in patients with neuroendocrine tumours. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined everolimus and radiation for neuroendocrine liver metastases. This single-arm, single-centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. Overall survival, progression-free survival and freedom from a change in systemic therapy were estimated by the Kaplan-Meier method. Forty metastases were treated in 14 patients. No grade 3 or higher toxicities were identified in the concurrent treatment phase; one patient developed grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One- and 2-year local control were 97% and 71%. Median progression-free survival was 12 months. One- and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation are well-tolerated for neuroendocrine liver metastases and are associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population.