cancers Cancers Cancers cancers 2072-6694 MDPI 10.3390/cancers4010113 cancers-04-00113 Review Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors Rinke Anja * Michl Patrick Gress Thomas Department of Gastroenterology, University Hospital Marburg, Baldinger Strasse, Marburg D-35043, Germany; E-Mails: michlp@med.uni-marburg.de (P.M.); gress@med.uni-marburg.de (T.G.) Author to whom correspondence should be addressed; E-Mail: sprengea@staff.uni-marburg.de; Tel.: +49-6421-586-5968; Fax: +49-6421-586-8922. 08 02 2012 03 2012 4 1 113 129 01 12 2011 23 01 2012 30 01 2012 © 2012 by the authors; licensee MDPI, Basel, Switzerland. 2012

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-α, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.

 neuroendocrine tumor neuroendocrine carcinoma somatostatin analogues interferon-α mTOR inhibitor multikinase inhibitor chemotherapy 1. Introduction

Although neuroendocrine tumors (NET) of the gastrointestinal tract are rare neoplasms, their incidence has been increasing over the last decades [1,2,3]. The clinical presentation as well as the course and prognosis of NETs may vary considerably. The new WHO classification categorizes neuroendocrine neoplasms (NEN) of the gastroenteropancreatic tract into well-differentiated neuroendocrine tumors (NET) G1 and G2 and neuroendocrine carcinomas (NEC) [4] (Table 1). Neuroendocrine tumors may present with characteristic hormone-driven syndromes such as the carcinoid syndrome and the Zollinger Ellison syndrome, but may also be functionally inactive. In patients with hormonally inactive tumors diagnosis frequently occurs incidentally during endoscopic or ultrasound examinations for unspecific or unrelated symptoms. NECs are usually hormonally inactive and patients often present with weight loss, weakness or abdominal pain.

cancers-04-00113-t001_Table 1

WHO classification of neuroendocrine neoplasms of the gastroenteropancreatic system [4].

WHO 2000 WHO 2010
1. Well-differentiated endocrine tumour (WDET) 1. NET G1 (carcinoid) NET G2 (carcinoid) *
2. Well-differentiated endocrine carcinoma (WDEC)
3. Poorly differentiated endocrine carinoma/small cell carcinoma (PDEC) 2. NEC G3 large or small cell type
4. Mixed exocrine-endocrine carcinoma (MEEC) 3. Mixed adenoneuroendocrine carcinoma (MANEC)
5. Tumour-like lesions (TLL) 4. Hyperplastic and preneoplastic lesions

* In case that the Ki67 index exceeds 20%, this NET may be labelled G3.

Approximately half of the NEN patients have already developed distant metastases at the time of diagnosis with liver metastases being the predominant localization in most cases. Surgical resection and locoregional treatments of liver metastases are therefore integral parts of the treatment plan in NET patients.

Medical treatment strategies have to consider hormonal activity, localization of the primary tumor, disease extent, growth behavior and prognosis. The proliferation rate is an important predictor of growth behavior and prognosis. The grading system of NEN is based on the immunohistochemical determination of Ki67 as proliferation marker and mitotic counts [5,6]. In patients with G3 tumors (Ki67 > 20%) platin-based chemotherapy is indicated whereas low-proliferating gastrointestinal NET are usually not chemosensitive.

With the advent of novel small molecule inhibitors such as sunitinib and everolimus the therapeutic armamentarium available for G1 and G2 pancreatic NET has substantially broadened. This review provides an overview on the current therapeutic options for NEN.

 2. Medical Treatment of NEN 2.1. Aims of Treatment

Aims of treatment include:

Inhibition of hormone secretion for symptomatic relief in hormonally active tumors;

Improving or maintaining quality of life;

Inhibition of tumor growth;

Prevention of complications (carcinoid crisis, carcinoid heart disease, bleeding, ileus);

Prolongation of survival.

Medical treatment in NEN patients includes somatostatin analogues, proton pump inhibitors in patients with gastrinoma and Zollinger Ellison syndrome (ZES), diazoxid in insulinoma patients, interferon, chemotherapy, small molecules including multikinase inhibitors and mTOR inhibitors. Bisphosphonates may be additionally used as treatment in patients with bone metastases.

In the following we will give an overview of the role of the different medical treatment options in the treatment algorithms for NEN patients.

 2.2. Somatostatin Analogues

Since the late 80s somatostatin analogues are well established in the treatment of hypersecretion syndromes to achieve symptomatic relief [7,8,9,10]. The effect is mediated by binding to specific somatostatin receptors on the tumor cells. Treatment with somatostatin analogues can therefore be regarded as the first “molecular targeted” treatment in NEN.

Both somatostatin analogues currently available, octreotide and lanreotide, bind to the receptor subtypes 2 and 5 with high affinity. Both drugs have a longer half-life than endogenous somatostatin. Additionally, depot preparations have been developed (octreotide LAR, lanreotide MP and AG) that allow an administration in monthly intervals.

Somatostatin analogues effectively inhibit hormonal secretion and ameliorate flushing and diarrhea in about 75% of patients with carcinoid syndrome (40%–100%) [7]. Perioperative and periinterventional treatment with octreotide can prevent carcinoid crisis [7,11]. Since the risk of carcinoid heart disease is associated with high serotonin levels [12], early treatment with somatostatin analogues may be able to delay or even prevent the development of carcinoid heart disease. Diarrhea in VIPoma patients is also effectively reduced by somatostatin analogues [7]. Somatostatin analogues reduce acid output in gastrinoma patients but proton pump inhibitors are superior in this indication [13,14]. In insulinoma patients hypoglycemia can be reduced in only half of the patients. As somatostatin analogues additionaly inhibit glucagon secretion and thus may worsen hypoglycemia in some patients, somatostatin analogues should not be initiated on an outpatient basis in these patients. Octreotide and lanreotide are regarded equally effective for the symptomatic control of patients with functioning tumors. The only study directly comparing both compounds did not show significant differences [15].

Pasireotide is a novel somatostatin analogue that exhibits higher binding affinity to receptor subtype 1, 3 and 5 than octreotide and lanreotide. Whether this higher binding affinity in particular to receptor subtype 5 results in a therapeutic advantage as previously suggested [16] is under further investigation (ongoing randomized phase III trial comparing pasireotide LAR and octreotide LAR; NCT00690430).

In addition to symptomatic control, somatostatin analogues have been suggested to elicit antiproliferative activity. The proposed mechanisms involve a direct, receptor-mediated antiproliferative effect due to inhibition of the cell cycle and pro-apoptotic activity as well as due to indirect effects including inhibition of the release of growth factors and trophic hormones, inhibition of angiogenesis and modulation of the immune system [7,17].

Several retrospective and small prospective trials reported disease stabilization in about half of the patients (28%–87.5%) treated with somatostatin analogues whereas tumor regression was rarely observed (less than 10%). Table 2 summarizes the studies reporting antiproliferative effects of octreotide and lanreotide [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33].

cancers-04-00113-t002_Table 2

Summary of studies reporting antiproliferative effects of somatostatin analogues.

First Author and Year Patients SSA/Dose Progression Prior to Treatment PR(%) SD(%) Additional Remarks
Vinik 1989 [18] 14; carcinoid and pNET Oct sc100 µg–250 µgq 6–12 h no 20 * 50 * any regression
Öberg 1991 [19] 23 midgut carcinoids Oct sc 50 µg–100 mgq 12 h no 28 36
Saltz 1993 [20] 34 carcinoid and pNET Oct 150 µg–250 µg t.i.d. yes 0 50
Arnold 1996 [21] 103 GEPNET Oct sc 200 µg–500 µgt.i.d. in 50% 0 37 a/54 b a in patients with documented progression b in patients without documented progression
di Bartolomeo 1996 [22] 58 GEPNET Oct sc 500 mg–1000 mgt.i.d. yes 3 47
Tomassetti 1998 [23] 18 GEPNET Lan i.m. 30 mg q 10 d no 0 78
Wymenga 1999 [24] 55 functioning GEPNET Lan i.m. 30 mg q 14 d to q 7 d no 6 81
Faiss 1999 [25] 30 GEPNET Lan sc 5000 µg t.i.d. yes 6.6 37
Ricci 2000 [26] 15 GEPNET Oct LAR 20 mg q 28 d yes 7 40
Tomassetti 2000 [27] 16 GEPNET Oct LAR 20 mg q 28 d no 0 87.5
Aparicio 2001 [28] 35 GEPNET Oct sc 100 µg t.i.d. or Lan i.m. 30 mg q 14 d to q 7 d or both yes 2.9 57.1
Shojamanesh 2002 [29] 15 gastrinoma Oct sc or Oct LAR yes 6 47
Faiss 2003 [30] 25 GEPNET Lan sc 1000 µg t.i.d. yes 4 28
Bajetta 2006 [31] 30 GEPNET LAN MP 60 q 21 d no 3.6 64.3
30 GEPNET LAN AG 120 q 42 d 0 67.9
Panzuto 2006 [32] 21 pNET Oct LAR 30 mg q 28 d yes 0 45
Rinke 2009 [33] 85 midgut NET Oct LAR 30 mg q 28 d versus placebo no 2.4 a 67 a a at 6 months of treatmentPFS 14.5 versus 6.0 months

SSA: somatostatin analogue; PR: partial remission; SD: stable disease; pNET: pancreatic neuroendocrine tumor; Oct: octreotide; sc: subcutaneous application; Lan: lanreotide; GEPNET: gastroenteropancreatic neuroendocrine tumor; i.m.: intramuscular application.

In our PROMID trial—a randomized phase III study to compare time to progression (TTP) in patients with metastatic midgut NET randomly assigned to octreotide LAR 30 mg monthly or placebo—we confirmed the antiproliferative efficacy of somatostatin analogues in this patient cohort.

In the octreotide group TTP was significantly increased to 14.3 months as compared to 6 months in the placebo group [33]. This effect was independent of the functional activity, whereas hepatic tumor load was shown to be of prognostic relevance. The greatest benefit was found in patients with a hepatic tumor burden not exceeding 10%. This suggests that an early treatment of patients with midgut NET might be beneficial although a survival advantage is not proven.

Another placebo controlled study with lanreotide AG 120 mg monthly in patients with hormonal inactive intestinal or pancreatic NET (CLARINET trial) has completed recruitment but results are not available yet. This study will provide further information on the role of somatostatin analogue treatment for the inhibition of tumor growth in particular for pNETs.

Currently, somatostatin analogues are only approved for the symptomatic treatment of carcinoid syndrome and functioning pNETs in most countries. Somatostatin analogues are usually well-tolerated. Side effects include abdominal cramps, nausea, diarrhea and flatulence. Less frequently observed side effects comprise cholelithiasis and cholecystitis, hepatitis, pancreatitis, alopecia and diabetes. Rarely prolongation of QT-interval and arrhythmias have been reported [7].

 2.3. α-Interferon

IFN-α has been used for the treatment of patients with carcinoid syndrome for more than 20 years. IFN-α binds specifically to surface receptors on the tumor cell and thereby reduces hypersecretion resulting in amelioration of carcinoid syndrome in up to 71% of patients [34]. IFN-α is clearly associated with more side effects than somatostatin analogues which therefore remain the treatment of choice in hormonally active tumors.

IFN-α also exerts antiproliferative effects via inhibition of protein synthesis, immunomodulation and inhibition of angiogenesis. A placebo-controlled trial is not available but several phase 2 studies reported a tumor regression in 0–27% (mean 11%) and tumor stabilization in around 40% of the patients. The median duration of tumor response was 12 to 36 months [35].

In two randomized trials the combination therapy of IFN-α and somatostatin analogue (lanreotide in one trial and octreotide in the other) was not superior to somatostatin analogue monotherapy [30,36]. Combination treatment with IFN-α and somatostatin analogues is therefore not indicated as first line treatment but is an option in patients with carcinoid syndrome not sufficiently controlled with somatostatin analogues alone.

Data on pegylated IFN in patients with NEN is very limited [37]. Pegylated IFN has fewer side effects and is better tolerated but has not been approved for NEN.

 2.4. mTOR Inhibitors

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that stimulates metabolism, angiogenesis, growth and proliferation in response to growth factors e.g., insulin like growth factor 1 (IGF-1). Activation of this pathway has been shown in several malignancies, including hereditary syndromes that are associated with neuroendocrine tumors. In patients with tuberous sclerosis complex (TSC) 1/2 as well as in patients with neurofibromatosis the causative gene defects result in a loss of natural inhibition of the mTOR pathway [38]. The specific inhibition of mTOR with drugs such as rapamycin or everolimus inhibits cell proliferation of pancreatic endocrine tumor cell lines [39].

In two phase II trials in patients with advanced neuroendocrine tumors of different origins promising results were shown with temsirolimus and everolimus, respectively [40,41].

In another phase II trial, the so called RADIANT1 study, the efficacy of everolimus in patients with metastatic pancreatic NETs (n = 160) who experienced progression on or after chemotherapy was evaluated. Patients already on octreotide treatment were continued with a combination therapy of octreotide and everolimus (stratum 2, n = 45), whereas the majority of patients received everolimus monotherapy (stratum 1, n = 115). More than two thirds of the patients demonstrated tumor stabilization (stratum 1: 67.8%; stratum 2: 80%), whereas partial remissions occurred in less than 10% of the patients (stratum 1: 9.7%; stratum 2: 4.4%) [42].

The efficacy of everolimus in patients with pancreatic NET was confirmed in the RADIANT 3 trial, a large (n = 410) placebo-controlled phase III study. Patients with progressive low-grade or intermediate-grade pancreatic NET were randomly assigned to 10 mg everolimus or placebo. The median progression-free survival (primary endpoint) was 11.4 months (95% CI, 10.8 to 14.8) with everolimus, as compared with 5.4 months (95% CI, 4.3 to 5.6) with placebo (hazard ratio for disease progression or death with everolimus, 0.34; 95% CI, 0.26 to 0.44; p < 0.001) [43]. As reported before, the benefit from everolimus in this patient cohort was seen primarily in tumor stabilization or minor tumor shrinkage (stable disease according to RECIST criteria in 73%) whereas the objective response rate was low (5%). Based on the RADIANT 3 data everolimus has been approved for the treatment of patients with pancreatic NET in the United States and Europe.

Another large phase III trial (RADIANT 2) investigated the role of everolimus in patients with progressive NET and a history of carcinoid syndrome. Only half of the 429 enrolled patients had NENs of the small intestine, the remaining patients comprised bronchopulmonary NETs (15% everolimus + octreotide group, 5% placebo + octreotide group), colonic NETs, pNETs and others. Patients received 10 mg everolimus daily + 30 mg octreotide LAR monthly or placebo + 30 mg octreotide LAR monthly, respectively. The primary endpoint was progression free survival (PFS). Based on central imaging assessment the combination of everolimus and octreotide led to a prolongation of PFS of 5.1 months as compared to placebo + octreotide (16.4 versus 11.3 months, HR 0.77; p = 0.026), but the pre-specified p level of 0.024 was narrowly missed. According to local radiological assessment in the centers, however, the combination showed a similar risk reduction (HR 0.78) and reached statistical significance (p = 0.018) [44].

Further investigations are necessary to define the subgroups of patients who benefit from everolimus monotherapy or combination treatments with somatostatin analogues. Everolimus has so far not been approved for the treatment of patients with carcinoid syndrome.

Toxicity

The most common toxicity of everolimus was stomatitis (64% of patients) which was mild in most cases (≥grade3: 7%). In 20%–23% of the patients infections were reported, which were ≥grade 3 in 2%–5%. Low grade diarrhea occurred in 27%–34% of the patients. Hematological toxicity was generally mild, but ≥grade 3 thrombocytopenia occurred in 5% of the patients. Everolimus may also induce or worsen hyperglycemia. A non-infectious pneumonitis was reported in 12%–17% (≥grade 3: 2%) and requires special attention and care [43,44]. Adverse events related to the study drug led to discontinuation of treatment in 13% of the patients receiving everolimus in the RADIANT 3 trial.

 2.5. Multikinase Inhibitors

As neuroendocrine tumors are highly vascularised and express receptors for vascular endothelial growths factors (VEGFR) there is a rationale for treatment with multikinase inihibitors targeting these receptors.

Several substances, including sorafenib, pazopanib and sunitinib have been administered in phase II trials [45,46,47,48,49] (see Table 3).

Sunitinib is an oral multikinase inhibitor with a broad spectrum of targets including VEGFR, PDGFR, c-kit and RET. An international multicenter phase III clinical trial investigated 37.5 mg sunitinib daily versus placebo in patients with progressive low to intermediate grade pNET. Recruitment was terminated prematurely after inclusion of half of the planned number of patients (171 of 340). The independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib in an interim analysis and recommended premature discontinuation of the trial.

Time to progression was significantly longer in the patients treated with sunitinib as compared to placebo (11.4 months versus 5.5 months; HR 0.42; p < 0.001). Although the majority of patients treated with sunitinib showed minor tumor shrinkage as best morphological result, the objective response rate was only 9.3% [48]. Based on these data, sunitinib was approved for the treatment of advanced pNET in the USA and Europe. The experience in treating extrapancreatic neuroendocrine tumors is limited and thus sunitinib is currently not approved for this indication.

cancers-04-00113-t003_Table 3

Overview on studies with targeted therapies in patients with neuroendocrine tumors.

First Author and Year patients Number of Patients Regimen PD Prior to Treatment Design PR TTP/PFS Additional Remarks
Hobday 2007 [45], (abstract) carcinoid 50 sorafenib 400 mg bid no phase II 10% 7.8 months 43% grade 3/4 toxicity
pNET 43 11.9 months
Yao 2008 [46] carcinoid 22 octreotide + bevacizumab no randomized phase II 18% 95% at week 18
22 octreotide + PEGIFN 0% 68% at week 18
Kulke 2008 [47] carcinoid 41 sunitinib 37.5 mg no phase II 2.4% 10.2 months
pNET 66 16.7% 7.7 months
Raymond 2011 [48] pNET 171 sunitinib 37.5 mg yes randomized phase III, placebo-controlled 9.3% 11.4 months versus 5.5 months (placebo) 340 planned patients; survival advantage
Phan 2010 [49], (abstract) carcinoid 20 octreotide + pazopanib 800 mg no phase II 0% 12.7 months grade 3/4 hypertension 11.7%
pNET 31 19% 11.7 months
Duran 2006 [40] GEPNET 37 temsirolimus yes phase II 6% 6 months
Yao 2008 [41] carcinoid 30 5–10 mg everolimus + octreotide no phase II 17% 63 weeks trend to better results at 10 mg dose level
pNET 30 27% 50 weeks
Yao 2010 [42] pNET 115 10 mg everolimus yes phase II 9.7% 9.7 months 2 strata, no randomization
45 10 mg everolimus + octreotide 4.4% 17 months
Yao 2011 [43] pNET 410 10 mg everolimus versus placebo yes randomized phase III, placebo-controlled 5% 11.4 months versus 5.4 months (placebo)
Pavel 2010 [44], (abstract) carcinoid syndrome 429 10 mg everolimus + octreotide versus placebo + octreotide yes randomized phase III, placebo-controlled 16.4 months versus 11.3 months only 50% intestinal primary, mixed population

PD: progressive disease; PR: partial remission; TTP: time to progression; PFS: progression-free survival; GEPNET: gastroenteropancreatic neuroendocrine tumor; pNET: pancreatic neuroendocrine tumor; PEGIFN: pegylated interferon-α.

 Toxicity and Quality of Life

The most frequent adverse events in the sunitinib group were diarrhea (59%), nausea (45%), vomiting (34%), asthenia (34%), and fatigue (32%). Severe adverse events included hypertension (10%), neutropenia (12%) hand foot syndrome (6%) and one case of cardiac failure. Global health related quality of life (measured with EORTC QLQ C30) did not differ between patient groups [48].

The place of mTOR inhibitors and sunitinib in the therapeutic algorithm of patients with pNETs still remains to be defined. The majority of patients in both phase III trials received everolimus and sunitinib, respectively, after failure of somatostatin analogues and/or chemotherapy.

 2.6. Chemotherapy

Chemotherapy is indicated in patients with poorly differentiated NETs regardless of the primary tumor localization. Systemic chemotherapy is also indicated in mixed adenoneuroendocrine carcinomas including goblet cell carcinoids of the appendix.

In patients with well differentiated G1/G2 pNETs chemotherapy is recommended when tumor progression is observed or as first line treatment (without documented progression) in patients with a high tumor load and G2 differentiation. In other foregut G2 tumors (bronchial, thymus, gastric, duodenal NET) chemotherapy is also an option. In contrast, well differentiated intestinal NET should not be treated with chemotherapy due to lack of documented efficacy.

2.6.1. Chemotherapy in G3 Neuroendocrine Carcinoma

In these highly malignant tumors, chemotherapy with cisplatin and etoposide is considered as standard treatment. Reported objective response rates are high (42%–67%) [50,51], but response duration is short (median 8–9 months) and median overall survival does not exceed 19 months. In elderly patients or patients with renal insufficiency cisplatin may be replaced by carboplatin.

Several other regimens which were investigated in G3 neuroendocrine carcinomas including paclitaxel + carboplatin + etoposide [52]; capecitabine + oxaliplatin [53] and carboplatin + vincristin + etoposide [54] were not shown to be superior to the standard cisplatin and etoposide regimen.

A small study in patients with gastric neuroendocrine carcinoma [55] reported promising results (response rate 75%, median survival 22.6 months, n = 12) using the combination cisplatin + irinotecan.

Furthermore, a Scandinavian group reported good results with a temozolomide based chemotherapy as second line treatment in G3 neuroendocrine carcinoma [56].

 2.6.2. Chemotherapy in G1/G2 NET of Pancreatic and Other Foregut Origin

Streptozocin in combination with 5-fluorouracil (5-FU) or/and doxorubicin is the standard regimen in this patient group. Older studies reporting response rates of up to 69% including the use of clinical parameters for the assessment of tumor response [57,58]. In newer studies using established imaging criteria the response rates do not exceed 40%. However, this is still superior to the results of other treatment options including targeted therapies. The duration of response often is long-lasting (time to progression 7–20 months) [59,60,61,62,63].

The main toxicity of streptozocin is renal dysfunction in more than 20% of treated patients including proteinuria and renal failure. Renal function including determination of glomerular filtration rate and proteinuria should therefore be monitored closely in streptozocin-treated patients. Other side effects include nausea/vomiting, impaired glucose tolerance and mild bone marrow toxicity.

Dacarbazine (DTIC) alone or in combination with epirubicin and 5-FU is an alternative regimen with ORR of around 30% [64,65,66]. Monotherapy of DTIC (650 mg/m2–850 mg/m2 every 4 weeks) can easily be applied in an outpatient setting. Main toxicities are nausea/vomiting and bone marrow suppression.

Temozolomide is an oral chemotherapeutic drug sharing the active metabolite metozolomide with DTIC. Small studies report promising results as monotherapy or in combination with bevacizumab, thalidomide and capecitabine [67,68,69]. The combination of temozolomide and capecitabine as first line treatment in pNET resulted in an impressive response rate of 70% and a 2 year survival rate of 92% [69]. However, this was a retrospective study with a limited number of patients (n = 30) that should be confirmed in a larger prospective clinical trial.

 2.7. Ongoing Trials and Future Perspectives

Further targeted treatments that are currently investigated include atiprimod (oral STAT3 and AKT inhibitor), cabozantinib (oral multikinase inhibitor), drugs targeting the insulin like growth factor receptor-1 (IGF-1-R) (cixutumumab, MK0646, AMG 479), pazopanib (oral multikinase inhibitor), axitinib (angiogenesis inhibitor, oral multikinase inhibitor), thalidomide, selective and non-selective PI3K inhibitors and the proteasome inhibitor bortezomib.

The efficacy of sunitinib in patients with poorly differentiated neuroendocrine tumors is evaluated in a phase II study.

An ongoing phase III trial compares bevacizumab and octreotide versus interferon-α2b and octreotide in patients with progressive carcinoid tumors. Another placebo-controlled phase III trial of everolimus in patients with carcinoid tumors is planned (RADIANT-4) to further evaluate the role of mTOR inhibition in this patient population.

New substances that might be interesting for treatment of NEN comprise inhibitors of heat shock protein 90, inhibitors of the src pathway and hedgehog inhibitors [70,71,72].

Blocking a single signaling pathway in tumor cells often leads to the development of escape mechanisms. This phenomenon could for example be demonstrated in intestinal neuroendocrine tumor cell lines treated with the mTOR inhibitor everolimus [73]. Therefore combination treatments may be more effective in NEN patients. A combinatorial approach can include two targeted treatments (e.g., EGF-R inhibition + mTOR inhibition [74] or IGF-1-R inhibition + mTOR inhibition) but also the combination of one targeted treatment and locoregional treatments (e.g., hepatic artery embolization followed by sunitinib or everolimus; SIRT in combination with sunitinib or everolimus) and the combination of chemotherapy and targeted treatments. In trials with combination treatments a focus on side effects and quality of life is essential.

We clearly need prospective comparative phase III trials of the different therapeutic modalities in pNET patients to evaluate superiority regarding efficacy, tolerance and quality of life. In the future, a better understanding of the different tumor biology and analysis of molecular mechanisms will help to provide a basis for individualized treatment.

 3. Conclusions

With the advent of novel small molecule inhibitors such as sunitinib and everolimus the therapeutic armamentarium available for G1 and G2 pancreatic NET has substantially broadened. The place of mTOR inhibitors and sunitinib in the therapeutic algorithm of patients with pNETs in respect to presently used therapies such as PPRT or somatostatin analogues still remains to be defined. There is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.

 Conflict of interest

Anja Rinke has served as a speaker for Novartis, Pfizer and Ipsen and as an advisory board member for Ipsen. Thomas Gress received funding for meeting organisation and honoraria for invited talks from Ipsen, Novartis and Pfizer.

 References Yao J.C. Hassan M. Phan A. Dagohoy C. Leary C. Mares J.E. Abdalla E.K. Fleming J.B. Vauthey J.N. Rashid A. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States J. Clin. Oncol. 2008 26 3063 3072 10.1200/JCO.2007.15.437718565894 Hauso O. Gustafsson B.I. Kidd M. Waldum H.L. Drozdov I. Chan A.K. Modlin I.M. Neuroendocrine tumor epidemiology: Contrasting Norway and North America Cancer 2008 113 2655 2664 10.1002/cncr.23883 Niederle M.B. Hackl M. Kaserer K. Niederle B. Gastroenteropancreatic neuroendocrine tumours: The current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: An analysis based on prospectively collected parameters Endocr. Relat. Cancer 2010 17 909 918 10.1677/ERC-10-0152 Rindi G. Arnold R. Bosman F.T. Capella C. Klimstra D.S. Klöppel G. Komminoth P. Solcia P. Nomenclature and classification of neuroendocrine neoplasms of the digestive system WHO Classification of Tumors of the Digestive System Bosman F.T. Carneiro F. Hruban R.H. Theise N.D. IARC Lyon, France 2010 S13 S14 Rindi G. Klöppel G. Alhman H. Caplin M. Couvelard A. de Herder W.W. Erikssson B. Falchetti A. Falconi M. Komminoth P. TNM staging of foregut (neuro)endocrine tumors: A consensus proposal including a grading system Virchows Arch. 2006 449 395 401 10.1007/s00428-006-0250-1 Rindi G. Klöppel G. Couvelard A. Komminoth P. Körner M. Lopes J.M. McNicol A.M. Nilsson O. Perren A. Scarpa A. TNM staging of midgut and hindgut (neuro)endocrine tumors: A consensus proposal including a grading system Virchows Arch. 2007 451 757 762 10.1007/s00428-007-0452-1 Modlin I.M. Pavel M. Kidd M. Gustafsson B.I. Review article: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours Aliment. Pharmacol. Ther. 2010 31 169 188 19845567 Long R.G. Peters J.R. Bloom S.R. Brown M.R. Vale W. Rivier J.E. Grahame-Smith D.G. Somatostatin, gastrointestinal peptides, and the carcinoid syndrome Gut 1981 22 549 553 10.1136/gut.22.7.549 Wood S.M. Kraenzlin M.E. Adrian T.E. Bloom S.R. Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses Gut 1985 26 438 444 10.1136/gut.26.5.438 Kvols L.K. Moertel C.G. O'Connell M.J. Schutt A.J. Rubin J. Hahn R.G. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue N. Engl. J. Med. 1986 315 663 666 10.1056/NEJM198609113151102 Kvols L.K. Martin J.K. Marsh H.M. Moertel C.G. Rapid reversal of carcinoid crisis with a somatostatin analogue N. Engl. J. Med. 1985 313 1229 1230 3877239 Bhattacharyya S. Toumpanakis C. Chilkunda D. Caplin M.E. Davar J. Risk factors for the development and progression of carcinoid heart disease Am. J. Cardiol. 2011 107 1221 1226 10.1016/j.amjcard.2010.12.025 Koop H. Klein M. Arnold R. Acid inhibitory effects of somatostatin analog in malignant gastrinomas J. Clin. Gastroenterol. 1990 12 120 121 2303679 Jensen R.T. Niederle B. Mitry E. Ramage J.K. Steinmuller T. Lewington V. Scarpa A. Sundin A. Perren A. Gross D. Gastrinoma (duodenal and pancreatic) Neuroendocrinology 2006 84 173 182 10.1159/000098009 O'Toole D. Ducreux M. Bommelaer G. Wemeau J.L. Bouché O. Catus F. Blumberg J. Ruszniewski P. Treatment of carcinoid syndrome: A prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance Cancer 2000 88 770 776 10.1002/(SICI)1097-0142(20000215)88:4<770::AID-CNCR6>3.0.CO;2-0 Schmid H.A. Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors Neuroendocrinology 2004 80 47 50 10.1159/000080741 Susini C. Buscail L. Rationale for the use of somatostatin analogs as antitumor agents Ann. Oncol. 2006 17 1733 1742 10.1093/annonc/mdl105 Vinik A. Moattari A.R. Use of somatostatin analog in management of carcinoid syndrome Dig. Dis. Sci. 1989 34 14 27 10.1007/BF01536042 Oberg K. Norheim I. Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide Acta Oncol. 1991 30 503 507 10.3109/02841869109092409 Saltz L. Trochanowski B. Buckley M. Heffernan B. Niedzwiecki D. Tao Y. Kelsen D. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors Cancer 1993 72 244 248 10.1002/1097-0142(19930701)72:1<244::AID-CNCR2820720143>3.0.CO;2-Q Arnold R. Trautmann M.E. Creutzfeldt W. Benning R. Benning M. Neuhaus C. Jürgensen R. Stein K. Schäfer H. Bruns C. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours Gut 1996 38 430 438 10.1136/gut.38.3.430 di Bartolomeo M. Bajetta E. Buzzoni R. Mariani L. Carnaghi C. Somma L. Zilembo N. di Leo A. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group Cancer 1996 77 402 408 10.1002/(SICI)1097-0142(19960115)77:2<402::AID-CNCR25>3.0.CO;2-4 Tomassetti P. Migliori M. Gullo L. Slow-release lanreotide treatment in endocrine gastrointestinal tumors Am. J. Gastroenterol. 1998 93 1468 1471 10.1111/j.1572-0241.1998.465_q.x Wymenga A.N. Eriksson B. Salmela P.I. Jacobsen M.B. van Cutsem E.J. Fiasse R.H. Välimäki M.J. Renstrup J. de Vries E.G. Oberg K.E. Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms J. Clin. Oncol. 1999 17 1111 10561168 Faiss S. Räth U. Mansmann U. Caird D. Clemens N. Riecken E.O. Wiedenmann B. Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors Digestion 1999 60 469 476 10.1159/000007693 Ricci S. Antonuzzo A. Galli L. Ferdeghini M. Bodei L. Orlandini C. Conte P.F. Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide Ann. Oncol. 2000 11 1127 1130 10.1023/A:1008383132024 Tomassetti P. Migliori M. Corinaldesi R. Gullo L. Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR Aliment. Pharmacol. Ther. 2000 14 557 560 10.1046/j.1365-2036.2000.00738.x Aparicio T. Ducreux M. Baudin E. Sabourin J.C. de Baere T. Mitry E. Schlumberger M. Rougier P. Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours Eur. J. Cancer 2001 37 1014 1019 10.1016/S0959-8049(01)00073-911334727 Shojamanesh H. Gibril F. Louie A. Ojeaburu J.V. Bashir S. Abou-Saif A. Jensen R.T. Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma Cancer 2002 94 331 343 10.1002/cncr.10195 Faiss S. Pape U.F. Böhmig M. Dörffel Y. Mansmann U. Golder W. Riecken E.O. Wiedenmann B. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—The International Lanreotide and Interferon Alfa Study Group J. Clin. Oncol. 2003 21 2689 2696 10.1200/JCO.2003.12.14212860945 Bajetta E. Procopio G. Catena L. Martinetti A. de Dosso S. Ricci S. Lecchi A.S. Boscani P.F. Iacobelli S. Carteni G. Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: A Phase III Study Cancer 2006 107 2474 2481 10.1002/cncr.2227217054107 Panzuto F. di Fonzo M. Iannicelli E. Sciuto R. Maini C.L. Capurso G. Milione M. Cattaruzza M.S. Falconi M. David V. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma Ann. Oncol. 2006 17 461 466 10.1093/annonc/mdj11316364959 Rinke A. Müller H.H. Schade-Brittinger C. Klose K.J. Barth P. Wied M. Mayer C. Aminossadati B. Pape U.F. Bläker M. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group J. Clin. Oncol. 2009 27 4656 4663 10.1200/JCO.2009.22.851019704057 Oberg K. Interferon in the management of neuroendocrine GEP-tumors: A review Digestion 2000 62 92 97 10.1159/000051862 Oberg K. Norheim I. Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide Acta Oncol. 1991 30 503 507 10.3109/02841869109092409 Arnold R. Rinke A. Klose K. Müller H. Wied M. Zamzow K. Schmidt C. Schade-Brittinger C. Barth P. Moll R. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: A randomized trial Clin. Gastroenterol. Hepatol. 2005 3 761 771 10.1016/S1542-3565(05)00481-716234004 Pavel M.E. Baum U. Hahn E.G. Schuppan D. Lohmann T. Efficacy and tolerability of pegylated IFN-alpha in patients with neuroendocrine gastroenteropancreatic carcinomas J. Interferon Cytokine Res. 2006 26 8 13 10.1089/jir.2006.26.8 Johannessen C.M. Reczek E.E. James M.F. Brems H. Legius E. Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR Proc. Natl. Acad. Sci. USA 2005 102 8573 8578 10.1073/pnas.050322410215937108 Missiaglia E. Dalai I. Barbi S. Beghelli S. Falconi M. della Peruta M. Piemonti L. Capurso G. di Florio A. delle Fave G. Pancreatic endocrine tumors: Expression profiling evidences a role for AKT-mTOR pathway J. Clin. Oncol. 2010 28 245 255 10.1200/JCO.2008.21.598819917848 Duran I. Kortmansky J. Singh D. Hirte H. Kocha W. Goss G. Le L. Oza A. Nicklee T. Ho J. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas Br. J. Cancer 2006 95 1148 1154 10.1038/sj.bjc.6603419 Yao J.C. Phan A.T. Chang D.Z. Wolff R.A. Hess K. Gupta S. Jacobs C. Mares J.E. Landgraf A.N. Rashid A. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study J. Clin. Oncol. 2008 26 4311 4318 10.1200/JCO.2008.16.785818779618 Yao J.C. Lombard-Bohas C. Baudin E. Kvols L.K. Rougier P. Ruszniewski P. Hoosen S. St. Peter J. Haas T. Lebwohl D. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial J. Clin. Oncol. 2010 28 69 76 10.1200/JCO.2009.24.266919933912 Yao J.C. Shah M.H. Ito T. Bohas C.L. Wolin E.M. van Cutsem E. Hobday T.J. Okusaka T. Capdevila J. de Vries E.G. Everolimus for advanced pancreatic neuroendocrine tumors N. Engl. J. Med. 2011 364 514 523 10.1056/NEJMoa100929021306238 Pavel M.E. Hainsworth J.D. Baudin E. Peeters M. Hörsch D. Winkler R.E. Klimovski J. Lebwohl D. Jehl V. Wolin E.M. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): A randomised, placebo-controlled, phase 3 study Lancet 2011 378 2005 2012 10.1016/S0140-6736(11)61742-X22119496 Hobday T.J. Rubin J. Holen K. Picus J. Donehower R. Marschke R. Maples W. Lloyd R. Mahoney M. Erlichman C. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study J. Clin. Oncol. 2007 25 4504 (Meeting Abstracts) 10.1200/JCO.2007.12.3901 Yao J.C. Phan A. Hoff P.M. Chen H.X. Charnsangavej C. Yeung S.C. Hess K. Ng C. Abbruzzese J.L. Ajani J.A. Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b J. Clin. Oncol. 2008 26 1316 1323 10.1200/JCO.2007.13.637418323556 Kulke M.H. Lenz H.J. Meropol N.J. Posey J. Ryan D.P. Picus J. Bergsland E. Stuart K. Tye L. Huang X. Activity of sunitinib in patients with advanced neuroendocrine tumors J. Clin. Oncol. 2008 26 3403 3410 10.1200/JCO.2007.15.902018612155 Raymond E. Dahan L. Raoul J.L. Bang Y.J. Borbath I. Lombard-Bohas C. Valle J. Metrakos P. Smith D. Vinik A. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors N. Engl. J. Med. 2011 364 501 513 10.1056/NEJMoa100382521306237 Phan A.T. Yao J.C. Fogelman D.R. Hess K.R. Ng C.S. Bullock S.A. Malinowski P. Regan E. Kulke M. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC) J. Clin. Oncol. 2010 28 4001 (Meeting Abstracts) Moertel C.G. Kvols L.K. O'Connell M.J. Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms Cancer 1991 68 227 232 10.1002/1097-0142(19910715)68:2<227::AID-CNCR2820680202>3.0.CO;2-I Mitry E. Baudin E. Ducreux M. Sabourin J.C. Rufié P. Aparicio T. Lasser P. Elias D. Duvillard P. Schlumberger M. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin Br. J. Cancer 1999 81 1351 1355 10.1038/sj.bjc.669032510604732 Hainsworth J.D. Spigel D.R. Litchy S. Greco F.A. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: A minnie pearl cancer research network study J. Clin. Oncol. 2006 24 3548 3554 10.1200/JCO.2005.05.057516877720 Bajetta E. Catena L. Procopio G. de Dosso S. Bichisao E. Ferrari L. Martinetti A. Platania M. Verzoni E. Formisano B. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother. Pharmacol. 2007 59 637 642 10.1007/s00280-006-0306-6 Olsen I.H. Langer S.W. Jepsen I. Assens M. Federspiel B. Hasselby J.P. Hansen C.P. Kjær A. Knigge U. First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: A single institution experience Acta Oncol. 2012 51 97 100 10.3109/0284186X.2011.582881 Okita N.T. Kato K. Takahari D. Hirashima Y. Nakajima T.E. Matsubara J. Hamaguchi T. Yamada Y. Shimada Y. Taniguchi H. Neuroendocrine tumors of the stomach: Chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma Gastric. Cancer 2011 14 161 165 10.1007/s10120-011-0025-521327441 Welin S. Sorbye H. Sebjornsen S. Knappskog S. Busch C. Oberg K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy Cancer 2011 117 4617 4622 10.1002/cncr.2612421456005 Moertel C.G. Hanley J.A. Johnson L.A. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma N. Engl. J. Med. 1980 303 1189 1194 10.1056/NEJM198011203032101 Moertel C.G. Lefkopoulo M. Lipsitz S. Hahn R.G. Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma N. Engl. J. Med. 1992 326 519 523 10.1056/NEJM1992022032608041310159 Eriksson B. Skogseid B. Lundqvist G. Wide L. Wilander E. Oberg K. Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors Cancer 1990 65 1883 1890 10.1002/1097-0142(19900501)65:9<1883::AID-CNCR2820650902>3.0.CO;2-3 Delaunoit T. Ducreux M. Boige V. Dromain C. Sabourin J.C. Duvillard P. Schlumberger M. de Baere T. Rougier P. Ruffie P. The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option? Eur. J. Cancer 2004 40 515 520 10.1016/j.ejca.2003.09.03514962717 Cheng P.N. Saltz L.B. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma Cancer 1999 86 944 948 10.1002/(SICI)1097-0142(19990915)86:6<944::AID-CNCR8>3.0.CO;2-P Kouvaraki M.A. Ajani J.A. Hoff P. Wolff R. Evans D.B. Lozano R. Yao J.C. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas J. Clin. Oncol. 2004 22 4762 4771 10.1200/JCO.2004.04.024 Sun W. Lipsitz S. Catalano P. Mailliard J.A. Haller D.G. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281 J. Clin. Oncol. 2005 23 4897 4904 10.1200/JCO.2005.03.616 Altimari A.F. Badrinath K. Reisel H.J. Prinz R.A. DTIC therapy in patients with malignant intra-abdominal neuroendocrine tumors Surgery 1987 102 1009 1017 2825370 Ramanathan R.K. Cnaan A. Hahn R.G. Carbone P.P. Haller D.G. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282 Ann. Oncol. 2001 12 1139 1143 10.1023/A:1011632713360 Bajetta E. Rimassa L. Carnaghi C. Seregni E. Ferrari L. di Bartolomeo M. Regalia E. Cassata A. Procopio G. Mariani L. 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors Cancer 1998 83 372 378 10.1002/(SICI)1097-0142(19980715)83:2<372::AID-CNCR23>3.0.CO;2-P9669822 Ekeblad S. Sundin A. Janson E.T. Welin S. Granberg D. Kindmark H. Dunder K. Kozlovacki G. Orlefors H. Sigurd M. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors Clin. Cancer Res. 2007 13 2986 2991 10.1158/1078-0432.CCR-06-205317505000 Kulke M.H. Stuart K. Enzinger P.C. Ryan D.P. Clark J.W. Muzikansky A. Vincitore M. Michelini A. Fuchs C.S. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors J. Clin. Oncol. 2006 24 401 406 10.1200/JCO.2005.03.604616421420 Strosberg J.R. Fine R.L. Choi J. Nasir A. Coppola D. Chen D.T. Helm J. Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas Cancer 2011 117 268 275 10.1002/cncr.2542520824724 Gilbert J.A. Adhikari L.J. Lloyd R.V. Rubin J. Haluska P. Carboni J.M. Gottardis M.M. Ames M.M. Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors Endocr. Relat. Cancer 2010 17 623 636 10.1677/ERC-09-0318 di Florio A. Adesso L. Pedrotti S. Capurso G. Pilozzi E. Corbo V. Scarpa A. Geremia R. Delle Fave G. Sette C. Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells Endocr. Relat. Cancer 2011 18 541 554 10.1530/ERC-10-0153 Fendrich V. Wiese D. Waldmann J. Lauth M. Heverhagen A.E. Rehm J. Bartsch D.K. Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms Ann. Surg. 2011 254 818 823 10.1097/SLA.0b013e318236bc0f Svejda B. Kidd M. Kazberouk A. Lawrence B. Pfragner R. Modlin I.M. Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT Cancer 2011 117 4141 4154 10.1002/cncr.26011 Chiu C.W. Nozawa H. Hanahan D. Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis J. Clin. Oncol. 2010 28 4425 4433 10.1200/JCO.2010.28.0198