Well-differentiated neuroendocrine tumors: a review covering basic principles to loco-regional and targeted therapies

Abstract

Neuroendocrine tumors (NETs) are a complex group of malignancies with variable prognosis and response to treatment. For pancreatic neuroendocrine and carcinoid tumors, traditional cytotoxic chemotherapies have demonstrated minimal activity. Current approaches for treatment of metastatic disease use a combination of loco-regional and targeted biological therapies. Clinical trials remain critical for evaluation of new and promising therapeutic options for patients with NETs.

Introduction

Neuroendocrine tumors (NETs) comprise a spectrum of neoplasms with variable biological behavior and prognosis. Derived from the neural crest origin, NETs originate from many organs, including small intestine, appendix, stomach, colon or rectum, pancreas, lung and ovary. The historical nomenclature describing NETs based on site of origin is often confusing. Islet cell carcinoma or pancreatic neuroendocrine tumor (PNET) refers to NETs arising from pancreatic endocrine cells. The term carcinoid tumor is best used to describe NETs, which arise from aerodigestive tissues and have well- or moderately differentiated histology. Some refer to NETs with moderately differentiated grade as atypical carcinoids, and to NETs with poorly differentiated histology as small cell carcinomas.

Presentation and initial evaluation

Functional NETs may produce hormones, resulting in a condition known as the carcinoid syndrome, characterized commonly by skin flushing, diarrhea or palpitations. Approximately, half of patients with NETs, from gastrointestinal or pancreatic primary tumors, have symptoms related to carcinoid syndrome, and in general the presence of these symptoms implies the presence of liver metastases, as hormones produced by the primary tumor are metabolized in the liver to non-functional by-products. Liver metastases, on the other hand, are able to secrete hormones directly into the hepatic veins and systemic circulation. Hence, hormone-related symptoms are often an indicator of metastatic disease, although primary tumors with access to systemic circulation may rarely cause similar symptoms. Pancreatic primary tumors may be non-functional or produce hormones causing other symptoms and syndromes unrelated to carcinoid syndrome. These functional PNETs are named for the primary hormone produced, such as insulinomas, gastrinomas, glucagonomas and somatostatinomas.

The appropriate evaluation for any patient with a new diagnosis of NET involves a complete history and physical examination, with attention to questions regarding symptoms possibly related to the carcinoid syndrome and family history relevant for syndromes, such as multiple endocrine neoplasia and Von Hippel-Lindau disease. Initial diagnostic tests include multiple laboratory and several imaging studies. The results of these investigations guide therapy related to symptom control, and management of primary and often metastatic tumors. Because many NETs produce hormones with or without associated symptoms, we routinely measure several polypeptides during the first evaluation of any patient with NET (Table 1), and any elevated markers are subsequently followed to aid in surveillance following therapy or during observation. Most centers routinely measure 24-h urine 5-hydroxyindoleacetic acid and serum chromogranin-A levels in the evaluation of NETs. We find it useful to measure serum pancreastatin, a post-translational split product of chromogranin-A, and we have previously demonstrated a correlation between decreased pancreastatin levels and radiological response to regional liver therapy in patients with metastatic NETs (Bloomston et al., 2007). Others have also found pancreastatin to be a useful biomarker for NETs, specifically in that elevated plasma concentrations before therapy are associated with number of liver metastases, increased periprocedural mortality after hepatic arterial embolization and overall poor outcome (Vinik et al., 2009).

Table 1.

The Ohio State University total polypeptide panel for initial evaluation of neuroendocrine tumors

Peptide	Reference range	Elevated
Calcitonin	<5.0 pg/ml	Uncommon (10%)
Gastrin	0–122 pg/ml	Uncommon (3–18%)
Gastrin-releasing peptide	<500 pg/ml	Rare (3%)
Neurotensin	<100 pg/ml	Uncommon (10–12%)
Pancreastatin	<135 pg/ml	Common (81–100%)
Pancreatic polypeptide	<500 pg/ml	Uncommon (13–29%)
Substance P	0–240 pg/ml	Uncommon (18–19%)
Vasoactive intestinal peptide	0–84 pg/ml	Rare (<5%)

References: Calhoun et al., 2003; Varker et al., 2008; Yao et al., 2008.

It is also important to evaluate electrolytes, liver transaminases, bilirubin and alkaline phosphatase, any of which may be abnormal in patients with NET, especially in those patients with a large burden of liver metastases. Cross-sectional imaging with high-quality multidetector computed tomography scans of the chest, abdomen and pelvis (triple phase study for the abdomen and pelvis includes series without intravenous contrast, and with contrast in the arterial and portal venous phases) provides high yield for both the initial evaluation of metastatic disease and to assess response to therapies (Figure 1). Magnetic resonance imaging is occasionally necessary to classify indeterminate findings in the liver on CT scan.

Figure 1.

Computed tomography (CT) scan imaging for neuroendocrine tumors. (a) Selected axial CT images of a patient with a large pancreatic primary neuroendocrine carcinoma and multiple hepatic metastases (top and bottom). (b) CT axial image after right lobar hepatic transarterial chemoembolization (TACE) for liver metastases (top) with three-dimensional reconstruction and subtracted view (bottom).

The radiolabeled somastostatin analog, octreotide, can be imaged by a nuclear medicine gamma camera and used to detect primary and metastatic NETs. This modality, termed somatostatin scintigraphy, allows for total body scanning and has high sensitivity (range 61–100% depending on tumor subtype) and positive predictive value for detection of NETs (Krenning et al., 1993; Modlin et al., 2005). Positive scintigraphy has been associated with expression of the somatostatin receptor subtype 2 and improved overall survival (Asnacios et al., 2008). The addition of single photon emission computed tomography to somatostatin scintigraphy allows for increased anatomic detail to the functional information gained with nuclear imaging (Figure 2). At our center, we use somatostatin scintigraphy in the initial evaluation of patients with metastatic NET before planned surgical resection or when otherwise clinically indicated, such as for evaluation of unexplained new symptoms, change in performance status or unusual computed tomography scan findings.

Figure 2.

Octreoscan imaging for neuroendocrine tumors. Coronal octreoscan image demonstrating radiotracer uptake in multiple liver metastases and a large pancreatic primary neuroendocrine carcinoma. (b) Coronal octreoscan fusion images with single positron emission tomography (SPECT) providing increased anatomic detail. (c) Axial octreoscan fusion images with SPECT.

Given the variability in the biological activity of NETs with well-differentiated histology, ranging from indolent disease, with no or slow growth over many years, to aggressive malignancies, which can be fatal weeks to months after initial diagnosis, histological segregation of disease, has a role in treatment selection (Figure 3). Previous studies have demonstrated the association of poorer survival in NET patients with poor histological grade, perineural or lymphovascular invasion, mitotic index as measured by Ki-67 staining, tumor size or hormone production (Reidy et al., 2009). Both the World Health Organization and others have developed classification systems for NETs, based largely upon cell of origin and histological subtypes (Solcia et al., 2000; Rindi et al., 2006, 2007). Correct interpretation of pathological findings after biopsy is therefore critical, and our usual practice is to perform an internal review of any pathological slides obtained at other referring institutions, with a priority given to determining histological grade and Ki-67 staining.

Figure 3.

Histological subtypes of neuroendocrine tumors. (a) Microscopic section from a well-differentiated neuroendocrine carcinoma demonstrating low mitotic rate and low-grade bland histology. (b) Microscopic section from a poorly differentiated neuroendocrine carcinoma demonstrating high mitotic rate and high-grade histology similar in appearance to small cell carcinomas.

This review will discuss treatment options for patients, with primary and metastatic NETs, primarily focusing on well-differentiated carcinomas arising from pancreatic or intestinal cell origin. These tumors are described as typical carcinoids by the 2004 World Health Organization classification. The management of other malignancies, which broadly fit the classification of NET, such as cutaneous neuroendocrine carcinomas/Merkel cell carcinoma, medullary thyroid cancer, functional adrenal adenomas, pheochromocytoma, paraganglioma and small cell carcinomas will not be discussed. The bulk of the prospective trials presented in this paper will be those taken from the last 10 years, with particular attention to biologically targeted therapies.

Local and regional therapies

No review about NET management is complete without discussion of local and regional therapies for primary tumors and metastases. Surgical resection is the main-stay of therapy for localized primary tumors, although observation may be appropriate for slow-growing asymptomatic primary tumors for which surgical resection would be associated with a high risk of morbidity or mortality. Surgery is the only potentially curative treatment for early stage carcinoid or PNETs. Surgical debulking or cytoreduction of metastatic disease, usually liver or mesenteric lymph node metastases, is appropriate in selected patients for palliation of pain, bowel obstruction or carcinoid syndrome. Although surgical resection has been associated with better prolonged symptom control compared with other modalities, studies supporting this claim are subject to selection bias (Que et al., 1995; Osborne et al., 2006). There are no controlled studies to support the use of surgical debulking in asymptomatic patients with a large burden of tumor in the liver although retrospective studies demonstrate improved outcomes in these patients compared with those who do not undergo surgical resection (Hodul et al., 2008).

Liver transplantation is feasible for patients with unresectable metastatic NET metastases, although the worldwide experience is limited. A review of the French experience with transplantation for metastatic NETs was reported by Le Treut, in which 85 patients underwent liver transplant over a 16-year period (Le Treut et al., 2008). Most of the patients in the study had PNETs or carcinoid tumors. The perioperative mortality was 14% (n=12), with median survival of 56 months, and most patients dying as a result of recurrent disease. As such, transplantation is rarely used worldwide except for highly selected patients.

Transarterial embolization or chemoembolization (TACE) of liver metastases is a common therapy for NET patients. Such liver-directed therapy is effective in controlling NET growth because of disruption of tumor blood supply, derived largely from the hepatic arterial system with or without focused delivery of high-dose chemotherapy. The durability of response is quite variable, ranging from months to years, and higher response rates have been associated with aggressive management using multiple therapeutic modalities such as serial TACE treatments with hepatic resection (Touzios et al., 2005). The median progression-free survival after TACE for metastatic NETs at our center was 10 months, with overall survival 33 months (Bloomston et al., 2007).

Possible complications of TACE include carcinoid crisis, cholecystitis, pancreatitis, gastritis or enteritis, liver abscess, biliary complications and liver or renal failure; mortality ranges from 1 to 5% (Kiely et al., 2006). More common side-effects are pain, fever, nausea and fatigue, which can be fairly severe and last for 6–8 weeks (Bloomston et al., 2007; Varker et al., 2007). We have found that a staged approach in patients with bilobar liver metastases treating one liver lobe per TACE session is better tolerated than whole-liver TACE during a single session. Treatment with TACE at out center involves a multidisciplinary team approach and a specific protocol for supportive care, including periprocedural intravenous octreotide, patient counseling, education and intense post-procedure surveillance.

Another loco-regional therapy for metastatic NETs in the liver, similar to TACE in approach, is selective internal radiation therapy with Yttrium-90. Yttrium-90 is a radioactive beta-emitter with a half-life of 64 h, which is bound to microspheres for use in selective internal radiation therapy and delivered through the hepatic artery. One of the largest experiences reported combines the data from 10 centers and includes 148 patients who underwent treatment with Yttrium- 90-selective internal radiation therapy for hepatic NET metastases (Kennedy et al., 2008). A partial radiographic response was noted in 60% of patients with a median survival of 70 months after the initial procedure. Only one-third of patients in the study experienced any Common Terminology Criteria grade 3 or 4 toxicities, and there were no deaths reported related to Yttrium-90-selective internal radiation therapy.

Isolated hepatic perfusion with high-dose melphalan or tumor necrosis factor have been used by investigators at the National Cancer Institute with advanced progressive hepatic metastatic NETs, with a radiological response rate of 50% (Grover et al., 2004). Approximately, three-fourths of patients experienced grade III and IV toxicities, most notably a transient elevation in liver transaminases, which resolved without intervention in 62% and elevated creatinine in 31% of patients. Other toxicities occurring in more than 10% of patients included thrombocytopenia (15%) and pleural effusion (15%). There was one death in the study. A clinical trial using percutaneous hepatic perfusion of liver metastases from multiple primary tumors, including NETs, is ongoing at the National Cancer Institute.

Cytotoxic chemotherapy

In general, well-differentiated NETs, including most carcinoid tumors and PNETs are resistant to cytotoxic chemotherapy. Historically, fluoruracil (5-FU) and streptozotocin-based regimens have been used for metastatic NETs, although controversy exists over reported response rates and clinical efficacy (Reidy et al., 2009). Combination therapy with 5-FU and streptozotocin was compared with 5-FU and doxorubicin (FUDOX) in a phase II/III study by Sun and colleagues. Response rates were similar in both groups (16%) but the 5-FU and streptozotocin regimen was associated with longer median overall survival (24.3 months) than the 5-FU and doxorubicin regimen (15.7 months); life-threatening toxicity occurred in 11% of patients with a 1.9% mortality rate (Sun et al., 2005). More encouraging results have been obtained over the past decade using chemotherapy combinations with improved activity for NETs. Some regimens that have demonstrated radiological response rates around 20–30% include dose intense 5-FU, dacarbazine and epirubicin (Bajetta et al., 2002) or cisplatin and etopside (Fjällskog et al., 2001). Pavel and colleagues treated 10 patients with streptozotocin and doxorubicin after progression on other therapies (interferon alpha (IFN-α) or somatostatin analogs) and reported a 33% (n=3) radiological response rate (Pavel et al., 2005).

A provocative study by Kulke and coauthors demonstrates an association with O⁶-methylguanine DNA methyltransferase (MGMT) and treatment response to temozolamide (Kulke et al., 2009). In their study, immunohistochemistry was used to identify the presence or absence of MGMT in NET tissue, and MGMT expression was observed in 19 of 37 (51%) PNETs and in none of the 60 carcinoid tumors. Interestingly, a deficiency of MGMT in PNETs was associated with sensitivity to temozolamide. In 21 patients with tumor tissue evaluated, four of five patients with MGMT-deficient tumors (all PNETs) responded to treatment with temozolamide-based therapy, whereas none of the 16 patients with intact MGMT responded (P=0.001).

Prospective trials evaluating other treatment regimens for advanced NETs have shown low response rates (<10%), including high-dose paclitaxel (Ansell et al., 2001), high-dose infusional 5-FU and hydroxy-urea (Kaubisch et al., 2004), gemcitabine (Kulke et al., 2004a), docetaxel (Kulke et al., 2004b) and irinotecan with cisplatin (Kulke et al., 2006c). Because of low response rates and significant toxicities of cytotoxic chemotherapies, in general for NETs, we favor local and regional therapies when possible for disease control at our institution and strongly encourage eligible patients to enroll in ongoing clinical trials.

Targeted therapies for neuroendocrine carcinomas

Increasing understanding of tumor biology at the molecular level has led to the advent of molecular biological agents for use in cancer therapy, allowing targeted treatment of solid tumors based on information about alterations in cellular pathways and the cell cycle genomics, proteomics and epigenetics. Many studies have been performed over the past decade describing the use of targeted-biological therapy for various cancers, including NETs. Several studies, most of them phase II clinical trials, have been published examining the activity of biologically targeted agents in NETs, and some have shown encouraging results in terms of antitumor activity with favorable rates of partial responses or stable disease (Table 2).

Table 2.

Summary of selected clinical trials for unresectable or advanced NETs

Drug tested	Key targets	N=Total patients N=carcinoid/PNET	Octreotide or LAR	PR carcinoid PNET	SD carcinoid PNET	PD carcinoid PNET	PFS (median) carcinoid PNET	Reference
Octreotide LAR	Somatostatin receptor	N=42 LAR N=43 placebo	vs Placebo	N=1/85	38% LAR 5% placebo	62% LAR 95% placebo	14.3 months (LAR) vs 6 months	Rinke et al., 2009
Octreotide with/without IFN-α	Somatostatin receptor IFN-αR	N=68 carcinoid only	All	0%	82% (27/33) combination 46% (16/35) Octreotide alone	18% (6/33) combination 54% (19/35) Octreotide alone	NA	Kolby et al., 2003
IFN-γ	IFN-γR	N=48	Not allowed	6% (N=3)	58% (N=28)	31% (N=15)	5.5 months	Stuart et al., 2004
Bortezomib	26S Proteasome	N=16 N=12/4	Allowed N=6	0%	69% (N=11)	31% (N=5)	NA	Shah et al., 2006
Thalidomide	TNF-α	N=18 N=9/5	Allowed	0%	69% (N=11)	31% (N=5)	7 months	Varker et al., 2008
Imatinib	Abl; c-kit; PDGFR-α/β	N=27 carcinoid only	Allowed N=17	3.7% (N=1)	83% (N=17)	33% (N=9)	5.9 months	Yao et al., 2007
Endostatin	Vascular endothelium	N=42 N=20/22	Allowed	0%	80% (N=32)	20% (N=8)	7.6 months, 5.8 months	Kulke et al., 2006a, b, c
Temozolamide and thalidomide	Cytotoxic; TNF-α	N=26 N=15/11	Allowed N=11	7% (N=1) 45% (N=5)	68% (N=19)	7% (N=2)	Not reached	Kulke et al., 2006a, b, c
Temsirolimus	MTOR	N=36 N=21/15	Allowed N=9	4.8% (N=1) 6.7% (N=1)	57% (N=12) 60% (N=9)	29% (N=6) 27% (N=4)	6 months, 10.6 months	Duran et al., 2006
Everolimus	MTOR	N=60 N=30/30	All	17% (N=5) 27% (N=8)	80% (N=24) 70% (N=18)	3% (N=1) 13% (N=4)	15.7 months, 12.5 months	Yao et al., 2008
Sunitinib	VEGFR 1–3 PDGFR-α/β	N=107 N=41/66	Allowed (N=22/18)	2.4% (N=1) 17% (N=11)	83% (N=34) 68% (N=45)	2.4% (N=1) 7.6% (N=5)	10.2 months, 7.7 months	Kulke et al., 2008
Bevacizumab and IFN-α	VEGF; IFN-αR	N=44 carcinoid only	All	18% (Bevacizumab) 0% (INF-α)	77% (Bevacizumab) 68% (INF-α)	5%	15.7 months	Yao et al., 2008

Abbreviations: Abl, Abelson oncogene; IFN, interferon; LAR, long-acting repeatable; MTOR, mammalian target of Rapamycin; NA, not available; NETs, neuroendocrine tumors; PDGFR, platelet-derived growth factor receptor; PFR, progression-free rate; PNET, pancreatic neuroendocrine tumor; PR, partial remission; SD, stable disease; TNF, tumor necrosis factor; VEGFR, vascular endothelial growth factor receptor.

Somatostatin

Somatostatin is an endogenous peptide secreted by neuroendocrine cells with general inhibitory actions on gastrointestinal cells. Somatostatin analogs such as the drug octreotide (Sandostatin, Novartis Pharmaceuticals, Basel, Switzerland) have been developed, which bind to somatostatin receptors, and these compounds are widely used in the treatment of NETs. One goal for use of somatostatin analogs is amelioration of symptoms related to the carcinoid syndrome. Diarrhea and flushing are the most common patient complaints, and the use of octreotide or lanreotide has demonstrated efficacy in reducing the frequency of carcinoid syndrome symptoms (Ruszniewski et al., 2004; Berkovi et al., 2007).

Somatostatin analogs also inhibit the growth of gastrointestinal cells and may have a tumoristatic effect on NETs. Although many studies have been published regarding the use of octreotide and lanreotide for this purpose, attribution of the study drug to stabilization of NET is difficult because of the slow-growing nature of such cancers. The most exciting and encouraging data comes from a recently published randomized prospective phase III trial comparing use of month long-acting octreotide versus placebo in treatment-naïve patients with well-differentiated metastatic midgut primary NETs (Rinke et al., 2009). An interim analysis in the 85 patients enrolled at that time, revealed a significant benefit in the treatment arm with a median time to progression of 14.3 months compared with 6 months in the placebo group. Nearly twice as many patients in the treatment arm compared with the placebo arm had stable disease at 6 months.

An intriguing use of somatostatin analogs for treatment of NETs combines the ability of the compound to specifically bind somatostatin receptors with internalization of cytotoxic radioactive isotopes bound to the ligand. This therapy is not currently approved for use in the United States, but is available in several European countries. The published studies to date include both heterogeneous patient populations and treatment approaches and therefore the results vary (Table 3). Nevertheless, in properly selected patients this may be a valuable treatment strategy, and furthermore represents an innovative approach in targeting radiation therapy based on the molecular characteristics of NETs.

Table 3.

Selected studies evaluating radiolabeled somatostatin analogs for treatment of NETs

Study	N	Radiolabeled somatostatin analog	Response rates (PR+CR)	Symptom relief or reduction	Median overall survival
Bushnell, 2010 USA	90	90-Y-edotreotide	4%	>50%	26.9 months
Delpassand, 2008 USA	18	In-111 pentetreotide	11%	NA	13.3 months
Kwekkeboom 2008 Netherlands	310	Lu-177-octreotate	30%	NA	46 months
Forrer 2006 Switzerland	116	90-Y-DOTATOC	27%	83%	NA
Anthony 2002 USA	26	In-111 pentetreotide	8%	62%	18 months

Abbreviations: CR, complete remission; In-111, indium 111; Lu-177, leutium-177; NA, not available; PR, partial remission; 90-Y, 90-yttrium.

References: Anthony et al., 2002; Bushnell et al., 2010; Delpassand et al., 2008; Forrer et al., 2006; Kwekkeboom et al., 2008.

Interferon alpha

Like somatostatin and its analogs, IFN-α has an antiproliferative effect on NETs. In one of the first prospective studies comparing these treatment modalities, the combination of IFN and the somatostatin analog lanreotide was given to 80 patients with NETs and progression of disease. Combination therapy or the use of either agent alone was comparable to stable disease in 18–26% of patients, but with further progression of disease in half of the patients in each arm and only 4 out of 80 patients showing partial tumor response in the entire study (Faiss et al., 2003). Another multicenter prospective trial compared treatment with octreotide alone or in combination with IFN-α in 68 patients, with more encouraging results (Kolby et al., 2003). With a median follow-up of 24 months, combination therapy was associated with an improved progression-free survival (18% progression) compared with those treated with octreotide alone (54% progression, P=0.008); there was also a trend towards improved overall survival with combination therapy; mean 5-year survival was 56.8% in the IFN group compared with 36.6% (P=0.132) in the placebo group.

Treatment with IFN-α is associated with significant side-effects, such as fatigue or flu-like symptoms, and a high rate of non-compliance with therapy; the use of pegylated IFN has been associated with improved patient tolerability (Pavel et al., 2006). Given the high rate of side-effects and modest antitumor activity, use of IFN-α for treatment of NETs is less common than other modalities or clinical trials. Of note, treatment with IFN-γ was studied in 51 patients with metastatic carcinoid tumors by the Eastern Cooperative Oncology Group, and the radiological response rate was 6% (Stuart et al., 2004).

Other biological therapies

Imatinib mesylate is a tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. In an elegant study by Yao and colleagues, imatinib was also demonstrated to have a dose-dependent cytotoxic in vitro effect for bronchial and PNET cell lines, although clinical activity was modest with only one partial tumor response in 27 evaluable patients (Yao et al., 2007). An interesting finding in this study was the association of biochemical response to imatinib therapy (measurable decrease or normalization of serum markers chromogranin A or pancreatic polypeptide), with improved progression-free survival. Although tumor response to initial therapy and the later development of resistance to therapy are dependent on molecular subtypes in patients treated with imatinib for gastrointestinal stromal tumors, small-cell lung carcinomas are resistant to imatinib even when c-kit is positive (Krug et al., 2005; Agaram et al., 2007).

Thalidomide is an immunomodulatory drug with antiangiogenic properties. A phase II trial in which 18 patients with NETs were treated with daily oral thalidomide at 200 mg escalated to 400 mg did not result in any partial tumor responses (Varker et al., 2008). However, the addition of oral temozolamide, an oral alkylating agent, at a dose of 150 mg/m² for 7 days every other week to treatment with oral thalidomide at doses ranging from 50 to 400 mg daily, resulted in a radiological response rate of 25% and a biochemical response rate of 40% in a study of 29 patients with NETs (Kulke et al., 2006b). The combination regimen of temozolamide and thalidomide was associated with a high rate of toxicity in the study, and 16 (55%) patients discontinued treatment because of toxicity at a median time of 8.4 months; common toxicities included neuropathy (38%), thrombocytopenia (14%) and infection (14%).

A clinical trial examining the effect of the histone deacetylase inhibitor depsipeptide was terminated because of unacceptable cardiac toxicities (Shah et al., 2006). Endostatin, a recombinant human protein fragment of collagen XVIII, with antiangiogenic behavior, did not demonstrate any antitumor activity in patients with NETs in one phase II trial (Kulke et al., 2006a). The proteasome inhibitor bortezomib was studied in 16 patients with NETs, and although the surrogate biological end point measured in the study was achieved, there were no partial tumor responses (Shah et al., 2004). Despite these somewhat discouraging results, in recent years several biological agents described below have shown significant promise.

Metastatic NETs in the liver predominantly derive their blood supply from hepatic arteries as described in the section on loco-regional therapies. Furthermore, these tumors are known to secrete vascular endothelial growth factor and to express the receptor of vascular endothelial growth factor. Therefore, biologically targeted therapies affecting this pathway have been studied in NETs. Bevacizumab is an antibody that binds vascular endothelial growth factor-A, preventing interaction with its receptor. In a study performed at the MD Anderson Cancer Center, bevacizumab achieved a partial response in 4 of 22 patients (18%) and stable disease in all of the remaining patients except one over an 18-week period (Yao et al., 2008). Of note, patients may have had stable disease before enrollment, making it difficult to determine whether patients with stable disease derived any benefit from therapy. On the basis of these preliminary results, a multicenter phase III trial, comparing octreotide LAR in combination with either IFN-α or bevacuzimab, is being conducted by the Southwest Oncology Group (SWOG).

Sunitinib, an oral tyrosine kinase inhibitor, with activity against vascular endothelial growth factor receptors, was given to 107 patients with advanced NETs in a phase II study (Kulke et al., 2008). Response rates were higher in PNETs (16.7%) compared with carcinoid tumors (2.4%). Preliminary results from a randomized phase III study comparing sunitinib versus placebo in patients with advanced PNETs were recently presented in abstract form at the American Society of Clinical Oncology’s 2010 Gastrointestinal Cancers Symposium. This study was stopped early because of an interim analysis, demonstrating improved median progression-free survival in the sunitinib arm (11.4 months) compared with the placebo arm (5.5 months, P=0.0001).

A phase-II study examining the role of the mammalian target of rapamycin inhibitor temsirolimus in 37 patients, with advanced NETs, demonstrated an overall response rate of 5.6% (Duran et al., 2006). Of note, patients enrolled in this clinical trial had progressive metastatic disease documented within 6 months of enrollment. Another study examining treatment, with the combination of the mammalian target of rapamycin inhibitor everolimus and long-acting octreotide, in patients with metastatic PNETs or carcinoid tumors reported a radiological response rate of 22% (n=13 of 60 patients). Median progression-free survival in the study was 60 weeks (Yao et al., 2008). A randomized phase III trial comparing everolimus to placebo in patients with metastatic PNETs and carcinoid tumors has recently been completed and results are eagerly anticipated.

Conclusion

Neuroendocrine carcinomas are rare tumors with a wide range of biological activity and prognosis. Despite low response rates to conventional chemotherapies, recent advances in loco-regional approaches and targeted radioactive and biological therapies provide hope that control of tumor growth is possible in those with progression or a life-threatening burden of disease. The use of a personalized approach to treatment with particular attention to molecular classification of tumors will be critical in tailoring future therapeutic options to find the most potentially effective treatment for each patient.