Treatment Options for High Grade (Grade 3) NETS

Grade 3 well-differentiated neuroendocrine tumors (NETs) present unique clinical challenges, as emphasized by the panel of specialists. Distinguishing these from poorly differentiated carcinomas is essential, as treatment strategies differ markedly. Key factors in management include an accurate Ki-67 proliferation index, somatostatin receptor (SSTR) status, and an understanding of tumor heterogeneity—since clinical behavior and appropriate therapeutic choices may evolve over time. For SSTR-positive grade 3 NETs, peptide receptor radionuclide therapy (PRRT) can be considered early, while temozolomide-based chemotherapy is often preferred for high-burden or SSTR-negative pancreatic NETs. Newer targeted agents like cabozantinib have shown promise, but data remain limited to small subsets. Molecular profiling is encouraged, especially in aggressive presentations or unusual sites, to uncover actionable targets such as BRAF mutations. Although newer studies like NETTER-2 and ECOG 2142 provide some guidance, standardization remains incomplete, and treatment often requires nuanced, case-by-case decision making guided by multidisciplinary expertise.