Upfront Oxaliplatin–Fluoropyrimidine Chemotherapy and Somatostatin Analogues in Advanced Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Tumors

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted a retrospective analysis to assess the effectiveness of combining oxaliplatin–fluoropyrimidine chemotherapy with SSA as an upfront strategy in newly diagnosed metastatic G2/G3 GEP-NET patients treated with oxaliplatin–fluoropyrimidine-based chemotherapy; (3) Results: Between March 2017 and October 2023, 32 pts (19 males, 13 females; M:F = 1.5:1; median age 54 years, range 31–82) were deemed eligible to receive oxaliplatin–fluoropyrimidine chemotherapy in addition to SSA; 14 received XELOX and 18 FOLFOX. After a median follow-up of 26 mo., each patient had completed at least two cycles of chemotherapy. The ORR was 25%, with a median DoR of 21.3 mo. The DCR was 87.5%. Notably, 28.1% of patients experienced tumor shrinkage sufficient for radical surgery on residual tumor lesions, encompassing both primary tumors and metastases; (4) Conclusions: Upfront treatment with the combination of oxaliplatin–fluoropyrimidine and SSA demonstrated effectiveness and safety. This approach may be considered to facilitate conversion surgery in eligible patients.