Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances

Abstract

Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years.

Fig. 1

Computed tomographic (CT) scan (top) and somatostatin receptor scintigraphy (SRS) (bottom) results in a patient with previously resected pancreatic neuroendocrine tumor (pNET). This patient previously (2 years prior) had a pNET resected and during follow up the CT scan was negative, as was the magnetic resonance imaging (MRI) scan and abdominal ultrasound (not shown); however, SRS performed with ¹¹¹In-penetreotide (Octreoscan) demonstrated metastases both in the liver and in lymph nodes. These results illustrate the greater sensitivity of SRS over conventional imaging studies (CT, ultrasound, MRI) for detecting metastases in patients with malignant pNETs [3, 14, 25, 26, 71, 72]

Fig. 2

Mammalian target of rapamycin (mTOR) pathway and everolimus. Activation of the PI3 K (phosphoinositde 3-kinase)-Akt pathway is observed in many types of cancers. This pathway is involved in cell growth and proliferation, through the serine-threonine kinase mTOR. mTOR acts as a central regulator of growth, proliferation, cellular metabolism, and angiogenesis. Everolimus is a targeted oral inhibitor of mTOR and demonstrates anti-tumor activity in pancreatic neuroendocrine tumors (pNETs), as shown in the figure. IGF-1 Insulin-like growth factor-1