Locally advanced pancreatic neuroendocrine neoplasms has spread to adjacent organs or peripancreatic vessels, but has not spread to distant organs. When there is a good chance the tumor can be completely removed, surgery can be undertaken. Resection with complete tumor clearance seems to improve survival significantly.

Surgical options include pancreaticoduodenectomy for neoplasms located in the pancreatic head, in the duodenum and in periampullary region; and left pancreatectomy with splenectomy for lesions located in the body and tail of the pancreas. When intraoperative frozen section shows positive resection margins, the resection should be extended up to total pancreatectomy. A regional lymphadenectomy should be always carried out. Infiltration of nearby organs (stomach, colon, kidney, adrenal) does not represent a contraindication to en bloc multivisceral resections. The role of venous resection (superior mesenteric vein/portal vein) as part of pancreaticoduodenectomy, left pancreatectomy or total pancreatectomy) has been established, unless a portal cavernoma is found; whereas the role of arterial resection is controversial. Resection of celiac trunk and superior mesenteric artery are associated with substantially increased morbidity. 

Surgical debulking (resection with macroscopic tumor residual, or R2 resection) does not seem to improve survival. Moreover, debulking is associated with a substantial risk of peritoneal tumor seeding.  

In highly selected patients with locally advanced disease, Peptide Receptor Radionuclide Therapy (PPRT) has been used to downstage the tumor. This means that the neoplasm has shrunk, making resection more feasible. Peptide receptor radionuclide therapy (PRRT) combines somatostatin analogues (octreotide) with a radionuclide to form molecules called radiolabeled somatostatin analogues. These radiopeptides are injected and bind to neuroendocrine neoplastic cells, that have receptors for them. Once bound, radiopeptides emit radiation and kill the tumor cells they are bound to. The two radionuclides that are attached to octreotide to create radiopeptides are yttrium-90 (90Y-DOTA-TOC) and lutetium-177 (177Lu-DOTA-TATE). This type of therapy is most used in metastatic neuroendocrine neoplasms, and can be applied only to individuals whose tumors express somatostatin receptors (as shown by OCTREOSCAN™ or 68-Ga-DOTA-TATE PET-CT). Downstaging by PPRT is an experimental procedure, and should be advised by experienced multidisciplinary discussion. The preliminary results seem encouraging.