Paul Eliezer Oberstein1* and Muhammad Wasif Saif2
1Columbia University College of Physicians and Surgeons at New York Presbyterian Hospital. New York, NY, USA.
2Tufts University School of Medicine, Boston, MA, USA
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.
Drug Therapy; everolimus; Neuroendocrine Tumors; Pancreatic Neoplasms; sunitinib; Vascular Endothelial Growth Factors
NET: neuroendocrine tumors; pNET: pancreatic neuroendocrine tumors; PS: performance status.
Neuroendocrine tumors (NETs) consist of a diverse group of tumors composed of cells showing neuroendocrine cell differentiation (secretory granules), a subset of which can be further classified by their dominant secretory products. Although it was thought that the neuroendocrine cells that give rise to NETs migrated from the neural crest to the gut endoderm, it is now apparent that enteropancreatic neuroendocrine cells originate from multipotent stem cells that give rise to all epithelial cell types in the gastrointestinal tract and pancreas . NETs show heterogeneity in morphologic, functional and clinical features . A subset of NETs involving the pancreas previously termed islet cell tumors or islet cell carcinomas are designated pancreatic NETs (pNETs.) Although pNET represent a small percentage of all pancreatic tumors (1.3%), the prevalence of these tumors is significant (9.9% of all pancreatic tumors) and the incidence is increasing . In tertiary oncology centers, the majority of patients with malignant pNETs represent advanced stage tumors with approximately 65% of patients presenting with unresectable or metastatic disease .
Prior to 2011, the only approved agent for unresectable disease was streptozocin which was approved prior to 1984 after demonstrating some efficacy in early trials (either alone  or in combination with doxorubicin  or 5-FU ). Further studies have questioned the efficacy of streptozocin  and there had not been any new drugs approved in the last 20 years. As a result patients with unresectable pNETs have a poor prognosis. The median survival time for patients with distant metastatic disease is 24 months , the 5-year survival rate of patients with metastatic disease is 30-40%  and has not changed for 20 years. The effort to find improved therapeutics for pNET was bolstered by the observation that there are several inherited cancer syndromes which are associated with pNET (including multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease (vHL), neurofibromatosis 1 (NF1), and the tuberous sclerosis complex (TSC)) . Unfortunately the underlying genetic abnormalities in these syndromes are relevant in only a subset of the sporadic pNETs . A global gene expression analysis of pNETs revealed that at least two important genes in the mammalian target of rapamycin (mTOR) pathway (TSC2 and PTEN) were downregulated in 85% of primary tumors [12, 13]. Additionally, aberrant expression of several tyrosine kinase receptors and overexpression of vascular endothelial growth factor (VEGF) have also been noted in pNET . Utilizing this preclinical data, two targeted agents demonstrated prolongation of progression free survival in advanced pNET and were approved for this indication in 2011. In the RAD001 in Advanced Neuroendocrine Tumors (RADIANT)-3 trial, an inhibitor of the mammalian target of rapamycin (mTOR), everolimus was superior to placebo in prolonging progression free survival in patients with unresectable, advanced pNET from 4.6 to 11.0 months . Another phase III trial looked at the multi-kinase inhibitor, sunitinib, in unresectable pNET and found an improvement in progression free survival from 5.5 to 11.4 months when compared to placebo . Despite these impressive results in improving progression free survival, the response rate to these targeted therapies remains low. There are ongoing efforts to improve on this therapy by more potent targeting of these pathways, by combination therapy, and by identification of additional targets. One promising target is the insulin-like growth factor pathway since both the ligand (IGF) and the cognate receptor (IGF-1R) are frequently expressed in neuroendocrine tumors . There is also at least one report that indicates that some patients with neuroendocrine tumors have upregulation of the HER- 2 protein  and that this may be an additional target for therapy.
At the 2012 ASCO Annual Meeting, several abstracts were presented highlighting this novel research and reported the results of clinical trials to identify novel and improved therapy for the treatment of pNET. These reports are reviewed and summarized here.
Updated Chemotherapy Regimens
Chemotherapy has been used in the treatment of NET for many years; streptozocin was approved by the FDA for this indication prior to 1984. A randomized controlled trial demonstrated that addition of 5-FU to streptozocin was associated with improved response  and this combination has been frequently used. In many tumors, the oral prodrug capecitabine has shown similar efficacy when used as replacement for 5-FU, often with a favorable safety profile. A case series described several responses with the combination of streptozocin, capecitabine, and cisplatin  and this provided the rationale for a clinical trial of this combination. In Abstract #4121 , Corrie et al. described the results of this clinical trial. They conducted a prospective, randomized phase II trial looking at the role of combination capecitabine/ streptozocin plus or minus cisplatin in advanced NETs with 48% of the patients enrolled with pNET. As summarized in Table 1 they found similar outcomes with the two treatment groups with increased toxicity in the more aggressive treatment arm (cisplatin group.) Of note, the response rate of both arms was low with partial response seen in 14% and 8% but the overall disease control rate was close to 80% with either regimen.
Addition of Bevacizumab
Several abstracts looked at the role of bevacizumab in the treatment of advanced pNET. Sunitinib is thought to work at least in part by inhibition of the VEGF pathway and VEGF is overexpressed in pNET  leading to significant interest in incorporating the anti- VEGF monoclonal antibody bevacizumab in the treatment of this disease.
In Abstract #4036 , Ducreux et al. reported results from one group of a phase II trial looking at the activity of bevacizumab in combination with standard chemotherapy with 5-FU/streptozocin in patients with metastatic, progressive, well differentiated pNETs. The primary outcome was progression free-survival and at this report the median progression free survival was 23.7 months. The combination therapy was associated with a very high rate of response (19 of 34; 55.9%) but grade 3 or 4 adverse events (as measured by common toxicity criteria (CTC)) were also common, occurring in 23 of 34 patients (67.6%). This combination seems to have encouraging activity and may be further investigated in appropriate patients in a phase III setting.
In Abstract #4127 , Firdaus et al. reported on an ambitious phase II trials looking at a combination of targeted agents. The investigators enrolled healthy patients with advanced, well differentiated NETs (including 26% with pNET) and treated them with octreotide (Sandostatin® LAR, Novartis Pharmaceuticals Co., East Hanover, NJ, USA), bevacizumab, and pertuzumab- a monoclonal antibody that disrupts HER-2 signaling. The combination was associated with some response (as noted in Table 1) and may lead to further investigation in a controlled trial.
In Abstract #4048 , Hobday et al. reported the results of an interim analysis of a phase II trial looking at the combination of mTOR inhibition with temsirolimus and VEGF inhibition with bevacizumab. The combination treatment is being investigated in patients with well or moderately differentiated pNET who have progressive disease. The interim analysis was performed after enrolling 25 of the planned 50 patients and it showed a high rate of response with 13 patients (52%) demonstrating a radiographic partial response. The study is continuing accrual, further safety analysis will be important to evaluate tolerability of this regimen but the high response rate is encouraging.
Other Targeted Agents
In Abstract #4125 , Kulke et al. reported on a phase II trial evaluating the use of an investigational targeted therapy directed against IGF-1R. The insulin growth factor receptor is thought to play a role in progression of neuroendocrine tumors so they evaluated the role of a monoclonal antibody against IGF-1R in patients with metastatic, progression neuroendocrine tumors. Although this agent was well tolerated, there were no radiographic responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. It is not known if there will eventually be a biomarker that may select a subset of patients that can benefit from this therapy but at this time is was not effective in this unselected population.
Finally, in Abstract #4118 , Vinik et al. reported updated results from the large phase III trial that demonstrated superiority of sunitinib compared to placebo in prolonging time to progression. At the time of the initial analysis there were few deaths (30 out of 171 or 18%), potentially limiting the survival analysis. At the time of this updated analysis, 51% of the patients have died (87 of 171) and the median overall survival is now estimated at 33.0 months in the intervention group (sunitinib) and 26.7 months in the placebo group. This result did not reach significance with a hazard ratio of 0.71 (95% CI: 0.47-1.09; P=0.11). As previously reported most patients in the placebo arm (69%) crossed over to receive sunitinib on progression limiting the ability to detect a difference in mortality due to this intervention.
As NETs increase in incidence the spectrum of available therapy is also increasing. There has been a suggestion that some of the increased incidence in this diagnosis is due to improvements in diagnostic imaging with detection of smaller lesions in addition to the incidental diagnosis of asymptomatic cases . However, for the group of advanced or malignant NET, effective treatment options will need to be identified through well designed clinical trials. Recently two targeted agents have been approved by the FDA for the treatment of progressive pNET. Everolimus is an mTOR inhibitor which inhibits cell growth, proliferation, and angiogenesis. Sunitinib is a multikinase inhibitor that is thought to have an effect in pNET through inhibition of vascular endothelial growth factor (VEGF) which plays a role in angiogenesis. As summarized above, there were several abstracts presented at the 2012 ASCO Annual Meeting which represent important contributions to this field. Chemotherapy plays an important role for many patients and report by Corrie et al.  suggest that capecitabine is a safe combination with streptozocin; however, the response rate is low and it does not seem that cisplatin adds substantially to this regimen. Ducreux et al.  have demonstrated that chemotherapy and targeted therapy can be combined in the treatment of pNET with impressive efficacy, though the need to minimize toxicity is noted. Inhibition of IGF-1R does not seem to lead to response in pNET but there were promising preliminary results suggesting that combination of mTOR inhibition and VEGF blockade may add substantial benefit.
In summary, the abstracts presented at the 2012 ASCO Annual Meeting highlight the continued progress in developing novel treatments to improve outcomes in advanced pancreatic neuroendocrine tumors. The continued identification of new agents that are being tested in clinical trials suggests that there is promise in the future treatment for patients suffering from this form of pancreatic malignancy.
The authors have no potential conflicts of interest