Pancreatic neuroendocrine tumors - Wiley Online Library

IJC International Journal of Cancer

Pancreatic neuroendocrine tumors: A comprehensive review Chenfei Zhou1, Jun Zhang1, Ying Zheng2 and Zhenggang Zhu1 1

Pancreatic neuroendocrine tumors (NETs) are a heterogeneous group of tumors. Despite being relatively rare, representing just 1–2% of all pancreatic neoplasms, the incidence of pancreatic NET has increased over the past two decades. Although the primary treatment for localized NET is surgical resection, there is still a lack of effective therapeutic options for patients with R , Pfizer Inc, NYC) and advanced unresectable pancreatic NET. Recently, the targeted agents sunitinib malate (SUTENTV R , Novartis, Basel, Switzerland)—both with different mechanisms of action—received United States Food everolimus (AFINITORV and Drug Administration approval for the treatment of progressive, well-differentiated, pancreatic NET in patients with R also received approval for this indication by the European unresectable, locally advanced or metastatic disease. SUTENTV Commission in 2010. Our article presents an overview of pancreatic NET, with a focus on their diagnostic work-up, clinical presentation and treatment options. Topics for further investigation of targeted therapy are also discussed.

Pancreatic neuroendocrine tumors (NETs) originate from diffuse neuroendocrine cells. There are two probable origins of pancreatic NET: mature endocrine cells in the pancreas (e.g., a-, b-, d- and c-cells) and multipotent stem cells that can differentiate into endocrine and exocrine cells in the pancreas.1,2 Islet cell carcinoma and carcinoid were terms initially used to describe pancreatic NET. Pancreatic carcinoid tumors that secrete serotonin, histamine or dopamine have also been observed; however, they are rare.3 Consequently, the term ‘‘neuroendocrine neoplasm’’ was recommended by the World Health Organization (WHO) to describe NET located in the gastroenteropancreatic system, as well as to avoid the equivocality of ‘‘carcinoid’’ and emphasize the potential malignant behavior.4 NETs express at least two of the following NET

markers: chromogranin A (CgA), synaptophysin and/or neuron-specific enolase (NSE). These tumors can secrete different types of neuropeptides and cause a wide range of clinical symptoms (e.g., carcinoid syndrome).5

Epidemiology and Pathogenesis A review of data from the National Cancer Institute Surveillance, Epidemiology and End Results program indicated that the annual pancreatic NET incidence was 0.3–0.4 per 100,000 in the United States.6 A study in Japan showed a higher incidence (1.01 per 100,000 in 2005).7 Pancreatic NET is rarely seen in pediatric patients, and its incidence increases with age. Peak age ranges from 50 to 70 years. Genetic abnormities have been investigated to elucidate the pathogenesis of pancreatic NET. For hereditary

Key words: pancreatic neuroendocrine tumor, classification, targeted therapy Abbreviations: AJCC: American Joint Committee on Cancer; CgA: chromogranin A; CI: confidence interval; CT: computed tomography; DOX: doxorubicin; EGFR: epidermal growth factor receptor; ENETS: European Neuroendocrine Tumor Society; EUS: endoscopic ultrasound; F-pancreatic NET: functional pancreatic NET; 5-FU: 5-fluoruracil; HR: hazard ratio; IGF-1: insulin-like growth factor-1; IGF-1R: insulin-like growth factor-1 receptor; KIT: stem-cell factor; KRAS: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; LAR: long-acting release; MGMT: O6-methylguanine DNA methyltransferase; MRI: magnetic resonance imaging; mTOR: mammalian target of rapamycin; NET: neuroendocrine tumor; NSE: neuron-specific enolase; NF-pancreatic NET: nonfunctional pancreatic NET; ORR: objective response rate; OS: overall survival; PDGFR: platelet-derived growth factor receptor; PET: positron emission tomography; PFS: progression-free survival; PR: partial response; PRRT: peptide receptor radionuclide therapy; PTEN: phosphatase and tensin analog; RADIANT: RAD001 in Advanced Neuroendocrine Tumors; RCC: renal cell carcinoma; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease; SRS: somatostatin receptor scintigraphy; SSA: somatostatin analogs; SSR: somatostatin receptors; STZ: streptozocin; TKI: tyrosine kinase inhibitor; TNM: tumor, nodes and metastases; TTP: time to progression; US FDA: United States Food and Drug Administration; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; WHO: World Health Organization Grant sponsor: National Natural Science Foundation of China; Grant number: 30801371 DOI: 10.1002/ijc.27543 History: Received 10 Aug 2011; Accepted 21 Feb 2012; Online 21 Mar 2012 Correspondence to: Jun Zhang, Department of General Surgery, Ruijin Hospital, Room 1002, Building 11, No. 197, Ruijin er Road, Shanghai 200025, People’s Republic of China, Tel.: þ86-21-6467-0644, Fax: þ86-21-6437-3909, E-mail: [email protected]

C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

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Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China 2 Department of Cancer Control and Prevention, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, People’s Republic of China

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Pancreatic NET: A comprehensive review

Figure 1. Clinical work-up of pancreatic NET diagnosis.5,19–23 Abbreviations: F-pancreatic NET: functional pancreatic NET; VIP: vasoactive intestinal peptide; HIAA: hydroxyindoleacetic acid; CT: computed tomography; MRI: magnetic resonance imaging; EUS: endoscopic ultrasound; SRS: somatostatin receptor scintigraphy; IHC: immunohistochemistry; CgA: chromogranin A; Syn: synaptophysin; NSE: neuronspecific enolase; NF-pancreatic NET: nonfunctional pancreatic NET.

pancreatic NET, alterations of MEN1, Vhl, TSC and NF are the main factors that drive tumorigenesis.8 Allelic losses associated with NET have been reported on chromosomes 1q, 3p, 3q, 6q, 11q13, 17p13, 22q, Y and X, and gains have been reported on chromosomes 4pq, 5q, 7pq, 12q, 14q, 17pq and 20q.9,10 Gain of 9q22.2-q33.2 and loss of 22q13.1-q13.31 were considered as the earliest alteration in insulinoma, whereas 11q23.3-q24.3, 22q13.31-q13.32 loss or other chromosomal instabilities might favor tumor progression.11 In patients with sporadic pancreatic NET, 20–40% express somatic mutation of MEN1, though specific types vary. MEN1 mutation was frequently associated with gastrinoma and glucagoma, but was rare in insulinoma and nonfunctional pancreatic NET (NF-pancreatic NET).12 Several specific mutated genes including DAXX (25%), ATRX (17.6%) and TSC2 (8.8%) were also detected.13 Common gene mutations that occur in other solid tumors (e.g., p53, K-ras and phosphatase and tensin analog [PTEN]) are rare in pancreatic NET,12 whereas transcriptional modification might be important in gene expression and activity. Inactivation of p16INK4a, a tumor suppressor gene with frequent promoter hypermethylation in pancreatic NET, correlated with poor outcomes and may be an early event in pathogenesis.14,15 Other aberrant gene expression including gene upregulation (MDM2, MDM4, WIP1 and IGFBP3) and downregulation (PTEN, TSC2, p21 and MIC2), p53 inhibition, PI3K/Akt/ mammalian target of rapamycin (mTOR) activation and cell proliferation have also been investigated in sporadic pancreatic NET.16–18

Diagnostic Work-up Clinical presentation

Figure 1 shows a schematic diagram outlining the clinical work-up for pancreatic NET. Based on the functional activity of the tumor, pancreatic NET can be divided into functional pancreatic NET (F-pancreatic NET) and NF-pancreatic NET. Almost half of pancreatic NETs are functional. Insulinoma is the most common pancreatic NET type; other common types are gastrinoma, glucagonoma and somatostatinoma. F-pancreatic NET can present with a range of clinical symptoms, including Whipple’s triad, carcinoid syndrome and watery diarrhea/hypokalemia/achlorhydria syndrome.5 These symptoms, along with specific serum abnormality, allow for early diagnosis. NF-pancreatic NET is more likely to present with symptoms of local compression (obstructive jaundice and back and waist pain) and metastatic lesions. Imaging examination

Imaging techniques used for detecting pancreatic NET include computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET).19–21,24 CT/MRI are the most common techniques for the diagnosis of pancreatic NET, especially for NF-pancreatic NET, and have sensitivity and specificity >90%.20 CT/ MRI can also be used for preoperative staging, follow-up and evaluation of treatment efficacy. EUS is a highly sensitive technique for the localization of small lesions with diameters from 0.3 to 0.5 cm.19 Although EUS is an invasive procedure, it is widely used because of its C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

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Tumor

SSTR2 (%)

SSTR3 (%)

SSTR5 (%)

Insulinoma

13/21 (61.9)

13/21 (61.9)

9/21 (42.9)

7/17 (41.2)

Nd

15/17 (88.2)

5/6 (83.3)

Nd

Nd

5/5

3/5

4/5

3/3

Nd

Nd

Glucagonoma

5/5

2/5

3/5

VIPoma

1/1

1/1

1/1

Somatostatinoma

2/4

2/4

4/4

NF-pancreatic NET

10/13 (76.9)

8/13 (61.5)

8/13 (61.5)

6/6

Nd

Nd

Gastrinoma

Abbreviations: SSTR: somatostatin receptor; Nd: not done; VIP: vasoactive intestinal peptide; NF-pancreatic NET: nonfunctional pancreatic NET.

high accuracy, safety and probability for pathological diagnosis. Most pancreatic NET cells express at least two subtypes of somatostatin receptors (SSRs) (Table 1).25–28 SRS uses radiolabeled somatostatin analogs (SSAs) and can detect tiny primary lesions and distant metastases. Recent results indicate approximately equivalent sensitivity of SRS and CT/MRI for the diagnosis of pancreatic NET.20 PET may be suitable for the detection of poorly differentiated tumors.24 Tumor markers

The role of serum tumor markers in diagnosing pancreatic NET is limited. CgA is a member of the chromogranin family and is often elevated in serum of patients with pancreatic NET.29 The studies showed a moderate diagnostic value of CgA in pancreatic NET.29–32 In pancreatic NET, CgA concentration likely correlates with the extent of tumor differentiation, liver metastasis, disease progression and treatment efficiency.33 NSE has also been evaluated in the diagnosis of pancreatic NET. The specificity of NSE in diagnosing NET is almost 100%, but the sensitivity is low (30–40%).34

Classification/Staging Pancreatic NET are generally classified according to 2004 WHO criteria, though the criteria are not widely accepted, especially in European countries.3 In 2005, the European Neuroendocrine Tumor Society (ENETS) introduced its grading system that emphasized nuclear mitosis and the Ki-67 index.35 Several studies evaluated the prognostic value of the WHO criteria and ENETS grading system.36,37 The results showed that both systems could effectively stratify low- and high-grade tumors; however, effective intermediate-grade tumor stratification was limited. In an effort to gain wide acceptance, WHO updated its classification system in 2010 by integrating cell morphology and the proliferation index (Table 2).4,38 Further practical evidence, however, must be C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

Table 2. WHO 2010 classification for neuroendocrine neoplasms4,38 Classification

Definition

Neuroendocrine tumor G1

Well-differentiated neuroendocrine neoplasm, with similar cell morphology to normal gut endocrine cells.

Neuroendocrine tumor G2 Neuroendocrine carcinoma

Poorly differentiated neoplasm, with small or large cells and high proliferation characteristics (G3).

Mixed adenoneuroendocrine carcinoma

Composed of both glandular epithelium and neuroendocrine characteristics, with both components at least 30%.

Hyperplasic and preneoplastic lesions Grade classification

G1

Mitosis

Ki-67 index (%)

20/10 HPF

and/or

3–20 >20

Abbreviation: HPF: high-power field.

accumulated to assess the clinical value of the updated classification criteria. Currently, there is no standard tumor, nodes and metastases (TNM) staging system for pancreatic NET. Bilimoria39 analyzed 4,793 cases of pancreatic NET using the pancreatic cancer classification system from the American Joint Committee on Cancer (AJCC), and the results showed that the median overall survival (OS) of patients with Stages I, II, III and IV was 112, 63, 36 and 14 months, respectively. In the AJCC cancer staging manual (seventh edition), pancreatic NET was included in a single pancreatic staging system with exocrine pancreatic cancer.40 The biological behavior and prognosis of pancreatic NET and pancreatic exocrine cancer are quite different, and it may not be appropriate to introduce the conventional TNM staging system directly. ENETS recommends another TNM staging system for pancreatic NET.35 A retrospective study with 131 patients with pancreatic NET showed a 100% survival rate at 5 years with Stage I tumors compared to a 55.4% survival rate at 5 years (mean 88.8 6 11.4 months) with Stage IV tumors, but no difference between low-stage tumor (Stage I vs. Stage II, p ¼ 0.227; Stage II vs. Stage III, p ¼ 0.171).41 Because of the abovementioned limitations, modification was proposed to WHO classification and TNM staging by some investigators. Scarpa et al.42 suggested that the cutoff value of Ki-67 index at 5% in grading system and a modified definition of T3 and T4 codes could better distinguish patients’ outcome. Although current classification and staging systems still need to be validated, they supply most disease information of pancreatic NET, including biological behaviors of tumor cells and tumor status when diagnosed.

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Table 1. Immunohistochemistry staining of SSTR expression in pancreatic NET25–28

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Table 3. Medical treatment of pancreatic NET45–52 Scheme

CR PR Cases (%) (%)

SD (%)

PFS/TTP OS (months) (months)

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Cytotoxic chemotherapy STZ þ DOX þ 5-FU 84

1.2 38.1 50

STZ þ DOX

16

0

6

38

XELOX

11

0

27

45

–

–

Temozolomide

53

–

34

–

13.6

35.3

18 3.9

37 20.2

CDDP þ etoposide 10

0

10

–

GEMOX

5

0

40

–

–

–

21

0

0

38

41

45

91

4.4 38.5 24.2 –

1.5

6.2

SSA Octreotide LAR PRRT 177

Lu-DOTATATE

–

Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PFS: progression-free survival; TTP: time to progression; OS: overall survival; STZ: streptozocin; DOX: doxorubicin; 5-FU: 5fluorouracil; XELOX: capecitabine and oxaliplatin; CDDP: cisplatin; GEMOX: gemcitabine and oxaliplatin; SSA: somatostatin analogs; LAR: long-acting release; PRRT: peptide receptor radionuclide therapy.

Combination of the two criteria will be helpful to assess prognosis and to decide optimized therapeutic strategy.

Surgical Management Surgical resection is the only curative strategy for pancreatic NET.6 Furthermore, cytoreductive surgery can control the secretion of activated hormones and improve the survival for patients with advanced pancreatic NET and can be an optional strategy for physically fit patients with metastatic, well-differentiated pancreatic NET. Results from a retrospective study that included 728 patients with pancreatic NET indicated that the survival times of patients who underwent surgery versus those who did not were 60 and 31 months, respectively (p < 0.00001).43 Patients with poorly differentiated pancreatic NET and a high tumor burden may not gain benefit from cytoreductive surgery because of a high risk of recurrence.44

Systemic Medical Management Traditional medical treatment of pancreatic NET includes streptozocin (STZ)-based or platinum-based chemotherapy (Table 3).45–52 Radioactive elements,51 SSA, interferon-a and other cytotoxic agents are also used; however, they have not been fully validated in clinical studies. The molecular-targeted therapies, sunitinib and everolimus, have demonstrated efficacy in patients with advanced pancreatic NET and are now approved by the United States Food and Drug Administration (US FDA) for this indication. Cytotoxic chemotherapy

The chemosensitivity of pancreatic NET varies with type and differentiation status. Well-differentiated pancreatic NET

proliferate slowly and are generally resistant to most chemotherapeutic agents. Kouvaraki et al.48 reviewed data from 84 patients (79 previously untreated) with pancreatic NET who received STZ, fluorouracil and doxorubicin (DOX). The response rate was 39%, with a median progression-free survival (PFS) of 18 months. Several small-scale studies have indicated efficacy for the combination of STZ and 5-fluoruracil (5-FU) or DOX or oxaliplatin with capecitabine. Temozolomide, an alkylating agent, was also investigated in NET.53 O6-Methylguanine DNA methyltransferase (MGMT), which can restore methylated O6 position of guanine induced by temozolomide and prevent DNA mismatch, is thought to be the major mechanism of resistance to alkylating agents.54 Pancreatic NET showed a relatively high deficiency rate of MGMT compared to lung and intestinal NET (51% vs. 0%), a better response rate (34% vs. 2%) and improved survival outcome (PFS 13.6 vs. 9.6 months; OS 35.3 vs. 19.4 months) during temozolomide-based therapy.49 Monotherapy of temozolomide (200 mg/m2 orally for 5 days, every 4 weeks) in 12 patients with advanced pancreatic NET achieved one partial response (PR) and eight stable diseases (SD).55 Cisplatin plus etoposide is considered one of the common regimens for poorly differentiated NET.50,56 Mitry56 retrospectively analyzed 41 patients with poorly differentiated NET. The response rate (WHO criteria) was 41.5%, and median PFS was 8.9 months. Iwasa et al.50 treated 21 cases of poorly differentiated neuroendocrine carcinoma of the hepatobiliary tract and pancreas with cisplatin and etoposide regimen. Only one of the ten patients with pancreatic NET demonstrated PR according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median OS of the patients with pancreatic NET was 6.2 months. The heterogeneity of enrolled patients and the dosage difference of cisplatin likely contributed to the inconsistent results between these two studies. Available rescue chemotherapy after first-line treatment failure in pancreatic NET is uncertain. Cassier et al.47 used gemcitabine and oxaliplatin as rescue treatment in 18 patients with well-differentiated NET after first-line treatment failure and reported a response rate of 17% (RECIST). Although conventional chemotherapy is effective in some patients with pancreatic NET, it is also toxic. Results from one study of patients treated with STZ, 5-FU and DOX indicated that 23% had Grades 3 to 4 adverse events, including mucositis, vomiting, myelosuppression and fatigue.48 Toxic reactions to cisplatin and etoposide were more severe. About 60% of patients experienced Grades 3 to 4 hematological toxicities.50,56 Somatostatin analogs

The activation of SSR may trigger the inhibition of adenylate cyclase and calcium influx, thus in turn reduce the releasing of bioactive hormones including insulin and glucagon. SSA can activate the above physiological events and inhibit the secretion of these hormones in the gastrointestinal tract.57,58 C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

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Agent

Phase

Cases

CR (%)

Sunitinib

3

Sunitinib: 86

2

PR (%)

SD (%)

PFS/TTP (months)

7

63

11.4

Placebo: 85

0

0

60

5.5

2

66

0

16.7

68.2

7.7

Sorafenib

2

43

0

10

–

–

Pazopanib

2

30

0

17

–

11.7

Bevacizumab þ temozolomide

2

18

0

24

71

–

Temsirolimus

2

15

0

6.7

60.0

10.6

Everolimus

3

Everolimus: 207

0

5

73

11.0

Placebo: 203

0

2

51

4.6

Everolimus 6 octreotide LAR

Everolimus þ octreotide LAR

2

2

Monotherapy: 115

0

9.6

67.8

9.7

Combination: 45

0

4.4

80.0

16.7

30

0

60

12.5

27

Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PFS: progression-free survival; TTP: time to progression; LAR: longacting release.

In clinical practice, SSA is often used to control pancreatic NET-related symptoms before and after surgery. A preclinical study showed that in vitro proliferation of a rat-derived insulinoma cell line (INS1) was significantly inhibited after octreotide administration.59 Activation of the tyrosine phosphatase cascade by SSR1/2 can inhibit the epidermal growth factor receptor (EGFR) signaling pathway and may influence cell mitosis.60 Theoretically, SSR expression correlates with the efficacy of SSA. Volante et al.61 reported two PRs and 16 SD in 25 patients with SSR Type 2A positive NET after octreotide long-acting release (LAR) treatment; however, these results have yet to be validated in a randomized controlled trial. Several Phase 2 trials evaluated the antitumor efficacy of SSA in patients with NET.62 The placebo-controlled, doubleblind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine MIDgut tumors trial compared octreotide LAR versus placebo in 85 treatment-naı¨ve patients to metastatic midgut NET.63 The time to progression (TTP) for the octreotide LAR group was 14.3 versus 6 months for the placebo group (hazard ratio [HR] ¼ 0.34; 95% confidence interval [CI] ¼ 0.20–0.59; p ¼ 0.000072). One patient had a PR, and 66.7% had SD. The results indicated that SSA can delay disease progression and tumor growth, but with little or no tumor shrinkage effect in midgut NET; however, its efficacy in pancreatic NET remains uncertain. An ongoing Phase 3 study of lanreotide (NCT00353496) in patients with NF-NET is enrolling patients with pancreatic NET and may provide more information about the antitumor efficacy of SSA in pancreatic NET.

Targeted Therapy Targeted therapeutic agents, especially those inhibiting molecules involving angiogenesis or growth factor receptor-related C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

signal pathways, have revolutionized the treatment strategy of many cancers. A number of these agents have been tested and evaluated in pancreatic NET, including sunitinib, everolimus, bevacizumab, imatinib, gefitinib and bortezomib.64,65 In the following section, sunitinib and everolimus in the treatment of pancreatic NET are reviewed. The two drugs are currently the only targeted agents approved in the United States and Europe to treat patients with pancreatic NET (Table 4).66–74

Agents for antiangiogenesis

Tumor survival requires a blood supply, and the agents that interfere with the actions of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGFR) have been extensively used for the treatment of a wide range of tumors. Pancreatic NETs exhibit dense vasculature and overexpression of VEGF, VEGF receptor (VEGFR) and PDGFR.75–77 A preclinical study using the RIP-Tag2 mouse model of pancreatic islet carcinogenesis demonstrated the efficacy of antiangiogenic therapy in vivo.78 Accordingly, antiangiogenesis agents such as sunitinib and bevacizumab appear to be well suited for the treatment of pancreatic NET. Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGF receptors-1, 2 and 3, PDGFRsa and b, stem-cell factor (KIT) receptor, FMS-like tyrosine kinase 3, colony-stimulating factor 1 receptor and glial cell line-derived neurotrophic factor receptor and is approved for the treatment of advanced renal cell carcinoma (RCC) and for gastrointestinal stromal tumors after disease progression on or intolerance to imatinib mesylate therapy.79 In December 2010, the European Commission R for the treatment of unresectable or approved SUTENTV metastatic, well-differentiated pancreatic NET with disease

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Table 4. Targeted treatment of pancreatic NET66–74

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progression in adults, and in May 2011, the US FDA R approval for this indication. granted SUTENTV The antitumor activity of sunitinib in pancreatic NET was shown in a Phase 2 study. A total of 107 patients with NET, among which 66 cases of pancreatic NET, were treated with sunitinib (50 mg/day orally for 4 weeks, followed by 2 weeks of treatment). The response rates (RECIST) of pancreatic NET and NET arising from other sites (lung, stomach, small bowel, appendix, colon and rectum) were 16.7% and 2.4%, respectively. The respective TTPs were 7.7 and 10.2 months. Grades 3 to 4 adverse events included neutropenia (33.7%), fatigue (24.3%) and hypertension (10.3%).68 Recently, the results of a Phase 3, double-blind, placebocontrolled, randomized trial demonstrated the efficacy of sunitinib for the treatment of advanced pancreatic NET. A total of 171 patients with well-differentiated pancreatic NET and disease progression within the past 12 months were randomly assigned (1:1) to receive sunitinib 37.5 mg/day orally, continuous dosing (until disease progression) or placebo. The PFS for sunitinib group was significantly longer than that for placebo group (11.4 vs. 5.5 months; HR ¼ 0.42; 95% CI ¼ 0.26–0.66; p < 0.001). The objective response rates (ORRs) were 9.3% and 0% (p ¼ 0.007), respectively. The most common Grades 3 to 4 adverse events with sunitinib were neutropenia (12%), hypertension (10%) and fatigue (5%).71 This result showed that sunitinib monotherapy can significantly prolong PFS, increase ORR and display an acceptable safety profile in patients with advanced pancreatic NET. R ; Bayer Healthcare PharmaceutiSorafenib (NEXAVARV cals, Wayne, NJ), an oral receptor TKI with multiple targets, including Raf (a serine/threonine kinase), VEGFR-1,-2 and 3, PDGFR-b, c-Kit and FLT-3, has been evaluated in 43 patients with chemoresistant metastatic pancreatic NET. All patients received sorafenib (400 mg bid orally) until disease progression or intolerance. PR was observed in four of 41 evaluable patients (10%), and 6-month PFS was observed in 14 of 23 evaluable patients.67 R ; GlaxoSmithKline, Research TriPazopanib (VOTRIENTV angle Park, NC) is an oral, multitargeted TKI that interferes with the actions of molecules involved in angiogenesis, VEGFR1-3, PDGFR-a/b and c-KIT. It is currently registered for the treatment of RCC.80 Pazopanib has been evaluated in a Phase 2 study of 52 patients with advanced low-grade NET (30 pancreatic NETs) who received pazopanib (800 mg/day orally) and octreotide LAR. In pancreatic NET group, five patients had PR (RECIST), and median PFS was 11.7 months, Grades 3 to 4 toxicities in whole cohort included hypertension (six cases), neutropenia (three cases), elevated transaminases (three cases), diarrhea (three cases) and fatigue (three cases).69 R , Genentech, South San FranBevacizumab (AVASTINV cisco, CA) is a monoclonal antibody directed against VEGF. For most solid tumors, bevacizumab must be combined with cytotoxicity agents. Combination therapy with bevacizumab has also been investigated in pancreatic NET. Bevacizumab


(5 mg/kg, intravenously, every 2 weeks) was combined with temozolomide in a Phase 2 study that included 34 patients with unresectable or metastatic NET (18 pancreatic NETs). Four patients with pancreatic NET had PR (RECIST and biomarker).70 mTOR inhibitors

mTOR is an intracellular protein kinase that participates in PI3K/Akt signal transduction. Activation of mTOR influences multiple behaviors of tumor cells including growth, proliferation, angiogenesis and metabolism. Downregulation of PTEN and TSC2, two negative regulators of PI3K/Akt/mTOR pathway, and overexpression of insulin-like growth factor (IGF)1/IGF-1 receptor (IGF-1R) were detected in pancreatic NET, which indicated that mTOR activation may participate in pancreatic NET progression.18,81 An in vitro study showed antiproliferation activity during mTOR inhibition in pancreatic NET cell lines (BON-1, QGP-1 and CM).18 Everolimus (RAD001), a rapamycin analog, was evaluated for pancreatic NET in the RAD001 in Advanced Neuroendocrine Tumors (RADIANT) studies, which is now approved by the US FDA for this indication.82 Yao et al.74 reported results from a Phase 2 study of everolimus combined with octreotide LAR for low- to intermediate-grade NET. Sixty patients received low-dose (5 mg/day orally) or high-dose (10 mg/day orally) everolimus along with octreotide LAR 30 mg every 28 days. Among 30 patients with pancreatic NET, PR (RECIST) was 27%, and median PFS was 50 weeks. A longer PFS was observed in the highdose group. On the basis of the above results, Yao et al.73 carried out RADIANT-01, a Phase 2 study of patients stratified by ongoing octreotide therapy at study entry. Patients not treated with octreotide were assigned to one group, and patients who were on octreotide LAR for 3 months prior to another for the treatment (everolimus 10 mg/day orally until progressive disease or intolerant) of unresectable or metastatic pancreatic NET. A total of 160 patients with progressive disease during or after cytotoxic chemotherapy were included. Median PFS was longer with combination therapy versus monotherapy (16.7 vs. 9.7 months). The study also analyzed the relationship between the change of serum tumor markers and efficacy. In patients with elevated baseline CgA and NSE levels, median PFS was prolonged among those with early CgA or NSE response (30% decrease at Week 4; CgA 13.3 vs. 7.5 months, p ¼ 0.00004; NSE 8.6 vs. 2.9 months, p ¼ 0.00062). Common adverse events included stomatitis, rash, diarrhea and fatigue. Toxicities causing dosage adjustment or interruption of treatment were thrombocytopenia (11.1%), stomatitis (8.9%), hyperglycemia (7.8%) and diarrhea (5.2%). The multicenter, randomized, double-blind Phase 3 trial (RADIANT-03) compared everolimus to placebo, each combined with best supportive care, in 410 patients with low- or intermediate-grade pancreatic NET. Everolimus reduced the C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

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Topics for Further Investigation of Targeted Therapy Agents targeted to vascular growth factors, their receptors, associated receptor tyrosine kinases or other key elements (e.g., mTOR) in intracellular signaling pathways have been shown to prolong survival in patients with pancreatic NET and are reasonably well tolerated. Response rates of targeted therapies are low (about 10%), but can be elevated when combined with cytotoxic drugs. Serum levels of CgA and NSE appear to be useful surrogate markers for efficacy of targeted therapies. There are still many questions to be answered about targeted treatments being used in patients with pancreatic NET, and they are considered in the following sections. Resistance to targeted therapy

The period of using targeted therapy in pancreatic NET is short, and it is unclear whether resistance mechanisms observed in other tumors also occur in NET. For example, inhibition of mTOR in breast cancer and prostate cancer cell lines by rapamycin may increase the expression of insulin receptor substrate, which may result in Akt activation and thus blunt its antiproliferative actions.83 Antiangiogenic effects associated with receptor TKIs, such as sunitinib, may be reversed by increased activity in alternative angiogenic pathways.84,85 Predictive markers of targeted therapy

Predictive markers are quite important for guiding treatment in patients with cancer. They may help in the selection of initial therapy and provide guidance for switching treatment in patients with pancreatic NET. In colorectal cancer, patients with tumors containing wild-type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) derive greater benefit from cetuximab than those with KRAS mutations.86 SSR expression and MGMT deficiency may correlate with efficacy of SSA and temozolomide; however, currently, there are no validated markers that predict sensitivity to specific therapies in patients with pancreatic NET. Effects of treatment on serum CgA and NSE after everolimus treatment are correlated to the prognosis; however, these molecules cannot be used as predictive markers. The possibility of targeting therapy in preoperative treatment

A review of the literature from 1998 to 2008 involving surgical intervention in pancreatic NET and prognostic factors related to surgical outcome and survival suggested that C 2012 UICC Int. J. Cancer: 131, 1013–1022 (2012) V

Table 5. Ongoing trials of targeted therapy enrolling patients with pancreatic NET Agents

Target

Phase

Primary end point

AMG 479

IGF-1R

2

Radiographic response rate

Pazopanib

VEGFR, PDGFR and KIT

2

Clinical benefit rate at 6 months

Erlotinib þ everolimus

EGFR and mTOR

2

Radiographic response rate

Cixutumumab þ everolimus þ octreotide

IGF-1R, mTOR and SSR

1

Optimistic dosage; pharmacokinetics and pharmacodynamic markers

Abbreviations: IGF-1R: insulin-like growth factor-1 receptor; VEGFR: vascular endothelial growth factor receptor; PDGFR: platelet-derived growth factor receptor; KIT: stem-cell factor; EGFR: endothelial growth factor receptor; mTOR: mammalian target of rapamycin; SSR: somatostatin receptors.

patients with locally advanced and metastatic pancreatic NET could benefit from surgery, and patient outcomes may be enhanced by neoadjuvant-targeted therapy.44 Selection, sequencing and combination of targeted therapies

Antiangiogenic agents and mTOR inhibitors have demonstrated efficacy in patients with well-differentiated pancreatic NET; however, it is unclear which of these agents should be used as first-line treatment and which should be reserved for second-line use. Head-to-head comparisons of different targeted agents may provide additional information regarding their relative efficacy in patients with pancreatic NET. Multiple factors and signaling pathways participate simultaneously in many functions inside tumor cells, including proliferation, survival and angiogenesis; combination therapy aimed at complementary pathways may provide more durable treatment responses. Optimal combinations may include cytotoxic therapies or SSA with targeted agents and/or combinations of different targeted drugs.87 The results of RADIANT-02 showed an increased survival benefit when everolimus was combined with octreotide LAR.88 The combination of bevacizumab and everolimus in the treatment of 38 patients with well-differentiated NET showed a high disease control rate (10 PRs and 27 SDs).89 Combination therapy may increase the frequency of toxicity, but the benefit may outweigh this risk. Agents beyond sunitinib and everolimus

In addition to angiogenesis factors and PI3K/Akt pathway, aberrant expression of other molecules involving cell functions was also investigated in NET.90 EGFR overexpression and rare K-ras mutation indicated the possibility of anti-EGFR agents. Several novel molecules targeting IGF-1R, Hsp90 and Src were also investigated in NET cell lines in vitro.57,90 Meanwhile, several Phase 2 trials evaluating new agents in patients with pancreatic NET are ongoing (Table 5).

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risk of progression by 65% and significantly increased the median PFS from 5.4 to 11 months (HR ¼ 0.35, p < 0.001). The estimates of 18-month PFS were 34% for patients treated with everolimus compared to 9% for patients treated with placebo. The common Grades 3 to 4 events included stomatitis (7% vs. 0%), anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%).72 These results also demonstrated the efficacy and safety of everolimus in the treatment of advanced pancreatic NET.

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Conclusions Pancreatic NET are a group of pancreatic neoplasms with high heterogeneity and a better prognosis than exocrine pancreatic cancer. However, the prognosis worsens substantially in patients with poorly differentiated pancreatic NET or with metastases. Because of the specific clinical presentation of Fpancreatic NET, early diagnosis is possible. SSA or cytotoxic chemotherapy used to be the primary treatment for patients with unresectable tumors, followed by peptide receptor radionuclide therapy. The efficacy of sunitinib and everolimus support the role of targeted agents as a new option in the first- or second-line treatment of pancreatic NET.

There are still many unanswered questions about the optimized classification, staging and treatment of pancreatic NET. Early clinical trial results support the efficacy and tolerability of small-molecule-targeted therapies in patients with pancreatic NET. Further studies may focus on identification of biomarkers that predict responses to specific therapies, which can be used to guide selection of first- and, if necessary, second-line treatments.

Acknowledgements Editorial support was provided by Caroline Hoang at ACUMED (New York) and was funded by Pfizer Inc.

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