Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors

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Key points

  • Pancreatic neuroendocrine tumors (NETs) are genetically and clinically different than extrapancreatic NETs (ie, carcinoid tumors) and often respond to cytotoxic and targeted treatments.

  • Asymptomatic patients with low-volume advanced pancreatic NETs often have indolent disease, and some can be followed expectantly. Careful evaluation of each individual patient with an initial interval of observation and assessment can help define who needs treatment sooner.

  • Somatostatin analogues (octreotide and

Pathology

Since 2010, the classification of panNETs has been based on the revised criteria from the World Health Organization, which is defined by the cytologic grade and the proliferative index (as assessed by the Ki-67 and/or mitotic count).11 In these revised criteria, tumors are broken down by differentiation status (well and poorly differentiated) and grade (grade 1, low; grade 2, intermediate; and grade 3, high). Although the family of well-differentiated tumors are classically of the grade 1 or

Inherited Pancreatic Neuroendocrine Tumors

Although panNETs often develop sporadically, inherited panNETs occur and are generally associated with 4 genetic disorders. These disorders include multiple endocrine neoplasia type 1 (MEN1), von Hippel Lindau (VHL) disease, neurofibromatosis 1 (NF1; von Recklinghausen disease), and tuberous sclerosis complex (TSC). All of these genetic disorders demonstrate autosomal dominant inheritance; additionally, the genes implicated in these disorders (MEN1, VHL, NF1, and TSC1/2) are all tumor

Systemic treatment of advanced pancreatic neuroendocrine tumors

The treatment of patients with advanced, metastatic panNETs, whether inherited or sporadic, is approached in a multidisciplinary manner and may include surgical resection, liver-directed therapies, and/or systemic treatments. In unresectable patients, the goals of these therapies are to palliate tumor-related symptoms and prolong the life span.

There are multiple systemic therapy options available for the treatment of metastatic panNETs. These systemic options include somatostatin analogue

Targeted therapies

In recent years, targeted agents have been evaluated as therapy options for panNETs. All NETs are known to be highly vascular; for this reason, targeted angiogenic inhibitors have been heavily investigated as a treatment option in the spectrum of NETs.27 Specific biological agents that have been studied include those directed against vascular endothelial growth factor (VEGF) as well as those targeting mTOR. Sunitinib and everolimus are the only targeted therapies approved for progressive

Cytotoxic chemotherapy

Through multiple studies, a role for chemotherapy (both single drug and combination drugs) has been demonstrated in the management of panNETs. Chemotherapy is most commonly used in the presence of a more aggressive clinical course and symptomatic, heavy tumor burden. In the treatment of panNETs, chemotherapy has been demonstrated to have both palliative and antitumor effects, though evidence regarding OS is conflicting. Chemotherapy agents that have been investigated and commonly used for the

Peptide Receptor Radiation Therapy

Peptide receptor radiation therapy (PRRT), therapy that targets and treats NETs with radiolabeled somatostatin analogues, is based on the understanding that NETs highly expresses somatostatin receptors on their surface. In PRRT, a somatostatin analogue is linked to a therapeutic beta-emitting radioisotope, with the goal of the radiation emitted from the radiolabeled peptide binding to the surface of a tumor cell to both kill the tumor cell as well as neighboring cells, as the path length of

Summary and future directions

As discussed in this article, there are multiple types of systemic therapy options to manage and treat panNETs, including somatostatin analogue therapy, targeted therapy, and chemotherapy. Surgery remains the mainstay of treatment of patients with limited and localized disease and offers the potential for cure. However, as discussed, most patients with panNETs present with advanced disease; goals of therapy in the metastatic setting are directed toward control of symptoms (both due to tumor

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    Disclosure Statement: Dr D. Reidy-Lagunes is on the advisory board for Novartis, Pfizer, and Ipsen. In addition, Dr D. Reidy-Lagunes does both research and consulting for Novartis. Dr N. Raj has nothing to disclose.

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