Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors.

INTRODUCTION Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma (NEC). The optimal treatment for NET G3 has not been well-described. This study aims to evaluate metastatic NET G3 response to different treatment regimens. MATERIALS AND METHODS This is a retrospective study of NET G3 patients within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS). Secondary end points were objective response rate (ORR) and disease control rate (DCR). RESULTS Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included: capecitabine + temozolomide (CAPTEM) (n=20), lutetium 177 DOTATATE (PRRT) (n=10), carboplatin/cisplatin + etoposide (EP) (n=8), FOLFOX (n=7), and everolimus (n=2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% CI 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however median PFS durations were quite distinct at 2.94 and 13.04 months respectively. PRRT had ORR 20%, DCR 70%, and median PFS 9.13 months. CONCLUSIONS Among NET G3 patients, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3 but responses appear to be short-lived. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. IMPLICATIONS FOR PRACTICE High-grade well differentiated neuroendocrine tumors (NET G3) are considered different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide (CAPTEM) is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated NET, PRRT seems to have some efficacy in these tumors.