Faculty Bibliography

 Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. Pancreatic neuroendocrine tumors (pNET) are a subset of NETs which are increasing in incidence and prevalence. These tumors are generally slow growing and behave in an indolent fashion. However, when these tumors spread they can be life threatening and difficult to treat with current modalities. In 2011, the landscape of treatment for pNET was changed with the approval of two targeted agents, sunitinib and everolimus, the first new therapies for this disease in over 20 years. Data from these clinical trials and extensive preclinical work into the underlying molecular pathways in neuroendocrine tumors has generated intense interest in the quest to identify additional effective agents in this challenging disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several researchers presented updated data regarding the use of targeted agents, alternative chemotherapeutic agents and combinations of these in the treatment of pNET. Corrie et al. (Abstract #4121) reported data from a chemotherapy clinical trial replacing 5-FU with capecitabine and evaluating the addition of cisplatin in NETs. Several authors reviewed the addition of the anti VEGF monoclonal antibody bevacizumab into combination therapy. Ducreux et al (Abstract #4036) presented results from a trial of chemotherapy plus bevacizumab while Firdaus et al. (Abstract #4127) reported the results of combination therapy with octreotide, bevacizumab, and pertuzumab. Hobday et al. (Abstract #4048) reported positive results of an interim analysis of combination therapy with an mTOR inhibitor and bevacizumab. Kulke et al (Abstract #4125) reported the results of a clinical trial utilizing an antibody targeting the insulin growth factor receptor. Finally, Vinik et al. (Abstract #4118) provided updated survival data form the seminal phase III trial that led to approval of sunitinib in the treatment of pNET. The authors review and summarize these abstracts in this article. 

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are often indolent but they have the potential to cause symptoms through release of hormones and through local or distant spread. Pancreatic neuroendocrine tumors (pNET) represent a subset of NETs and they have a unique pattern of symptoms and disease progression. Due to the heterogeneity of this disease it is important to identify reliable markers to help guide prognosis and predict response to therapy. The recent approval of two new agents in the treatment of advanced pNET has raised additional interest in the significance of molecular markers in this disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several investigators reported on collaborative efforts to develop clinically useful biomarkers for this disease. Choti et al. (Abstract #4126) reported data about the functional characteristics of NETs and pNETs among a multi-institutional cohort finding that a substantial minority of patients have functional symptoms even when the disease is localized. Faggiano et al. (Abstract #1604) looked at a wide spectrum of NETs in several referral centers and reported on predictors of both short term and long term survival in this setting. Yao et al. (Abstract #4014) reported analysis of predictive biomarkers among patients in the RADIANT-2 trial which looked at the role of the mTOR inhibitor, everolimus compared to placebo in NET. Fischer et al. (Abstract #4128) looked at a novel biomarker, placental growth factor (PlGF) and evaluated the role of serum and tissue levels of this protein as a predictive marker. Finally, Khan et al. (Abstract #4123) investigated the role of circulating tumor cells in NET (and pNET) and found that this may have potential as a prognostic marker and an early marker of response to therapy. The authors review and summarize these abstracts in this article.

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are generally slow growing and behave in an indolent fashion. However, they have the potential to spread, primarily to the liver and when they do, they can be life threatening and difficult to treat with current modalities. A subset of NETs, the pancreatic neuroendocrine tumors (pNET) represent a small percentage of all pancreatic tumors (1.3%) but their incidence is rising. Prior to 2011, the only approved agent for unresectable pNETs was streptozocin (often used in combination with doxorubicin) but the efficacy of this drug was questionable. In 2011, the landscape of treatment for pNET was changed with the approval of the first new agents in 20 years, sunitinib and everolimus, that demonstrated improvement in time to progression in patients with progressive pNET. Sunitinib is a multikinase inhibitor and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. These drugs were approved by the Food and Drug Administration (FDA) on the basis of separate large randomized placebo-controlled trials. Data from these two trials and an additional phase III trial looking at everolimus in other neuroendocrine tumors has generated intense interest in this challenging disease. At the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, several researchers presented updated data regarding the risk stratification, treatment, and outcome for patients with pNET in the new era of targeted therapy. Choti et al. (Abstract #187) reviewed demographic data from a large set of patients who presented to National Comprehensive Cancer Network (NCCN) sites with neuroendocrine tumors. Casciano et al. (Abstract #226) and Signorovitch et al. (Abstract #237) presented post-approval analysis of the relative role of everolimus and sunitinib in the treatment of pNET. Alistar et al. (Abstract #166) explored predictive biomarkers in pNET, and Yao et al. (Abstract #157) conducted multivariate analysis of patients treated with everolimus in the phase III, RADIANT-2 trial which included the identification of relevant biomarkers. Hobday et al. (Abstract #260) and Bergsland et al. (Abstract #285) reported phase II data from two clinical trials looking at novel targeted combinations for the treatment of pNET. Finally the role of treatment for poorly differentiated NETs (including pNETs) remains ill-defined and Yamaguchi et al. (Abstract #274) presented a report reviewing the experience at 23 centers in Japan in treating this population. The authors review and summarize these abstracts in this article.

Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.

Pancreatic neuroendocrine tumors represent a small percentage of all pancreatic tumors (1.3%) but their incidence is rising. Prior to 2011, the only approved agent for unresectable disease was streptozicin (often used in combination with doxorubicin) but the efficacy of this drug is in question and there had not been any new drugs approved for this disease in more than 20 years. Recently there has been new excitement for the treatment of advanced neuroendocrine tumors including those of the pancreas (pNET) with FDA approval of 2 new agents in 2011. One of these agents was everolimus, an mTOR inhibitor, which was approved on the basis of a landmark phase III study (RADIANT-3). At the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, several abstracts were presented reviewing novel agents in the treatment of advanced NET. Three abstracts looked at characteristics of patients treated on the RADIANT-3 study and looked at the role of prior chemotherapy use (Abstract #4103), somatostatin analog use (Abstract #4010), and updated safety data (Abstract #4009) from this trial. Additionally, an abstract was presented (Abstract 4008) looking at updated data from the other targeted agent approved for advanced pNET, sunitinib, a multi-tyrosine kinase inhibitor, which demonstrated improvement in progression-free survival compared to placebo. Novel agents were also presented, including a phase II trial looking at the combination of sorafenib and bevacizumab (Abstract #4113), and a phase I trial looking at a novel somatostatin analog, pasireotide, in combination with everolimus (Abstract #4120) The authors review and summarize these abstracts in this article.

Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. Gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade, several randomized trials have tested the combination of gemcitabine plus a second agent, including platinum based agents, topoisomerase inhibitors, taxanes, bevacizumab and cetuximab, as biologically "targeted" agents. At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines).