Management of pancreatic neuroendocrine tumors - Future Medicine

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Abstract: Despite the rarity of the disease, there has been significant recent progress in the management of pancreatic neuroendocrine tumors (PNETs). Arterial ...
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Management of pancreatic neuroendocrine tumors E Waller Stanford Cancer Center, 875 Blake Wilber Drive, Stanford, CA, USA [email protected]

Abstract: Despite the rarity of the disease, there has been significant recent progress in the management of pancreatic neuroendocrine tumors (PNETs). Arterial phase imaging and somatostatin scintigraphy are important parts of the diagnostic and staging work-up of PNETs. The slow growth rate of PNETs can make observation a reasonable initial option in low volume asymptomatic disease or allow debulking surgery in selected patients with advanced disease. Somatostatin analogs, angiogenesis and mTOR inhibitors have proven benefit for PNET patients in randomized trials while retrospective and single-arm trials using chemotherapy or peptide receptor radiation therapy also appear promising. This review summarizes key aspects in the management of PNETs with emphasis on the most recent advances in systemic therapy.

Pancreatic neuroendocrine tumors (PNETs), previously known as islet cell tumors, are rare neoplasms accounting for approximately 3% of all primary pancreatic malignancies [1,2]. The vast majority are low (G1) or intermediate grade (G2) both of which are classified as ‘well differentiated.’ However, it is important to recognize the clinical behavior of the even more rare, high-grade (G3) or poorly differentiated PNETs as they are much more aggressive and require entirely different treatment strategies. However, this review will be restricted to welldifferentiated PNETs. The incidence of PNETs has increased significantly in recent decades [1]. This rise is most likely due to incidental detection with the increased resolution and utilization of 3D imaging (CT and MRI) and availability of endoscopic ultrasound. Autopsy studies suggest that a substantial number of NETs go undiagnosed as they can remain clinically silent for a lifetime [3]. The longer survival of patients with PNETs compared with pancreatic adenocarcinomas accounts for an increased prevalence of these tumors with some estimates of them comprising greater than 10% of all pancreatic cancers [4]. The most common genetic predisposition to PNETs arises from a mutation in the MEN1 gene, which encodes the protein menin. Menin is a scaffold protein that interacts with numerous transcription activators, repressors and signal transduction proteins [5]. Individuals with MEN1 mutations develop the cancer syndrome multiple endocrine neoplasia type 1, which is characterized by the formation of pituitary, parathyroid and PNETs [1]. A less common source of familial PNETs is caused by mutations in the TSC2 gene which is re-

C Future Medicine Ltd 10.2217/IJE.14.28 2015 

sponsible for the multisystem genetic disease known as tuberous sclerosis [6]. TSC2 is a key step in the cell signaling pathway upstream from mammalian target of rapamycin (mTOR). A third cancer syndrome that predisposes individuals to PNETs is von Hippel-Lindau disease, arising from a mutation in the tumor suppressor gene known as VHL [7]. Tumors that occur in the setting of VHL mutations often overexpress angiogenic factors driven by HIF 1α and VEGF. Hence these tumors may be particularly susceptible to VEGF pathway inhibitors such as bevacizumab or sunitinib though this has yet to be confirmed. The vast majority (>90%) of PNETs are sporadic with no known inherited genetic defect [8]. Nextgeneration DNA sequencing of PNETs has led to a deeper understanding of the genetic basis of the disease that may prove to be of both prognostic and predictive value. Of note, death-domain-associated protein (DAXX) and α-thalassemia/mental retardation syndrome X-linked (ATRX) mutations have been observed in 45% of PNETs and correlate with a favorable prognosis [9]. These genes are involved with telomere lengthening in a process that is independent of telomerase [10]. Somatic alterations in the mTOR pathway genes PTEN, TSC2 and PIK3CA may be potential drivers of cell proliferation in 16% of PNETs and targets for drug therapies [9]. Studies are ongoing in an attempt to correlate somatic or germline mutations in the mTOR pathway or VHL with sensitivity to mTOR inhibitors and antiangiogenic agents, respectively. The clinical presentation of PNETs can be varied. Functionally active PNETs can secrete a variety of

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Practice points r Though known for the hormonal syndromes (e.g., VIPoma, insulinoma and glucagonoma), the majority of pancreatic neuroendocrine tumors (PNETs) are not associated with secretory syndromes. r Classically hypervascular, PNETs are best assessed using contrast-enhanced imaging obtained in the arterial phase. r Specific mutations in ATRX/DAXX, MEN1 and key genes in the mTOR pathway may provide insight into the pathophysiology of PNETs as well as predictors of response to therapy. r Since the vast majority of PNETs express somatostatin receptors, somatostatin scintigraphy can be a helpful diagnostic and staging tool. r A subset of PNETs have such slow growth that treatment may be deferred for months or years. r Resection remains the only cure for PNETs; debulking surgeries may also be of clinical benefit in selected cases of unresectable disease. r Liver dominant disease may be managed by liver-directed therapies such as thermal ablation, stereotactic body radiotherapy or transarterial chemo or radioembolization. r Randomized controlled trials of somatostatin analogs, angiogenesis inhibitors and mTOR inhibitors have demonstrated statistically and clinically significant benefit in PNETs. r Chemotherapy regimens (e.g., temozolomide and capecitabine) and peptide receptor radiotherapy have favorable results in single-arm and retrospective trials. r Despite the rarity of the disease, successful completion of clinical trials have expedited progress in PNETs and should continue to be a priority for these patients.

peptides and neuroamines including insulin, gastrin, glucagon and vasoactive intestinal peptide (VIP), which result in hormonal syndromes (e.g., hypoglycemia with insulinomas, gastric ulcers with gastrinomas, weight loss with glucagonomas and watery diarrhea with VIPomas). In contemporary series, the majority of PNETs have no hormonal syndrome and are therefore termed ‘nonfunctional’ [11]. The term ‘functional’ applies to the existence of a hormonal syndrome, in other words, symptoms due to secretion of small peptides by the tumor. Often, tumors can make hormones detectable in the blood but remain asymptomatic otherwise. Therefore, a patient with an elevated gastrin level but no symptomatic evidence of gastric acid hypersecretion would be considered to have a ‘nonfunctional’ PNET [12]. Consequently, nonfunctional tumors can remain clinically silent until symptoms of discomfort and or weight loss develop due to a mass occupying effect of the tumor or its metastases. Thus, nonfunctional tumors tend to be diagnosed at later stages than functional tumors. Work-up Detection and staging studies have significantly improved with increasingly sensitive imaging techniques. As most NETs are highly vascular, cross-sectional imaging studies such as multiphasic contrast-enhanced CT and MRI provide sensitive and accurate imaging for use in detection, differential diagnosis and staging [13–18]. For CT examinations especially, arterial phase imaging can be critical to detection and accurate assessment of both primary and metastatic lesions (Figure 1). Use of radiolabeled somatostatin analogs (SA) has significantly improved the diagnosis and staging of NETs.

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Figure 1. Arterial and venous phase CT images of a liver metastasis from a pancreatic neuroendocrine tumor. Note how well delineated the tumor is on the arterial phase (A) as compared with the venous phase (B).

Most PNETs express somatostatin receptors. Tumors can therefore be visualized by somatostatin scintigraphy (OctreoScanTM ) using 111 Indium-labeled SA [19]. Combining OctreoScanTM with single photon emission computed tomography (SPECT), allows for increased differentiation between areas of pathologic and physio-

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logic uptake [20,21]. Widely available in Europe, imaging with gallium-linked somatostatin analogs (e.g., 68 GaDOTATATE) utilizes PET/CT imaging which offers both greater sensitivity and higher resolution than OctreoScansTM [22]. However, use is limited in the United States due to lack of regulatory approval and mechanisms for reimbursement [23]. While 18 F-labeled deoxyglucose PET can be used in the evaluation of high-grade tumors, applicability is limited in PNETs as many are well differentiated, slow growing and are often not as well visualized with imaging modalities which rely on metabolic mapping [14,24]. Clinical management of PNETs Surgical resection/debulking

Surgery is the only treatment capable of achieving cure in this disease. PNETs identified when tumors are localized or with limited metastatic disease should be evaluated by multidisciplinary tumor boards and oncologic surgeons with expertise in this disease. Those who can undergo safe and successful surgical resection, even in cases where tumors have metastasized, should be considered for surgery. With resectable disease limited to the pancreas, surgery should nearly always be the first choice. For selected patients with resectable but metastatic disease, systemic treatment (see below) may offer the advantage of learning more about the tumor biology and intrinsic aggressiveness of the disease before proceeding with an operation. Furthermore, successful shrinkage of unresectable disease with chemotherapy may render tumors amenable to a complete resection. Debulking, while not curative, can provide symptomatic relief by decreasing tumor burden and hormone production [13– 14,25–26]. Removal of the primary tumor can also reduce the risk of vascular compromise of mesenteric vessels and gastric outlet obstruction [27]. For peripherally located small pancreatic insulinomas and gastrinomas, enucleation may be considered, but for most other deep-seated tumors, conventional pancreatectomy with removal of draining lymph nodes is recommended [14,27]. Liver-directed therapies

In cases with liver-dominant unresectable metastatic disease, liver-directed therapies such as ablative therapy and transarterial options (chemoembolization or radioembolization) can be considered [14,16]. Studies have shown that ablation using heat (microwave or radiofrequency) or freezing (cryotherapy) may be an option for patients with fewer than five liver lesions that are smaller than 5 cm [28]. Application of highly focused ionizing radiation known as stereotactic body radiotherapy can also be an option, particularly for liver tumors that are close to ves-

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sels and therefore, difficult to heat due to the cooling effect of adjacent blood flow. Transarterial treatments of chemoembolization (using drug-eluting beads or drugs suspended in lipiodol) or radioembolization may be considered for patients with widespread liver metastases [14,29]. Radioembolization with 90 Y microspheres can be used to both embolize vessels to tumors and deliver potentially lethal doses of radiation to the interior of the tumor [14,29]. Unfortunately, there are no definitive studies that compare the risks and benefits of each of these palliative options. Therefore, hard evidence for efficacy of these procedures is lacking and generally limited to small series and case reports. The power of observation

Patients with newly diagnosed well-differentiated PNETs, unresectable, but small volume and asymptomatic disease often benefit from an initial observation period. This approach allows one to identify those with indolent growth rates who might not need any therapy for months or years while identifying others who might benefit from early intervention. A follow-up MRI or CT at a 2- or 3-month interval may be sufficient to determine those who need therapy versus those who can simply be observed with serial imaging. Somatostatin analogs

Somatostatin is a naturally occurring peptide that exerts its effects on the endocrine system through binding to one or more of five somatostatin receptors (SSTR1−−5 ). Most PNETs express these receptors (especially SSTR2 ) and somatostatin was initially considered as a treatment for NETs due to its ability to block hormone secretion and slow cell growth [14]. However, its short halflife limits its utility as a therapeutic agent, prompting the development of somatostatin analogs with enhanced pharmacokinetic profiles [30]. The somatostatin analogs octreotide and lanreotide have had a profound impact on patients with functionally active PNETs. The necrolytic migratory erythema that can accompany glucagonomas improves and sometimes resolves completely with somatostatin analogs. Similarly, watery diarrhea, hypokalemia and achlorhydria syndrome that affect many individuals with VIPomas have dramatically improved upon treatment with SA [12]. However, a word of caution is appropriate when considering use of a somatostatin analog for insulinomas. The inhibition of endogenous glucagon by somatostatin could result in profound hypoglycemia [31]. Though there is a clear role for SA in the management of functional PNETs, its role as an antiproliferative agent has only recently been confirmed. The PROMID

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trial randomized well-differentiated NETs arising in the midgut (i.e., carcinoids) to either octreotide or placebo and demonstrated a significantly prolonged progressionfree survival (PFS) in the treatment arm [32]. However, extrapolation of this finding to PNETs was speculative until recently. A multinational trial known as CLARINET confirmed the superiority of lanreotide depot compared with placebo in extending PFS in hormonally nonfunctional gastroenteropancreatic NETs. In CLARINET, 204 patients were randomized to receive depotlanreotide 120 mg or placebo. The primary endpoint, PFS, was significantly improved in the lanreotide arm with a hazard ratio of 0.47 (95% CI: 0.3–0.73) [33]. Out of the 91 PNET patients in this trial, the hazard ratio was 0.58 (95% CI: 0.32–1.04; p = 0.0637) [33]. Cytotoxic chemotherapy options

PNETs have higher response rates to cytotoxic agents than midgut NETs, where the role of chemotherapy remains in question. In 1982, streptozocin (STZ), a naturally derived alkylating agent, emerged as the first US FDA approved agent for PNETs [14]. Early trials with streptozocin have been questioned due to their reliance on nonradiographic response criteria (i.e., reduction in tumor markers or clinical assessment of hepatomegaly) that may have inflated true response rates. Upon reevaluation, one study investigated the combination of STZ, 5-FU and doxorubicin in individuals with metastatic PNETs and reported a response rate of 39% based on objective radiographic criteria with a median response duration of 9.3 months [34]. While streptozocin-based regimens remained a ‘standard of care’ for PNETs, many oncologists have been reluctant to adopt streptozocin due to the nausea, myelosuppression and occasional renal insufficiency associated with the drug. A less toxic and more convenient oral alkylating agent, temozolomide, has been shown to be effective against PNETs. In vitro analysis of the combination of capecitabine, an orally administered prodrug for 5-FU, and temozolomide suggested a synergistic relationship between the two agents and their ability to mutually induce apoptosis in neuroendocrine tumor cells [35]. Following this hypothesis, Strosberg et al. published a retrospective study of 30 chemona¨ıve patients with well-differentiated PNETs treated with capecitabine and temozolomide. An impressive objective radiographic response rate of 70% was reported in addition to PFS of 18 months. Grade 3 and 4 toxicities were reported at 12%, which are considerably lower than those observed with streptozocin-based therapies [36]. Confirmatory prospective trials of this combination are underway. Other chemotherapy combinations also have activity in PNETs (see Table 1) though most are either less conve-

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nient or more toxic than temozolomide-based regimens. Angiogenesis & mTOR inhibitors

PNETs are hypervascular (see Figure 1) perhaps due to the overexpression of VEGF and its corresponding transmembrane receptor (VEGFR) [56]. Inhibitors of the VEGF-VEGFR axis have proven to be active in PNETs. Sunitinib, a multitargeted oral tyrosine kinase inhibitor that inhibits the VEGFR tyrosine kinase was tested in a Phase III, double-blind, placebo-controlled trial of PNET patients with radiographically progressive disease. The trial was terminated early by the data safety monitoring board due to improved outcomes on the treatment arm. With enrollment of 171 patients, the primary endpoint, PFS, was 11.4 months in the sunitinib arm compared with 5.5 months in the placebo arm. Additionally, an objective response of 9.3% was observed with sunitinib [38]. In May 2011, the FDA approved sunitinib for the treatment of PNETs. As discussed above, the mTOR pathway and various associated genes (TSC2, PTEN and PIK3CA) are mutated in approximately 16% of PNETs. mTOR is a serine/threonine protein kinase, that lies downstream of and is central to the regulation of cell growth in the PI3K/Akt signaling pathway [57]. Increased activity of mTOR complex 1, resulting from the loss of inhibiting function of the TSC2 gene or PTEN, is marked by cell proliferation and angiogenesis [58]. Everolimus is an oral inhibitor of mTOR and was tested in a Phase III, doubleblinded trial (RADIANT-3) of 410 patients with advanced PNETs with radiographic progression. Patients received either everolimus 10 mg/day or placebo and were allowed to receive additional supportive care, including somatostatin analogs. While the objective response rate for everolimus was low at 5%, clinically and statistically significant improvements in PFS were demonstrated (11 vs 4.6 months; p < 0.001). Out of patients who progressed in the placebo arm, 73% were crossed over to active treatment. Presumably because of the crossover, no significant difference in overall survival was observed [42]. Combination therapies

With proof that cytotoxic chemotherapy, antiangiogenesis agents and mTOR inhibitors are active against PNETs, newer trials are assessing the efficacy of these agents in various combinations (see Table 1). A Phase II trial of temozolomide and bevacizumab in advanced NETs demonstrated a radiographic response rate of 33% (5 out of 15 patients) in the PNET subset. Median PFS was 14.3 months with an overall survival of 41.7 months [48].

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Table 1. Selected clinical studies of therapies in pancreatic neuroendocrine tumors. Targeted therapies† Agent

Molecular targets

Study type

Number of PNETs

Efficacy end points‡

Ref.

Sorafenib

BRAF, VEGFR2, PDGFR

Phase II

43

PNET: ORR 11%, PFS 11.9 months

[37]

Sunitinib vs placebo

VEGFR, PDGFR

Phase III

171

ORR 9.3%, PFS 11.4 months, OS 30.5 months. Placebo: ORR 0%, PFS 5.5 months, OS 24.4 months

[38]

Pazopanib

VEGFR, PDGFR

Phase II

29

PNET: ORR 17%, PFS 11.7 months

[39]

Temsirolimus

mTOR

Phase II

15

PNET: ORR 7%, PFS 6 months

[40]

Everolimus

mTOR

Phase II

27

ORR 12%, PFS 17.1 months

[41]

Everolimus vs placebo (RADIANT-3)

mTOR

Phase III

410

ORR 4.8%, PFS 11.0 months. Placebo: PFS 4.6 months

[42]

Lanreotide vs placebo (CLARINET)

SSTR2

Phase III

81

PFS 12.9 months

[33]

Cytotoxic chemotherapies Agent

Study type

Number of PNETs

Efficacy end points‡

Ref.

Chlorozotocin

Phase II

33

ORR 30%, PFS 17 months, OS 18 months

[43]

5-Fluorouracil FU + Streptozocin

Phase II

33

ORR 45%, PFS 14 months, OS 16.8 months

[43]

Doxorubicin + Streptozocin

Phase II

36

ORR 69%, PFS 18 months, OS 26.4 months

[43]

Dacarbazine (DITC)

Phase II

50

ORR 34%, OS 19.3 months

[44]

Streptozocin + Doxorubicin + Fluorouracil

Retrospective

84

ORR 39%, PFS 18 months, OS 37 months

[34]

Temozolomide (diverse regimens)

Retrospective

53

ORR 34%, PFS 13.6 months, OS 35.3 months

[45]

Temozolomide (single agent)

Retrospective

12

ORR 8%

[46]

Temozolomide + Capecitabine

Retrospective

30

ORR 70%, PFS 18 months

[36]

Study type

Number of PNETs

Efficacy end points‡

Ref.

Combination studies§ Agents Temsirolimus + Bevacizumab

Phase II

25

ORR: 44.0%

[47]

Bevacizumab + Temozolomide

Phase II

18

PNET: ORR 33%, PFS 14.3 months

[48]

Everolimus + OLAR

Phase II

30

PNET: ORR 27%, PFS 50 weeks

[49]

Temozolomide + Thalidomide

Phase II

11

ORR 45%

[50]

Temozolomide + Bevacizumab

Phase II

15

ORR 33%, PFS 14.3 months, OS 41.7 months

[48]

Temozolomide + Everolimus

Phase I/II

40

ORR 40%, PFS 15.4 months

[51]

Fluoropyrimidine + Oxaliplatin + Bevacizumab

Phase II

25

ORR 32%

[52,53]

†Selected angiogenesis, mTOR and somatostatin inhibitors only. ‡Inclusive of all evaluable patients in study unless otherwise noted. §Combinations of targeted agents or targeted agents plus chemotherapy. Either 5-FU or capecitabine. OLAR: Octreotide long-acting release; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PNET: Pancreatic neuroendocrine tumor.

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Table 1. (cont.). Selected clinical studies of therapies in pancreatic neuroendocrine tumors. Targeted therapies† Agent

Molecular targets

Study type

Number of PNETs

Efficacy end points‡

Ref.

Peptide receptor radionuclide therapies Radionuclide

Study type

Number of PNETs

Efficacy end points‡

Ref.

90-Y-DOTATOC

Retrospective

342

ORR 26.9%

[54]

177-Lu-DOTATATE

Retrospective

91

PNET: ORR 38.5%

[55]

†Selected angiogenesis, mTOR and somatostatin inhibitors only. ‡Inclusive of all evaluable patients in study unless otherwise noted. §Combinations of targeted agents or targeted agents plus chemotherapy. Either 5-FU or capecitabine. OLAR: Octreotide long-acting release; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PNET: Pancreatic neuroendocrine tumor.

Hobday et al. recently presented encouraging results of the intravenous mTOR inhibitor temsirolimus when given with bevacizumab, reporting a 41% radiographic response rate in 56 PNET patients [47]. Having established that selected chemotherapy agents and inhibitors of mTOR and angiogenesis are active in PNETs, current and future clinical trials will assess the incremental benefits (and risks) of combining these agents. Peptide receptor radionuclide therapy (PRRT)

Radiolabeled somatostatin analogs have been adopted as standard of care in Europe but have not been approved in the United States due to a lack of prospective randomized clinical trials demonstrating efficacy and safety. 90 Yttrium-DOTATOC and 177 LutetiumDOTATATE are the most commonly used radiopeptides for PRRT and demonstrate response rates that range from 15 to 35% with reportedly minimal toxicity [59]. The two reports with the largest number of NET patients treated with PRRT include a singlearm prospective, single-institution Phase II study of 90 Yttrium-DOTATOC [54] and a retrospective, singleinstitution experience of 177 Lutetium-DOTATATE [55]. Out of the 1109 patients treated in the90 YttriumDOTATOC study, there were 342 PNETs with a reported response rate of 26.9% though response was defined as any measurable decrease in the sum of the longest diameter of all detected lesions [54]. Out of the 310 patients treated with 177 Lutetium-DOTATATE that were evaluable for response, 91 were PNET patients and demonstrated 38.5% partial response by WHO criteria. However, 69% had either partial response, minor response or stable disease. Interestingly, survival did not differ for those patients in the various response categories including stable disease but were markedly improved compared with those with progressive disease. Though it is clear that PRRT can be an effective regimen for some, if not many, patients with PNETs, the lack of prospective randomized data makes its comparative value difficult to evaluate. A prospective randomized

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trial of PRRT versus high-dose octreotide for patients with midgut NETs is underway and if its benefit is sufficient for FDA approval, it is hoped that successor trials in PNET might be considered or that its use might be extended to NETs beyond those that arise in the midgut. Current clinical trials Many recently completed and ongoing clinical trials address key issues in the management of PNETs. Use of an mTOR inhibitor alone or in combination with an angiogenesis inhibitor is being addressed by CALGB 80701 (NCT01229943) in which PNET patients are randomized to receive either everolimus or everolimus with bevacizumab. This study has completed accrual with results likely to become available in 2014. With the recently proven antiproliferative activity of lanreotide in PNETs, the combination of a somatostatin analog and mTOR inhibitor is worth testing. The COOPERATE 2 Trial (NCT01374451) randomized advanced PNET patients to everolimus with or without pasireotide, a newer somatostatin analog. This study is also closed to accrual. Though the results of temozolomide and capecitabine by Strosberg et al. [36] are impressive, there has been no definitive proof that the combination is superior to temozolomide alone. This question is being addressed in ECOG 2211 (NCT01824875) in which PNET patients are randomly assigned to temozolomide with or without capecitabine. The SEQTOR study (GETNE1206) in Spain randomizes PNET patients between streptozocin followed by everolimus versus everolimus followed by streptozocin. This is the first trial to address sequencing of therapy as well as a direct comparison of a chemotherapy agent with an mTOR inhibitor [60]. Resection of PNET liver metastases is considered a viable option in selected patients, though there remains a high risk of recurrent disease. As such, ECOG 2212 (NCT02031536) randomizes patients who have had resection of their liver metastases to 1 year of everolimus

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versus placebo in the first ever randomized adjuvant trial of NETs. Conclusion & future perspective Pancreatic neuroendocrine tumors are clinically challenging with an increasing number of treatment options that span multiple subspecialties in oncology. This is why it is particularly important for PNET patients to be evaluated by multidisciplinary tumor boards at centers with extensive experience in diagnosing and treating this rare disease. Since the approval of streptozocin over 30 years ago, progress had been slow until recently. Small single-arm trials of new chemotherapy regimens have demonstrated encouraging response rates in this disease with acceptable toxicity profiles. A meeting of NET experts convened by the National Cancer Institute helped to define the eligibility, design and clinical endpoints of future trials [61]. This effort combined with success in accrual to randomized clinical

References 1

2

Yao JC, Hassan M, Phan A et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. 26(18), 3063–3072 (2008). Fesinmeyer MD, Austin MA, Li CI, De Roos AJ, Bowen DJ. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 14(7), 1766–1773 (2005).

trials has led to significant advances in just the last 5 years demonstrating efficacy of three different classes of drugs (somatostatin analog lanreotide, mTOR inhibitor everolimus and angiogenesis inhibitor sunitinib). Ongoing and future trials will address issues of new drug classes, drug combinations, drug selection by analysis of genetic vulnerabilities, liver-directed therapies and role of pre-operative and postoperative therapy. Accrual to clinical trials must remain a priority for physicians who diagnose and care for those afflicted with a PNET. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

11

Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas 38(3), 255–258 (2009).

12

Behr T, Arnold R, Wied M. Somatostatin analogues in the treatment of endocrine tumours of the gastrointestinal tract. Expert Opin. Pharmacother. 3(6), 643–656 (2002).

13

Halperin DM, Kulke MH. Management of pancreatic neuroendocrine tumors. Gastroenterol. Clin. North Am. 41(1), 119–131 (2012).

14

Kim KW, Krajewski KM, Nishino M et al. Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging. AJR Am. J. Roentgenol. 201(4), 811–824 (2013).

3

Berge T, Linell F. Carcinoid tumours. Acta Pathol. Microbiol. Scand. A 84(4), 322–330 (1976).

4

Yao JC, Leary C, Dagohoy C et al. Population-based study of islet cell carcinoma. Ann. Surg. Oncol. 14(12), 3492–3500 (2007).

5

Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem. Sci. 38(8), 394–402 (2013).

15

Legmann P, Vignaux O, Dousset B et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. Am. J. Roentgenol. 170(5), 1315–1322 (1998).

6

Verhoef S, van Diemen-Steenvoorde R, Akkersdijk W et al. Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur. J. Pediatr. 158(4), 284–287 (1999).

16

Kulke MH, Benson AB, Bergsland E et al. Neuroendocrine tumors. J. Natl Compr. Canc. Netw. 10(6), 724–764 (2012).

17

Khashab MA, Yong E, Lennon AM et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest. Endosc. 73(4), 691–696 (2011).

7

Hammel PR, Vilgrain V, Terris B et al. Pancreatic involvement in von Hippel-Lindau disease. Gastroenterology 119(4), 1087–1095 (2000).

18

8

Chen M, Van Ness M, Guo Y, Gregg J. Molecular pathology of pancreatic neuroendocrine tumors. J. Gastrointest. Oncol. 3(3), 182 (2012).

Dromain C, de Baere T, Baudin E et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. Am. J. Roentgenol. 180(1), 121–128 (2003).

19

9

Jiao Y, Shi C, Edil BH et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021), 1199–1203 (2011).

Prasad V, Ambrosini V, Hommann M, Hoersch D, Fanti S, Baum RP. Detection of unknown primary neuroendocrine tumours (CUP-NET) using 68Ga-DOTA-NOC receptor PET/CT. Eur. J. Nucl. Med. Mol. Imaging 37(1), 67–77 (2010).

10

Heaphy CM, de Wilde RF, Jiao Y et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041), 425–425 (2011).

20

Schillaci O, Corleto V, Annibale B, Scopinaro F, Delle Fave G. Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours. Ital. J. Gastroenterol. Hepatol. 31, S186–S189 (1999).

future science group

Review

www.futuremedicine.com

63

Review

Waller

21

Krausz Y, Keidar Z, Kogan I et al. SPECT/CT hybrid imaging with 111In-pentetreotide in assessment of neuroendocrine tumours. Clin. Endocrinol. 59(5), 565–573 (2003).

22

Buchmann I, Henze M, Engelbrecht S et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imaging 34(10), 1617–1626 (2007).

23

24

Dong M, Phan AT, Yao JC. New strategies for advanced neuroendocrine tumors in the era of targeted therapy. Clin. Cancer Res. 18(7), 1830–1836 (2012).

25

Valle JW, Eatock M, Clueit B, Gabriel Z, Ferdinand R, Mitchell S. A systematic review of non-surgical treatments for pancreatic neuroendocrine tumours. Cancer Treat. Rev. 40(3), 376–389 (2013).

26

Kinney T. Evidence-based imaging of pancreatic malignancies. Surg. Clin. North Am. 90(2), 235–249 (2010).

27

Akerstr¨om G, Hellman P. Surgery on neuroendocrine tumours. Best Pract. Res. Clin. Endocrinol. Metab. 21(1), 87–109 (2007).

28

Vogl TJ, Naguib NN, Zangos S, Eichler K, Hedayati A, Nour-Eldin N-EA. Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation. Eur. J. Radiol. 72(3), 517–528 (2009).

29

Mayo SC, de Jong MC, Pulitano C et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann. Surg. Oncol. 17(12), 3129–3136 (2010).

30

Evers BM, Parekh D, Townsend Jr CM, Thompson JC. Somatostatin and analogues in the treatment of cancer. A review. Ann. Surg. 213(3), 190–198 (1991).

31

Maton P. The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors. Gastroenterol. Clin. North Am. 18(4), 897–922 (1989).

32

33

64

Breeman WA, de Blois E, Sze Chan H, Konijnenberg M, Kwekkeboom DJ, Krenning EP. (68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives. Semin. Nucl. Med. 41(4), 314–321 (2011).

Rinke A, M¨uller H-H, Schade-Brittinger C et al. 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. 27(28), 4656–4663 (2009). Caplin ME, Phan A, Liyange N et al. Lanreotide autogel (depot) significantly improves tumor progression-free survival in patients with non-functioning gastroenteropancreatic neuroendocrine tumors: results of the CLARINET study. Presented at: North American Neuroendocrine Tumor Symposium. Charleston, SC, USA, 10 April–10 May 2013.

36

Strosberg JR, Fine RL, Choi J et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117(2), 268–275 (2011).

37

Hobday T, Rubin J, Holen K et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study. J. Clin. Oncol. 25(18S), 4504 (2007).

38

Raymond E, Dahan L, Raoul J-L et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 501–513 (2011).

39

Phan A, Yao J, Fogelman D et al. A prospective, multi-institutional Phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). Presented at: 2010 ASCO Annual Meeting/Clinical Science Symposium, Targeted Therapy for Neuroendocrine Tumors: Efficacy, Imaging, and Quality of Life. Chicago, IL, USA, 4–8 June 2010. (Abstract 4001).

40

Duran I, Kortmansky J, Singh D et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br. J. Cancer 95(9), 1148–1154 (2006).

41

Oh DY, Kim TW, Park YS et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 118(24), 6162–6170 (2012).

42

Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 514–523 (2011).

43

Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin–doxorubicin, streptozocin–fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 326(8), 519–523 (1992).

44

Ramanathan R, Cnaan A, Hahn R, Carbone P, Haller D. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann. Oncol. 12(8), 1139–1143 (2001).

45

Kulke MH, Hornick JL, Frauenhoffer C et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin. Cancer Res., 15(1), 338–345 (2009).

46

Ekeblad S, Sundin A, Janson ET et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin. Cancer Res. 13(10), 2986–2991 (2007).

47

Hobday TJ, Qin R, Moore MJ et al. Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET). J. Clin. Oncol. 31(Suppl. 15) (2013).

34

Kouvaraki MA, Ajani JA, Hoff P et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J. Clin. Oncol. 22(23), 4762–4771 (2004).

48

Chan JA, Stuart K, Earle CC et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 30(24), 2963–2968 (2012).

35

Fine R, Fogelman D, Schreibman S. Effective treatment of neuroendocrine tumors with temozolomide and capecitabine. J. Clin. Oncol. 23(16S), S4216 (2005).

49

Yao JC, Phan AT, Chang DZ et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low-to

Int. J. Endo. Oncol. (2015) 2(1)

future science group

Management of pancreatic neuroendocrine tumors

intermediate-grade neuroendocrine tumors: results of a phase II study. J. Clin. Oncol. 26(26), 4311–4318 (2008).

Tyr3] octreotate: toxicity, efficacy, and survival. J. Clin. Oncol. 26(13), 2124–2130 (2008).

50

Kulke MH, Stuart K, Enzinger PC et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J. Clin. Oncol. 24(3), 401–406 (2006).

56

Inoue M, Hager JH, Ferrara N, Gerber H-P, Hanahan D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis. Cancer cell 1(2), 193–202 (2002).

51

Chan JA, Blaszkowsky L, Stuart K et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer 119(17), 3212–3218 (2013).

57

Grozinsky-Glasberg S, Shimon I. The potential role of mTOR inhibitors in the treatment of endocrine tumors. J. Endocrinol. Invest. 33(4), 276–281 (2010).

58

52

Venook A, Ko A, Tempero M et al. Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J. Clin. Oncol. 26(15 Suppl.) 15545 (2008).

Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J. Chem. Biol. 1(1–4), 27–36 (2008).

59

Kunz P, Kuo T, Zahn J et al. A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J. Clin. Oncol. 28(Suppl. 15), 4104 (2010).

Bergsma H, van Vliet EI, Teunissen JJ et al. Peptide receptor radionuclide therapy (PRRT) for GEP-NETs. Best Pract. Res. Clin. Gastroenterol. 26(6), 867–881 (2012).

60

Trial G. A Newsletter for Medical Professionals and ENETS Members. (2013). www.google.co.uk/url?sa=t&rct=j&q= &esrc=s&source=web&cd=1&cad=rja&uact=8&ved= 0CCMQFjAA&url=http%3A%2F%2Fwww.enets.org%2Fd.n. 20.pdf&ei=y7suVJ-CCIvxaoC4gNAG&usg=AFQjCNHc3BngwGIsSaWZ8c-ett6IWINYw&bvm=bv.76802529,d.d2s

61

Kulke MH, Siu LL, Tepper JE et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J. Clin. Oncol. 29(7), 934–943 (2011).

53

54

55

Imhof A, Brunner P, Marincek N et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J. Clin. Oncol. 29(17), 2416–2423 (2011). Kwekkeboom DJ, de Herder WW, Kam BL et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,

future science group

Review

www.futuremedicine.com

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