Advertisement

A systematic review of non-surgical treatments for pancreatic neuroendocrine tumours

Open AccessPublished:December 02, 2013DOI:https://doi.org/10.1016/j.ctrv.2013.08.007

      Abstract

      Introduction

      Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base.

      Methods

      Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers.

      Results

      Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies.

      Discussion

      The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm.

      Keywords

      Introduction

      Pancreatic neuroendocrine tumours (pNETs) are rare. Worldwide, the annual incidence of pNET is estimated to range from 0.2 to 0.4 per 100,000 population, although due to the relatively indolent nature of these tumours the true prevalence may be much higher [
      • Ramage J.K.
      • Davies A.H.G.
      • Ardill J.
      • Bax N.
      • Caplin M.
      • Grossman A.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
      ,
      • Goldin S.B.
      • Aston J.
      • Wahi M.M.
      Sporadically occurring functional pancreatic endocrine tumors: review of recent literature.
      ,
      • Yao J.C.
      • Hassan M.
      • Phan A.
      • Dagohoy C.
      • Leary C.
      • Mares J.E.
      • et al.
      One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States.
      ]. At presentation, 65% of patients have unresectable or metastatic disease. The 5-year survival rate of patients with metastatic disease is 30–40% and has not changed significantly over the last 30 years [
      • Pape U.F.
      • Bohmig M.
      • Berndt U.
      • Tiling N.
      • Wiedenmann B.
      • Plockinger U.
      Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a German referral center.
      ].
      Clinically, pNETs are divided into two groups: functional (10–30%) or non-functional (70–90%). Functional pNETs secrete biologically active peptides, or hormones producing one of nine recognised specific hormonal syndromes. These tumours are associated with a reduced quality of life (QoL) in patients [
      • Kouvaraki M.A.
      • Ajani J.A.
      • Hoff P.
      • Wolff R.
      • Evans D.B.
      • Lozano R.
      • et al.
      Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. [Erratum appears in J Clin Oncol 2005 Jan 1;23(1):248].
      ]. The hormones secreted by functional tumours include gastrin, insulin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP), growth hormone-releasing factor and adrenocorticotrophic hormone [
      • Kouvaraki M.A.
      • Ajani J.A.
      • Hoff P.
      • Wolff R.
      • Evans D.B.
      • Lozano R.
      • et al.
      Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. [Erratum appears in J Clin Oncol 2005 Jan 1;23(1):248].
      ]. The hormonal syndromes are associated with diverse clinical features with regard to both metastatic potential and survival. For example 10% of patients who present with an insulinoma will develop metastases, compared with 50% of those with somatostatinoma and up to 70% of patients with VIPoma [
      • Ramage J.K.
      • Davies A.H.G.
      • Ardill J.
      • Bax N.
      • Caplin M.
      • Grossman A.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
      ].
      Surgery, where possible, is considered the first-line treatment for pNET patients. Due to the presence of distant metastatic disease or local extension of the tumour, surgery is often non-curative, but even in advanced cases surgical debulking of disease can reduce symptoms related to tumour burden and hormone production [
      • Delaunoit T.
      • Neczyporenko F.
      • Rubin J.
      • Erlichman C.
      • Hobday T.J.
      Medical management of pancreatic neuroendocrine tumors.
      ]. For patients who are not candidates for surgery, the choice of treatment depends on the stage of the disease, symptoms and histological features of the tumour [
      • Strosberg J.R.
      • Nasir A.
      Biology and treatment of metastatic gastrointestinal neuroendocrine tumors.
      ]. Treatment options include SSA and liver-directed therapies (for example, chemoembolisation, radioembolisation, arterial embolisation and radiofrequency ablation, which are palliative options for liver-dominant disease) [
      • Ramage J.K.
      • Davies A.H.G.
      • Ardill J.
      • Bax N.
      • Caplin M.
      • Grossman A.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
      ,
      • Delaunoit T.
      • Neczyporenko F.
      • Rubin J.
      • Erlichman C.
      • Hobday T.J.
      Medical management of pancreatic neuroendocrine tumors.
      ,
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • Kloppel G.
      • Lopes J.M.
      • O’Connor J.M.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      ,
      • Reidy D.L.
      • Tang L.H.
      • Saltz L.B.
      Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors.
      ,
      • Bajetta E.
      • Procopio G.
      • Pusceddu S.
      • Pietrantonio F.
      • Milione M.
      • MacCauro M.
      • et al.
      From biology to clinical experience: Evolution in the knowledge of neuroendocrine tumours.
      ]. In clinical practice, systemic chemotherapy is commonly used in the treatment of pNET, but with modest efficacy (responses are rarely complete) and the attendant toxicity profiles. Such chemotherapy agents include streptozocin, doxorubicin, 5-fluorouracil, dacarbazine, capecitabine and temozolomide [
      • Ramage J.K.
      • Davies A.H.G.
      • Ardill J.
      • Bax N.
      • Caplin M.
      • Grossman A.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
      ,
      • Delaunoit T.
      • Neczyporenko F.
      • Rubin J.
      • Erlichman C.
      • Hobday T.J.
      Medical management of pancreatic neuroendocrine tumors.
      ,
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • Kloppel G.
      • Lopes J.M.
      • O’Connor J.M.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      ,
      • Kaltsas G.
      • Mukherjee J.J.
      • Plowman P.N.
      Grossman Ashley B. The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours.
      ].
      There have been limited developments in the management of advanced pNET over the last two decades [
      • Kaltsas G.A.
      • Papadogias D.
      • Makras P.
      • Grossman A.B.
      Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues.
      ,
      • Reidy-Lagunes D.
      • Thornton R.
      Pancreatic neuroendocrine and carcinoid tumors: what’s new, what’s old, and what’s different?.
      ]. However, an improved understanding of the molecular mechanisms underlying pNET has led to more recent treatment options that include agents directed at inhibiting growth factors or their receptors that are produced by these tumours [
      • Metz D.C.
      • Jensen-Robert T.
      Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors.
      ,
      • Modlin I.M.
      • Oberg K.
      • Chung D.C.
      • Jensen R.T.
      • de Herder W.W.
      • Thakker R.V.
      • et al.
      Gastroenteropancreatic neuroendocrine tumours.
      ]. Several of these agents are still investigational and to date, only the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have been licensed by the European Medicines Agency and the FDA for the treatment of unresectable or metastatic, well-differentiated pNETs with disease progression in adults.
      A number of reviews of treatments specifically for pNET have been previously published [
      • Delaunoit T.
      • Neczyporenko F.
      • Rubin J.
      • Erlichman C.
      • Hobday T.J.
      Medical management of pancreatic neuroendocrine tumors.
      ,
      • Metz D.C.
      • Jensen-Robert T.
      Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors.
      ,
      • Fjallskog M.L.
      • Janson E.T.
      Treatment of endocrine pancreatic tumors.
      ], as well as reviews of treatments for all NETs [
      • Kaltsas G.
      • Mukherjee J.J.
      • Plowman P.N.
      Grossman Ashley B. The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours.
      ,
      • Toumpanakis C.
      • Meyer T.
      • Caplin M.E.
      Cytotoxic treatment including embolization/chemoembolization for neuroendocrine tumours.
      ,
      • Modlin I.M.
      • Pavel M.
      • Kidd M.
      • Gustafsson B.I.
      Review article: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours.
      ,
      • Plockinger U.
      • Wiedenmann B.
      Biotherapy.
      ]. Several evidence-based guidelines on the management of pNET are available which include recommendations for the treatment of pNET (e.g. guidelines from the UK and Ireland Neuroendocrine Tumour Society (UKINETS) [
      • Ramage J.K.
      • Davies A.H.G.
      • Ardill J.
      • Bax N.
      • Caplin M.
      • Grossman A.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
      ], the National Comprehensive Cancer Network (NCCN) [

      NCCN. NCCN Practice Guidelines in Oncology. 2009.

      ] and the European Neuroendocrine Tumour Society (ENETS) [
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • Kloppel G.
      • Lopes J.M.
      • O’Connor J.M.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      ].
      More recently, key recommendations from the NET Clinical Trials Planning Meeting included the separate examination of carcinoid tumours and pancreatic NETS in clinical trials and the avoidance of SSA washout periods when evaluating novel agents for the control of hormonal syndromes [
      • Kulke M.H.
      • Siu L.L.
      • Tepper J.E.
      • Fisher G.
      • Jaffe D.
      • Haller D.G.
      • et al.
      Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting.
      ]. An update to the UKINETS guidelines covers genetics, diagnosis, imaging, pathology, treatment, ablation and carcinoid heart disease [
      • Ramage J.K.
      • Ahmed A.
      • Ardill J.
      • Bax N.
      • Breen D.J.
      • Caplin M.E.
      • et al.
      Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).
      ]. Updated consensus guidelines from ENETS are also available [
      • Jensen R.T.
      • Cadiot G.
      • Brandi M.L.
      • de Herder W.W.
      • Kaltsas G.
      • Komminoth P.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes.
      ].
      As new targeted therapies emerge and become more widely used in the management of pNET, this review was undertaken to understand the current evidence base in terms of efficacy and safety of non-surgical treatments and to assess the trial methodology supporting the use of chemotherapies and new agents in this setting.

      Methods

      Inclusion criteria

      Randomised controlled trials (RCTs), non-RCTs and prospective single-arm studies were included if they enrolled adult patients with a confirmed diagnosis of pNET (as defined by recognised clinical guidelines). Studies enrolling patients with NETs of any aetiology (including pancreas) were included as long as relevant efficacy/safety outcomes were reported for the pNET subset of patients. Only studies with at least 10 pNET patients were included in this review as the robustness of results from smaller studies was felt to be questionable (Table 1).
      Table 1Inclusion and exclusion criteria.
      CriterionIncludedExcluded
      Population
      • Age: ⩾18 years
      • Race: any
      • Qualifying disease: pancreatic neuroendocrine tumours (pNET)
        Studies enrolling patients with neuroendocrine tumours of any aetiology (including pancreas) were be included as long as relevant efficacy/safety outcomes were reported for the pNET subset of patients.
      • No restriction on previous treatment/surgery (ie treatment naïve & refractory patients)
      • Age:⩽18 years• Non-pancreatic neuroendocrine tumours
      Perspective of study
      • Prospective (concurrent)
      • Comparative
      • Non-comparative
      • Retrospective
      Study characteristicsRCTs: parallel/Cross-over design (with adequate wash-out period between treatments

      Non-RCTs: cohort/case series
      • Case report• Case studies with single patient
      Language• Any-
      Trial length• All study durations-
      Sample size• ⩾10 pNET patients• <10 pNET patients
      Interventions/treatments
      • Systemic chemotherapy
      • Targeted therapies (including everolimus, bevacizumab, sorafenib, sunitinib, gefitinib)
      • Somatostatin analogue
      • Interferon/Biotherapy
      • Radionuclide therapy, including peptide receptor radionuclide therapy
      • Radiofrequency ablation
      • Chemo-embolisation
      • Hepatic artery embolisation (HAE) with/without chemotherapy (HACE)
      • Combination regimens.
      • No restriction on dose, formulation, or mode of delivery
      • Surgery
      Control intervention/treatments• Any of the interventions listed abovePlacebo/usual careNo treatment-
      Included trial outcomesEfficacy, including but not restricted to overall survival, progression free survival, objective overall response rate (PR + SD), Time to progression (TTP)/duration of response

      Safety, including withdrawals due to:

      • Any reason

      • Lack of efficacy

      • Adverse events

      Health-related quality of life
      Studies only reporting symptomatic relief outcomes for functioning tumours
      AE, adverse event; PR, partial response; RCT, randomised controlled trial; SD, stable disease.
      Studies enrolling patients with neuroendocrine tumours of any aetiology (including pancreas) were be included as long as relevant efficacy/safety outcomes were reported for the pNET subset of patients.

      Identification of studies

      A systematic review of electronic databases and conference proceedings was conducted to identify relevant studies. Medline, Embase, The Cochrane Library, BIOSIS and ISI Web of Knowledge were accessed in April 2012. The search combined pNET terms ‘neuroendocrine tumor’ and ‘pancreas’ with intervention terms for somatostatin, chemotherapy and pharmacotherapy agents, interferon, radionuclide therapies and liver-directed therapies. Conference proceedings from the American Society of Clinical Oncology (ASCO), European Neuroendocrine Tumor Society (ENETS) and the European Society for Medical Oncology (ESMO) were hand-searched (2006–2012 inclusive).
      Identified studies were independently assessed by two researchers in order to ascertain whether they met a set of pre-defined inclusion/exclusion criteria for inclusion in the systematic review (Table 1).

      Data extraction

      A pre-determined data extraction table was designed in an Excel® spreadsheet. The primary efficacy outcomes extracted included overall survival (OS), progression free survival (PFS), objective overall response rate (ORR), tumour response and time to progression (TTP)/duration of response. The safety outcomes of interest included incidence of death, incidence of withdrawal, and incidence of serious adverse events (AE). Health related quality of life (HRQoL) data (reported using generic- or disease-specific questionnaires) were also extracted.

      Quality assessment

      Study quality was assessed independently by two reviewers using the methods recommended in the Cochrane Reviewer’s handbook [

      Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. http://www.cochrane-handbook.org.

      ] for RCTs and the Chambers quality assessment checklist for single-arm studies [
      • Chambers R.
      • Rodgers M.
      • Woolacott N.
      Not only randomized controlled trials, but also case series should be considered in systematic reviews of rapidly developing technologies.
      ]. Any differences of opinion were resolved by discussion and consensus.

      Data analysis

      As discussed in more detail in the results section, there was considerable variation between the studies meeting eligibility criteria for inclusion in the review in terms of study design (majority of studies enrolled single-arm cohorts), reported outcomes and included populations. Therefore as a robust meta-analysis comparing the efficacy and safety of all available treatments was not feasible, results were summarised qualitatively.

      Results

      Study flow

      In total, 5,100 studies were identified from the literature search (following removal of duplicates). A further fourteen relevant publications were identified from searching reference lists and conference proceedings. After excluding papers not meeting the inclusion criteria, 52 publications of 47 studies were included in the systematic review (Fig. 1).

      Study characteristics

      Systemic chemotherapy was the most common intervention (two RCTs, 15 non-randomised studies) with many single-arm studies evaluating a wide range of agents (Table 2). The second most frequently reported treatments were SSAs and radiolabeled SSA therapies (nine non-randomised studies), followed by novel targeted agents (two RCTs and six non-randomised studies), liver-directed therapies (six non-randomised studies), mixed treatment regimens (one RCT, four non-randomised studies) and other interventions such as interferon and recombinant human endostatin (one non-randomised study each).
      Table 2Study characteristics of included studies. Primary outcome shown in bold.
      Study referenceStudy locationNo. of patientsTreatment, dose and durationStudy populationOutcomes reported
      Randomised controlled trials (n=5)
      Targeted therapies (n=2)
      Raymond 2011
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      Full text
      France, UK, Germany, Belgium, Taiwan, South Korea,Canada86Sunitinib, 37.5 mg/day, continuous daily dosingWell differentiated, pNET; disease progression < 12 monthsPFS, ORR, OS, safety, QoL
      85Placebo, continuous daily dosing
      Yao 2011, RADIANT-3
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.


      Full text
      USA, Japan, France, Belgium, Spain, Netherlands, Italy, Germany, Sweden207Everolimus, 10 mg/day, continuous daily dosingLow-grade or intermediate-grade advanced pNET and radiological documentation of disease progression in the 12 months preceding randomisationPFS, objective response rate, duration of response, OS, safety. ,
      203Placebo, continuous daily dosing
      Chemotherapy (n=2)
      Moertel 1992
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.


      Full text
      USA33Chlorozotocin IV 150 mg m2 BSA, every 7 weeksUnresectable or metastatic islet-cell carcinomaRegression, progression, survival, safety
      33Streptozocin IV 500 mg and Fluorouracil 400 mg per m2 BSA; 5 days, repeated every 6 weeks.
      36Streptozocin IV 500 mg per m2 BSA (5 days)Doxorubicin 50 mg m2 BSA, , day 1 and day 22 of each 6 week cycle
      Moertel 1980
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.


      Full text
      USA42Streptozocin IV 500 mg per m2 BSA/day; 5 days, repeated every 6 weeksUnresectable, metastatic islet-cell carcinoma diagnosed histologically.ORR, CR, median survival, safety
      40Streptozocin IV 500 mg per m2 BSADoxorubicin 50 mg m2 BSA5 days, repeated every 6 weeks
      Mixed treatment (n=1)
      Pavel 2008

      Pavel M, Heuck F, Plockinger U, Pape UF, Tiling N, Rinke A, et al. Prospective randomized trial: Biotherapy versus chemotherapy in malignant nonfunctional neuroendocrine tumors of the pancreas and brochial tract (ENET-1). ASCO GI conference. 2008.



      Abstract
      NR8Streptozotocin 500 mg/m2 + 5-FU 400 mg/m2 IV, day 1-5, repeated on day 43 for 9 cycles.Histologically proven, therapy-naïve pNETResponse (CR, PR, SD), TTP, safety
      8Octreotide LAR 30 mg IM, monthly
      Non-randomised studies (n=42)
      Targeted therapies (n=6)
      Hobday 2007

      Hobday T, Rubin J, Holen K, Picus J, Donehower R, Marschke RF, et al. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): A phase II Consortium (P2C) study. ASCO GI conference. 2007.



      Abstract
      USA41Sorafenib 400 mg BID, continuous daily dosingpNET and carcinoid tumours (n = 50); prior interferon/ prior or concurrent octreotide allowed.Response (PR, MR), PFS, safety
      Hobday 2006

      Hobday T, Holen K, Donehower R, Camoriano J, Kim G, Picus J, et al. A phase II trial of gefitinib in patients with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. ASCO GI conference. 2006.



      Abstract
      USA39Gefitinib 250 mg BID, continuous daily dosingpNET and carcinoid tumours (n = 57); prior interferon/ prior or concurrent octreotide allowed.PFS, response (PR, MR, SD), safety
      Yao 2010
      • Vinik A.
      • Cutsem E.V.
      • Niccoli P.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • et al.
      Progression-free survival (PFS) by blinded independent central review (BICR) and updated overall survival (OS) of sunitinib versus placebo for patients with progressive, unresectable, well differentiated pancreatic neuroendocrine tumor (NET).
      ,
      • Yao J.C.
      • Lombard-Bohas C.
      • Baudin E.
      • Kvols L.K.
      • Rougier P.
      • Ruszniewski P.
      • et al.
      Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial.
      Full text
      International (11 countries)115Everolimus 10 mg/day, continuous daily dosingHistologically confirmed, well to moderately differentiated, advanced pNETORR, PFS, duration of response, OS, safety
      45Everolimus 10 mg/day + octreotide LAR (⩽30 mg)
      Duran 2006
      • Duran I.
      • Kortmansky J.
      • Singh D.
      • Hirte H.
      • Kocha W.
      • Goss G.
      • et al.
      A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.


      Full text
      USA, Canada15Temsirolimus 25 mg IV/week for 8 weeksHistological/cytological confirmed carcinoid/ pancreatic islet cell tumour with documented progressive metastatic diseaseORR, SD, duration of SD, TTP, OS, safety
      Kulke 2010

      Kulke M, Blaszkowsky A, Zhu AX, Florio S, Regan E, Ryan DP, et al. Phase I/II study of everolimus (RAD001) in combination with temozolomide (TMZ) in patients with advanced pancreatic neuroendocrine tumors (NET). ASCO GI conference. 2010.



      Abstract
      USA24Everolimus 5 mg or 10 mg qd with temozolomide 150 mg/m2 qd given for 7 days, maximum of 6 4-week cyclesHistologic evidence of pNET, not suitable for curative surgeryResponse (PR, SD, PD); safety
      Kulke 2008
      • Kulke M.H.
      • Lenz H.-J.
      • Meropol N.J.
      • Posey J.
      • Ryan D.P.
      • Picus J.
      • et al.
      Activity of sunitinib in patients with advanced neuroendocrine tumors.


      Full text
      USA66Sunitinib, 50 mg/daily for 4 weeksHistologic evidence of PNET; not candidates for curative surgeryORR, TTP, OS, safety
      Chemotherapy (n=15)
      Bukowski
      • Bukowski R.M.
      • Tangen C.
      • Lee R.
      • Macdonald J.S.
      • Einstein Jr, A.B.
      • Peterson R.
      • et al.
      Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: A Southwest Oncology Group study.


      Full text
      USA44Good-risk. Chlorozotocin (CTZ) 175 mg/m2 IV day 1 + 5-FU 800 mg/m2/d IV days 1-4; maintenance dose of 100 mg CTZ and 600 mg of 5-FU. Poor-risk pts given lower dosage.Maximum of 18 monthsBiopsy-proven islet-cell carcinoma, not amenable to surgeryPR, ORR, OS Safety
      Eriksson
      • Eriksson B.
      • Skogseid B.
      • Lundqvist G.
      • Wide L.
      • Wilander E.
      • Oberg K.
      Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors.


      Full text
      Sweden25STZ IV 0.5 g/m2 for 5 days, maintenance of 1 gm/m2 every third week + doxorubicin 40 mg/m2 every third week.Median 12 monthsClinically verified endocrine pancreatic tumour (benign/ malignant tumours included)ORR, OS, safety
      19As above + 5-FU IV 400 mg/m2 every third week.Median 12 months
      Fjallskog
      • Fjallskog M.L.
      • Janson E.T.
      • Falkmer U.G.
      • Vatn M.H.
      • Oberg K.E.
      • Eriksson B.K.
      Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors.


      Full text
      Norway30Doxorubicin 30 mg/m2 on day 1 with 1 g Streptozotocin as bolus injection days 1-5. Median of 13 courses (course every 3 weeks) administeredHistopathologic confirmation of non-resectable pNETORR, PFS, OS, safety
      Ramanathan

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



      Full text
      USA50DTIC 850 mg/m2 IV. At least 2 courses(course every 4 weeks), continued until progressionHistopathologic confirmation of non-resectable, malignant islet cell carcinomaORR, OS, safety
      Bajetta
      • Bajetta E.
      • Ferrari L.
      • Procopio G.
      • Catena L.
      • Ferrario E.
      • Martinetti A.
      • et al.
      Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours.


      Full text
      Italy285-FU 500 mg/m2, DTIC 200 mg/m2, epiadriamycin 30 mg/m2) IV on days 1-3. Median: 4 monthsNET confirmed by pathologyORR, TTP, OS, safety
      Moertel
      • Moertel C.G.
      • Lavin P.T.
      • Hahn R.G.
      Phase II trial of doxorubicin therapy for advanced islet cell carcinoma.


      Full text
      USA, Canada, France, Switzerland20Doxorubicin 60 mg/m2 IV, repeated at 3 weeks, 6 weeks and then every 4 weeks.Until evidence of disease progression or until a total of doxorubicin dose of 500 mg/m2 had been administeredHistopathologic confirmation of locally unresectable or metastatic islet cell carcinomaORR, OS, safety
      Bajetta
      • Bajetta E.
      • Catena L.
      • Procopio G.
      • De Dosso S.
      • Bichisao E.
      • Ferrari L.
      • et al.
      Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?.


      Full text
      Italy11Oxaliplatin 130 mg/mq day 1 IV + capecitabine 2000 mg/mq/die from day 2-15 every 3 weeks.6cycles maximum(each cycle 3 weeks)High- low-grade malignant NETsORR, OS, TTP, safety
      Fjallskog
      • Fjallskog M.L.
      • Granberg D.P.
      • Welin S.L.
      • Eriksson C.
      • Oberg K.E.
      • Janson E.T.
      • et al.
      Treatment with cisplatin and etoposide in patients with neuroendocrine tumors.


      Full text
      Sweden14Etoposide 100 mg/m2 /day for 3 days + cisplatin 45 mg/m2 per day on days 2 and 3.Cycles repeated every 4 weeksHistopathologic confirmation of NETORR, OS, safety
      Bajetta
      • Bajetta E.
      • Rimassa L.
      • Carnaghi C.
      • Seregni E.
      • Ferrari L.
      • Di Bartolomeo M.
      • et al.
      5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors.


      Full text
      Italy15Fluorouracil 500 mg/m2, DTIC 200 mg/m2 + Epirubicin 30 mg/m2 IV, 3 consecutive days. Cycles repeated every 3 weeksHistologically proven locally advanced/metastatic NETs, not amenable to surgeryORR, PR, CR, safety
      Kulke
      • Kulke M.H.
      • Stuart K.
      • Enzinger P.C.
      • Ryan D.P.
      • Clark J.W.
      • Muzikansky A.
      • et al.
      Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.


      Full text
      USA29Temozolomide 150 mg/m2 on days 1 to 7 and days 15 to 21. Thalidomide 200 mg /day. Cycle repeated every 28 daysHistologically confirmed, locally unresectable or metastatic neuroendocrine tumoursORR, PR, SD, PD, safety
      Moertel
      • Moertel C.G.
      • Kvols L.K.
      O CMJ, Rubin J. Treatment of Neuroendocrine Carcinomas with Combined Etoposide and Cisplatin Evidence of Major Therapeutic Activity in the Anaplastic Variants of These Neoplasms.


      Full text
      USANREtoposide 130 mg/m2/day IV for 3 days, Cisplatin 45 mg/m2 on days 2 and 3. Cycle repeated every 4 weeksHistologic confirmation of metastatic neuroendocrine tumourORR, SD, OS safety
      Rivera
      • Rivera E.
      • Ajani J.A.
      Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma.


      Full text
      USA11Doxorubicin 40 mg/m2i.v on day 1, Streptozocin 400 mg/m2i.v and 5-Fluouracil 400 mg/2i.v on days 1 to 5. Cycle repeated every 4 weeksConfirmed pNETPR, SD, MR, OS, safety
      Sprenger

      Sprenger A, Wied M, Mueller HH, Klose K, Arnold R. Effect of dacarbacine (DTIC) on tumor growth in patients with metastatic neuroendocrine gastroenteropancreatic (GEP) tumors. Gastroenterology. 2000;118(4 Suppl. 2 Part 1):AGA A647.



      Abstract
      Germany14650 mg/m2Dacarbacine once monthly i.v.Metastatic neuroendocrine tumourPR, SD, safety
      Strosberg

      Strosberg J, Choi J, Gardner N, Kvols L. First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide. ASCO GI conference. 2008.



      Abstract
      USA17Capecitabine 750 mg/m2 twice daily on days 1-14 and temozolomide 200 mg/m2 daily on days 10-14Progressive metastatic pNETSD, PR, safety
      Brixi-Benmansour
      • Brixi-Benmansour H.
      • Jouve J.L.
      • Mitry E.
      • Bonnetain F.
      • Landi B.
      • Hentic O.
      • et al.
      Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma.


      Full text
      France20FOLFIRI chemotherapy: (irinotecan 180 mg/m2 infusion combined with simplifiedLV5FU2) every 14 days. Cycles repeated every 14 days using a chemotherapy free-interval schemeMetastatic or advanced well-differentiated pNET and progressive disease.6 month non-PR, PFS, TTF, OS, disease duration control, safety, biological responses at 6, 12, 18, 24 months
      SSA/radionuclide therapy (n=9)
      Kwekkeboom
      • Kwekkeboom D.J.
      • Teunissen J.J.
      • Bakker W.H.
      • Kooij P.P.
      • de Herder W.W.
      • Feelders R.A.
      • et al.
      Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors.


      Full text
      Netherlands42Radiolabeled 177Lu-DOTA,Tyr Octreotate injected IV over 4 hours with saline.Octreoscan-positive pNETResponse (CR, MR, SD, PD), safety
      Butturini
      • Butturini G.
      • Bettini R.
      • Missiaglia E.
      • Mantovani W.
      • Dalai I.
      • Capelli P.
      • et al.
      Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma.


      Full text
      Italy21Octreotide 100ug TID s.c. for 2 weeks followed by Octreotide LAR 20 mg every 28 days.Octreoscan-positive well-differentiated nonfunctioning pNETPFS, SD, safety
      Kvols
      • Kvols L.K. B.M.
      • Moertel C.G.
      • Schutt A.J.
      • Rubin J.
      • O’Connell M.J.
      • et al.
      Treatement of Metastatic Islet Cell carcinoam witha Somatostatin Analogue (SMS 201–995).


      Full text
      USA22SSA given s.c. 50ug BID day 1, 100ug BID day 2 then 150ug TID (n = 12).Dose increased to 250ug, 500ug and 500ug TID (n = 10).Median 5 months(range 1–15)Histologically confirmed metastatic islet cell carcinomaResponse (PR, MR, SD), safety
      Forrer
      • Forrer F.
      • Waldherr C.
      • Maecke H.R.
      Mueller Brand J. Targeted radionuclide therapy with Y-90-DOTATOC in patients with neuroendocrine tumors.


      Full text
      Switzerland11IV 77Lu-DOTATOC 7,400 MB with saline.Histologically confirmed metastatic neuroendocrine tumourResponse (PR, MR, SD), safety
      Frilling
      • Frilling A.
      • Weber F.
      • Saner F.
      • Bockisch A.
      • Hofmann M.
      • Mueller-Brand J.
      • et al.
      Treatment with (90)Y- and (177)Lu-DOTATOC in patients with metastatic neuroendocrine tumors.


      Full text
      Switzerland15Two applications of 90Lu-DOTATOC (37 to 11 MBq of 111 In-DOTATOC injected). Each patent underwent at least 2 treatment sessionsAdvanced histologically or cytologically proven progressive metastatic NET.Response (PR, MR, SD, safety),
      Panzuto
      • Panzuto F.
      • Di Fonzo M.
      • Iannicelli E.
      • Sciuto R.
      • Maini C.L.
      • Capurso G.
      • et al.
      Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma.


      Full text
      Italy18Octreotide LAR 30 mg or Lanreotide SR 60 mg IM injection every 28 days. Median 18 months (range 6–60)Well-differentiated endocrine carcinomaResponse, OS
      Saltz
      • Saltz L.
      • Trochanowski B.
      • Buckley M.
      • Hefferman B.
      • Niedzwiecki D.
      • Tao Y.
      • et al.
      Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors.


      Full text
      USA13Octreotide IM 50ug bid increasing to 250ug tidAdvanced, incurable NET with confirmed pathologic statusORR, OS, safety
      Shojamanesh
      • Shojamanesh H.
      • Gibril F.
      • Louie A.
      • Ojeaburu J.V.
      • Bashir S.
      • Abou-Saif A.
      • et al.
      Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma.


      Full text
      USA15Short acting Octreotide 200 ug every 12 hours, LR formulation then used monthly (30 mg IM)Gastrinoma with histologically proven liver metastases and disease progressionResponse, duration of response, safety
      Waldherr
      • Waldherr C.
      • Pless M.
      • Maecke H.R.
      • Schumacher T.
      • Crazzolara A.
      • Nitzsche E.U.
      • et al.
      Tumor response and clinical benefit in neuroendocrine tumors after 7.4 Gbq 90Y-DOTATOC.


      Full text
      Switzerland134 applications of 90Lu-DOTATOC (total 7.4 GBq/m2)Histologically confirmed metastatic neuroendocrine tumourResponse (SD, PR), OS, safety
      Mixed treatments (n=4)
      Eriksson
      • Eriksson B.
      • Oberg K.
      An update of the medical treatment of malignant endocrine pancreatic tumors.


      Full text
      Sweden92Chemotherapy: IV Streptozotocin0.5 g/m2 for 5 days followed by 1 gm/m2 every third week + 5-FU IV 400 mg/m2 for 3 days and then every third week.

      Interferon: 5 MU 3 times a week. Octreotide: 100ug bd
      Clinically verified malignant endocrine pancreatic tumourResponse, duration of response
      Yao
      • Yao J.C.
      • Phan A.T.
      • Chang D.Z.
      • Wolff R.A.
      • Hess K.
      • Gupta S.
      • et al.
      Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study.


      Full text
      USA30Octreotide LAR 30 mg every 28 days + everolimus 5-10 mg/d. Maximum of 12 cyclesHistologically confirmed metastatic/unresectablelocoregional LGNETs. Prior treatment permittedPFS, OS,ORR, response (PR, PD, SD), safety
      Fjallskog
      • Fjallskog M.L.
      • Sundin A.
      • Westlin J.E.
      • Oberg K.
      • Janson E.T.
      • Eriksson B.
      Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs.


      Full text
      Sweden16Median dose 9 MU/week interferon + Octreotide (450ug/day; n = 14) or Lanreotide (3000ug bd; n = 2). Follow up every 3 monthsHistopathologic confirmed pNETResponse, duration of response, safety
      Hobday
      • Hobday T.
      • Pommier R.
      • Cutsem E.V.
      • Panneerselvam A.
      • Saletan S.
      • Winkler R.E.
      • et al.
      Analysis of progression-free survival (PFS) by prior chemotherapy use and updated safety in radiant-3: A randomized, double-blind, placebo-controlled, multicenter, phase III trial of everolimus in patients with advanced low-or intermediate-grade pancreatic neuroendocrine tumors (PNET).


      Abstract
      USA35Temsirolimus 25 mg IV q week and bevacizumab 10 mg/kg IV q 2 weeksPatients with well or moderately differentiated pNET and PD by RECIST within seven months of study entryORR and 6-month PFS
      Liver-directed therapies (n=6)
      Moertel 1994
      • Moertel C.G.
      • Johnson C.M.
      • McKusick M.A.
      • Martin Jr, J.K.
      • Nagorney D.M.
      • Kvols L.K.
      • et al.
      The management of patients with advanced carcinoid tumors and islet cell carcinomas.


      Full text
      USA17Surgical patients: ligation of hepatic artery; other: catheterisation and embolisation.Histologically confirmed carcinoid or islet cell carcinoma with liver metastasesORR, duration of response; TTP, median survival; safety
      29Hepatic artery occlusion + chemotherapy

      Alternating cycles of doxorubcin and dacarbazine: 5 weeks later with streptozocin and 5-FU
      Rhee 2008
      • Rhee T.K.
      • Lewandowski R.J.
      • Liu D.M.
      • Mulcahy M.F.
      • Takahashi G.
      • Hansen P.D.
      • et al.
      90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience.


      Full text
      USA1190Y radioembolization. 3 month follow upMetastatic NET liver disease that had failed prior treatmentResponse (PR, SD, PD); safety
      Eriksson 1998
      • Eriksson B.K.
      • Larsson E.G.
      • Skogseid B.M.
      • Lofberg A.M.
      • Lorelius L.E.
      • Oberg K.E.
      Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors.


      Full text
      Sweden12Hepatic artery embolisationMetastatic NET liver disease that had failed prior treatmentResponse, duration of response, median survival; safety
      Ajani 1988
      • Ajani J.A.
      • Carrasco C.H.
      • Charnsangavej C.
      • Samaan N.A.
      • Levin B.
      • Wallace S.
      Islet cell tumors metastatic to the liver: effective palliation by sequential hepatic artery embolization.


      Full text
      USA20Hepatic artery embolisationHistologically confirmed islet cell carcinomaComplete/any response; safety
      Kim 1999

      Kim YH, Ajani JA, Humberto Carrasco C, Dumas P, Richli W, Lawrence D, et al. Selective hepatic arterial chemoembolization for liver metastases in patients with carcinoid tumor or islet cell carcinoma. Cancer Invest. 1999;17(7):474–8.



      Full text
      USA14Hepatic artery chemo-embolisation. Subsequent treatments every 8-12 weeks (+ concurrent octreotide)Histologically confirmed carcinoid/islet cell carcinoma with liver metastasesResponse, median survival, median duration of response, safety
      Capitanio 2010

      Capitanio V, Papa M, Zerbi A, Vitali G, De Cobelli F, Venturino M, et al. Transarterial chemoembolization (TACE) of liver metastasis from pancreatic well-differentiated endocrine carcinoma. Neuroendocrinology. 2010:4.



      Abstract
      Italy11Doxorubicin emulsified in Lipidol, followed by gelatine sponge particles embolisationMultifocal metastases with diameter less than 5 cm, without extrahepatic diseaseSafety , long term survival
      Interferon (n=1)
      Eriksson 1986
      • Eriksson B.
      • Oberg K.
      • Alm G.
      • Karlsson A.
      • Lundqvist G.
      • Andersson T.
      • et al.
      Treatment of malignant endocrine pancreatic tumours with human leucocyte interferon.


      Full text
      Sweden22Human leucocyte interferon, 3-6x106 IUMalignant PNET with histopathological diagnosisResponse (SD, PD); duration of response; safety
      Endostatin (n=1)
      Kulke 2006
      • Kulke M.H.
      • Bergsland E.K.
      • Ryan D.P.
      • Enzinger P.C.
      • Lynch T.J.
      • Zhu A.X.
      • et al.
      Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors.


      Full text
      USA20Recombinant human endostatin, 30 mg/m2 bid (28 day cycle). Median: 6.4 monthsMetastatic pNET; prior chemo permitted; ECOG 0 or 1Response (PR; CR; SD; progression); median PFS, OS; safety
      pNET, pancreatic neuroendocrine tumour; BSA, body surface area; CR, complete response; DTIC, dacarbazine; FU, fluorouracil; IM, intramuscular; IV, intravenous; ORR, objective response rate; OS, overall survival; MR, minor response; PFS, progression free survival; PR, partial response; SC, subcutaneous; SD, stable disease; PD, progressive disease; SSA, somatostatin analogue; STZ, streptozotocin; TTP, time to progression; TTF, time-to-treatment failure; QoL, quality of life; BID, twice daily; TID, three times daily; MU, milliunits.
      A summary of the included studies is reported in Table 2. The included studies were highly varied in terms of study design; duration and outcomes; sample size; doses and schedules of the interventions employed (particularly in systemic chemotherapy studies) and features of the enrolled patient populations. A significant proportion (15%) of the included studies were published over 15 years ago including two of the pivotal RCTs [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ,
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ]. These early studies often used criteria (e.g. physical examination) which are no longer considered appropriate to measure response to treatment. More recent studies have reported response rates using validated radiological criteria such as WHO [
      • Miller A.B.
      • Hoogstraten B.
      • Staquet M.
      • Winkler A.
      Reporting results of cancer treatment.
      ] and RECIST [
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • Wanders J.
      • Kaplan R.S.
      • Rubinstein L.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
      ].

      Study quality

      Two of the early conducted RCTs [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ,
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ] had an open-label study design and reported ambiguous allocation methods. Both of these criteria have been reported to be important determinants of trial bias and studies with inadequate reporting tend to overestimate the treatment effect [
      • Juni P.
      • Altman D.G.
      • Egger M.
      Systematic reviews in health care: assessing the quality of controlled clinical trials.
      ]. The mixed treatment RCT [

      Pavel M, Heuck F, Plockinger U, Pape UF, Tiling N, Rinke A, et al. Prospective randomized trial: Biotherapy versus chemotherapy in malignant nonfunctional neuroendocrine tumors of the pancreas and brochial tract (ENET-1). ASCO GI conference. 2008.

      ] was reported as a conference abstract only and therefore limited information on determinants of bias was reported. Two further placebo-controlled RCTs examining the targeted therapies sunitinib [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ] and everolimus [
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ] were powered to show standard oncological end-points (PFS and OS) and employed the standardised RECIST criteria to measure response.
      Many of the non-randomised studies enrolled small numbers of patients and are therefore underpowered to detect significant treatment effects. Forty of the 42 non-randomised studies enrolled 50 patients or less (median 19, [range 11–50] patients). The older studies tended to lack standardised inclusion criteria (e.g. including heterogenous tumour subtypes, patients with different exposure to prior therapy, severity of disease or evidence of disease progression at study entry).
      The majority of non-randomised studies reported partial information making it difficult to appraise study quality using the Chambers checklist [
      • Chambers R.
      • Rodgers M.
      • Woolacott N.
      Not only randomized controlled trials, but also case series should be considered in systematic reviews of rapidly developing technologies.
      ].

      Efficacy

      A summary of the survival and response data reported in RCT and non-randomised studies is reported in Table 3, Table 4 respectively; given the higher level of evidence they provide we will focus on the RCTs.
      Table 3Survival/response data reported in RCT studies. Additional HRs are reported in footnotes.
      Study referenceTreatmentSurvivalTumour response
      Median PFS, months (95% CI)OS, HR (95% CI)Median OS, yearsComplete response, %Partial response, %Stable disease, %Progressive disease, %Any response, %Objective response rate, %Median duration of response, months
      Targeted therapy (n=2)
      Raymond 2011
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ,
      • Blumenthal G.M.
      • Cortazar P.
      • Zhang J.J.
      • Tang S.
      • Sridhara R.
      • Murgo A.
      • et al.
      FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.
      Sunitinib11.4 (7.4–19.8)
      Investigator assessed.
      0.74 (0.47–1.17); p = 0.19
      Analysis conducted June 2010. The result is confounded by crossover; 69% of patients crossed from placebo to sunitinib. Additional HRs (95% CI) reported using four models to adjust for crossover (median follow-up 34.1months): (i) censoring at crossover, 0.43 (0.24–0.77); p=0.004; (ii) time-dependent Cox model, 0.49 (0.29–0.85); p=0.01; (iii) RPSFT model, 0.43 (0.17–1.20); p=0.12; (iv) RPSFT model adjusted for crossover time, 0.57 (0.18–1.09); p=0.12 [48].
      30.5 mo (20.6, NR)
      Investigator assessed.
      2
      Assessed using RECIST criteria.
      7
      Assessed using RECIST criteria.
      63
      Assessed using RECIST criteria.
      14
      Assessed using RECIST criteria.
      9.3
      p=0.007 vs. placebo.
      ,
      Assessed using RECIST criteria.
      Placebo5.5 (3.6–7.4)
      Investigator assessed.


      HR 0.42 (0.26–0.66); p < 0.0001 vs. placebo
      (i) Investigator assessed PFS: revised HR based on excluding patients who had WHO performance status of 2 from the RADIANT-3 trial (to match inclusion criteria of the Raymond, 2011 study: 0.38 (0.29–0.49) [42]; (ii) Analysis of data for a subgroup of 84 patients for whom MRI/CT scans were available to compare the results with central review assessment: sunitinib, 19.8months vs. placebo, 5.8months: investigator assessed HR 0.45 HR 0.45 (0.22–0.92) [39]; (iii) Retrospective blinded independent central review of the tumour imaging scans: sunitinib 12.6months vs. placebo 5.8months; HR 0.32 (0.18–0.55) [49].
      24.4 mo (16.3, NR)
      Investigator assessed.
      0
      Assessed using RECIST criteria.
      0
      Assessed using RECIST criteria.
      60
      Assessed using RECIST criteria.
      27
      Assessed using RECIST criteria.
      0
      Assessed using RECIST criteria.
      Yao 2011 RADIANT-3
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      Everolimus11.0 (8.4–13.9)
      Investigator assessed.
      HR 0.89 (0.64-1.23); p = 0.59
      OS Analysis cut-off Feb 2011 (146 events: 68 everolimus; 78 placebo). The result is confounded by crossover, 85% of patients crossed from placebo to everolimus. Median OS not reached for everolimus treatment arm, so data immature [80]. No crossover adjusted OS estimates have currently been published.
      Not reached
      Investigator assessed.
      7314
      Placebo4.6 (3.1–5.4)
      Investigator assessed.


      HR 0.35 (0.27–0.45); p < 0.001
      Central review assessment of final PFS: everolimus 11.4months (10.8-14.8) vs. placebo 5.4months (4.3-5.6); HR 0.34 (0.26–0.44) [34].
      36.6 mo
      Investigator assessed.
      5142
      Chemotherapy (n=2)
      Moertel 1992
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ChlorozotocinNRN1.5
      p<0.03 vs. Streptozocin+Doxorubicin.
      6
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      NRNRNR30
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      NR21
      Streptozocin + Fluorouracil1.4
      p<0.004 vs. Streptozocin+Doxorubicin.
      4
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      45
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      13
      Streptozocin + Doxorubicin2.214
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      69
      Response/regression definition used : Favourable objective response if tumour mass reduced by>50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      22
      Moertel 1980
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      StreptozocinNRNR16.5 mo12NRNRNR36NRNR
      Median duration of response: ‘all responses’, 17months; ‘complete responses’, 24months.
      Streptozocin + Fluorouracil26 mo3363
      Mixed treatments (n=1)
      Pavel 2008

      Pavel M, Heuck F, Plockinger U, Pape UF, Tiling N, Rinke A, et al. Prospective randomized trial: Biotherapy versus chemotherapy in malignant nonfunctional neuroendocrine tumors of the pancreas and brochial tract (ENET-1). ASCO GI conference. 2008.

      Streptozotocin/FluorouracilNRNRNR132563NRNRNRNR
      Octreotide01375
      CI, confidence interval; mo, months; NR, not reported; OS, overall survival; PFS, progression-free survival; HR, hazard ratio.
      Investigator assessed.
      p = 0.007 vs. placebo.
      § Assessed using RECIST criteria.
      p < 0.03 vs. Streptozocin + Doxorubicin.
      †† p < 0.004 vs. Streptozocin + Doxorubicin.
      ‡‡ Response/regression definition used : Favourable objective response if tumour mass reduced by > 50% or 30% if malignant hepatomegaly was used, lab assay reduced by 50% tumour regression.
      §§ Median duration of response: ‘all responses’, 17 months; ‘complete responses’, 24 months.
      ¶¶ OS Analysis cut-off Feb 2011 (146 events: 68 everolimus; 78 placebo). The result is confounded by crossover, 85% of patients crossed from placebo to everolimus. Median OS not reached for everolimus treatment arm, so data immature [80]. No crossover adjusted OS estimates have currently been published.
      ††† (i) Investigator assessed PFS: revised HR based on excluding patients who had WHO performance status of 2 from the RADIANT-3 trial (to match inclusion criteria of the Raymond, 2011 study: 0.38 (0.29–0.49)

      Signorovitch J, Swallow E, Kantor E, Wang X, Metrakos P. Overall survival with everolimus, sunitinib, and placebo for advnaced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials. J Clin Oncol. 2012;30(Suppl 4):Abstract 237.

      ; (ii) Analysis of data for a subgroup of 84 patients for whom MRI/CT scans were available to compare the results with central review assessment: sunitinib, 19.8 months vs. placebo, 5.8 months: investigator assessed HR 0.45 HR 0.45 (0.22–0.92)
      • Hammel P.
      • Castellano D.
      • Van Cutsem E.
      • Niccoli P.
      • Faivre S.
      • Patyna S.
      • et al.
      Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.
      ; (iii) Retrospective blinded independent central review of the tumour imaging scans: sunitinib 12.6 months vs. placebo 5.8 months; HR 0.32 (0.18–0.55)
      • Vinik A.
      • Cutsem E.V.
      • Niccoli P.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • et al.
      Progression-free survival (PFS) by blinded independent central review (BICR) and updated overall survival (OS) of sunitinib versus placebo for patients with progressive, unresectable, well differentiated pancreatic neuroendocrine tumor (NET).
      .
      ‡‡‡ Analysis conducted June 2010. The result is confounded by crossover; 69% of patients crossed from placebo to sunitinib. Additional HRs (95% CI) reported using four models to adjust for crossover (median follow-up 34.1 months): (i) censoring at crossover, 0.43 (0.24–0.77); p = 0.004; (ii) time-dependent Cox model, 0.49 (0.29–0.85); p = 0.01; (iii) RPSFT model, 0.43 (0.17–1.20); p = 0.12; (iv) RPSFT model adjusted for crossover time, 0.57 (0.18–1.09); p = 0.12

      Faivre S, Niccoli P, Raoul JL, Bang Y-J, Borbath I, Valle JW, et al., editors. Updated Overall Survival (OS) Analysis From A Phase Iii Study Of Sunitinib Vs Placebo In Patients (Pts) With Advanced, Unresectable Pancreatic Neuroendocrine Tumor (Net). ESMO; 2012 28th September-2nd October; Vienna, Austria.

      .
      §§§ Central review assessment of final PFS: everolimus 11.4 months (10.8-14.8) vs. placebo 5.4 months (4.3-5.6); HR 0.34 (0.26–0.44)
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      .
      Table 4Survival/response data reported in non-RCT studies.
      OutcomeChemotherapy (n = 15)Mixed treatments (n = 4)Targeted therapy (n = 6)SSA/radionuclide therapy (n = 9)Liver directed therapies (n = 6)Interferon (n = 1)Recombinant endostatin (n = 1)
      Survival. No. of studies (no. PNET patients receiving the intervention)
      No. studies reporting OS2 (30)NRNRNRNRNR1 (20)
      Reported range in OS (%)65–72
      2-year OS.
      NRNRNRNRNR17.2
      No. studies reporting median survival7 (169)NRNR1 (13)3 (72)NRNR
      Reported range in median survival (months)6–66NRNR239–40NRNR
      No. studies reporting 1-year survival rateNRNR2 (226)NRNRNRNR
      Reported range in 1-year survival rate (%)NRNR75–81NRNRNRNR
      No. studies reporting median TTPNRNRNRNR1 (46)NRNR
      Reported range in median TTP (months)NRNRNRNR4–22NRNR
      No. studies reporting median PFS2 (30)2 (65)1 (160)1 (21)NRNR1 (20)
      Reported range in median PFS (months)9.1-136-1210–1741NRNR5.8
      Response No. of studies (no. PNET patients receiving the intervention)
      No. studies reporting median duration of response5 (163)1 (107)1 (115)NR3 (72)1 (22)NR
      Data not reported for subset of pNET patients (20/42).
      Reported range in median duration of response (months)9–3616–2310.6NR3.6–248.5NR
      Data not reported for subset of pNET patients (20/42).
      No. studies reporting any responseNRNRNRNR4 (57)1 (22)NR
      Data not reported for subset of pNET patients (20/42).
      Reported range in no. of patients with any response, %NRNRNRNR17–8077NR
      Data not reported for subset of pNET patients (20/42).
      No. studies reporting complete response13 (278)3 (153)6 (338)5 (102)NR1 (22)1 (20)
      Reported range in no. of patients with complete response %0–8000–8NR50
      No. studies reporting partial response13 (278)3 (153)6 (338)6 (113)11 (22)1 (20)
      Reported range in no. of patients with partial response %0–7119–274–320–73NR50
      No. studies reporting minor responseNRNRNR2 (63)NRNRNR
      Reported range in no. of patients with minor response %NRNRNR0–21NRNRNR
      No. studies reporting stable disease11 (184)3 (153)4 (280)7 (133)1NRNR
      Data not reported for subset of pNET patients (20/42).
      Reported range in no. of patients with stable disease %11–7519–6910–8027–60NRNRNR
      Data not reported for subset of pNET patients (20/42).
      OS, overall survival; TTP, time to progression; SSA, somatostatin analogue.
      2-year OS.
      Data not reported for subset of pNET patients (20/42).
      Chemotherapy was the subject of two early RCTs published in 1980 [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ] and 1992 [
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ]. The first study established that doublet chemotherapy (streptozocin and 5-FU) resulted in a superior response rate (63% vs. 36%) and OS (26 vs. 16.5 months) compared with streptozocin monotherapy in 82 randomised patients [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ]. In the follow-on study comparing chlorozotocin vs. streptozocin/doxorubicin vs. streptozocin/5-FU, patients receiving combination chemotherapy once again fared better, with a response rate of 69% and OS of 2.2 years reported for the streptozocin/doxorubicin combination which appeared to be the most active regimen, although associated with significant toxicity [
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ]. Chemotherapy was adopted as the standard of care based on the results of these two early RCTs [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ,
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ].
      The two most recent RCTs (assessing the targeted agents sunitinib and everolimus), are the first and only published studies to documented an improvement in PFS compared with best supportive care (BSC)/placebo. Both studies had a similar design: selection of a homogeneous patient subgroup (pathologically-confirmed well-differentiated pNET with evidence of disease progression), use of a double-blind placebo-controlled design using a robust oncological end-point (PFS, by RECIST) and ability of patients to cross over from placebo to active drug on disease progression. Sunitinib demonstrated an improved PFS of 11.4 vs. 5.5 months (vs. placebo, HR 0.42 (0.26–0.66); p < 0.0001 vs. placebo) [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ] and everolimus also had a similar magnitude of effect with an improved PFS of 11.0 vs. 4.6 months (vs. placebo, HR 0.35 (0.27–0.45); p < 0.001) [
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ]. Although neither of the targeted agents reported a significantly improved OS compared with placebo [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ,
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ], this endpoint could not be reliably assessed due to extensive crossover from placebo to active treatment (69% of patients in the sunitinib trial and 74% of patients in the everolimus trial) [
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ,
      • Blumenthal G.M.
      • Cortazar P.
      • Zhang J.J.
      • Tang S.
      • Sridhara R.
      • Murgo A.
      • et al.
      FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.
      ]. An exploratory analysis attempting to correct for such patient crossover suggests an improved OS for sunitinib compared with placebo [

      Faivre S, Niccoli P, Raoul JL, Bang Y-J, Borbath I, Valle JW, et al., editors. Updated Overall Survival (OS) Analysis From A Phase Iii Study Of Sunitinib Vs Placebo In Patients (Pts) With Advanced, Unresectable Pancreatic Neuroendocrine Tumor (Net). ESMO; 2012 28th September-2nd October; Vienna, Austria.

      ].
      The final RCT (comparing streptozocin / 5-FU vs. octreotide) will not be discussed further given its small size (n = 16 patients) and the limited abstract-only available information.
      It was not possible to draw conclusions on the comparable efficacy of different interventions due to the significant heterogeneity between studies. There was significant variation in the duration of follow up between studies, which limits the assessment of survival outcomes. The comparability of efficacy between studies was also hampered by differences in eligibility criteria, baseline characteristics, and response criteria employed in these studies. For example, differences in PFS between studies could be attributed to studies not requiring disease progression or prior chemotherapy prior to enrolment. The importance of response criteria is illustrated by two RCTs which established streptozocin combined with either fluorouracil or doxorubicin as the treatment of choice in pNET based on “response rates” of 45–69%; however, these “responses” included reduction in clinical hepatomegaly, biochemical improvement and/or radiological regression [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ,
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ]. Over the last 30 years, significant advances in imaging techniques have resulted in more accurate determination of tumour bulk and validated criteria to describe tumour response such as the WHO criteria or, more recently, RECIST. Several subsequent studies, using these stricter radiological definitions of response rather than clinical ones, have, however failed to confirm the high response rates seen in the early RCTs [
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      ,
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      ].

      Health related quality of life (HRQoL)

      Despite the increasing importance of patient reported outcomes (PRO) in assessing the effectiveness of treatments, HRQoL has been rarely assessed in this patient population. Indeed, only two studies, both investigating the targeted therapy sunitinib, assessed QoL using validated PRO measures (EORTC Quality of Life Questionnaire [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ] and EQ-5D/FACIT Questionnaire [
      • Kulke M.H.
      • Lenz H.-J.
      • Meropol N.J.
      • Posey J.
      • Ryan D.P.
      • Picus J.
      • et al.
      Activity of sunitinib in patients with advanced neuroendocrine tumors.
      ], in the absence of a NET-specific quality of life tool). In both studies, despite its inherent toxicities, active treatment did not result in significant detriment from baseline in overall QoL measures compared with best supportive care.

      Safety

      A summary of selected AEs are reported in Table 5 (RCTs) and Table 6 (non-randomised studies). In general, the reported incidence of grade 3–4 AEs was similar to the previously characterised profile for the different classes of agents. Chemotherapy agents have high levels of reversible myelosuppression, emesis (especially prior to the use of modern anti-emetics) and agent-specific toxicities (e.g. doxorubicin-induced cardiotoxicity; fluoropyrimidine-induced diarrhea). The targeted therapies (sunitinib and everolimus) have fewer grade 3–4 toxicities compared with chemotherapeutic agents in keeping with experience of these drugs in other tumour types.
      Table 5Summary of safety data reported in RCT studies.
      Study referenceTreatmentTreatment-related deaths, %Withdrawals due to AEs, %Neutropenia, %Thrombocytopenia, %Nausea, %Vomiting, %Diarrhoea, %Stomatitis, %
      Targeted therapy (n=2)
      Raymond 2011
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      Sunitinib117All grade, 29

      Grade 3/4, 12
      All grade, 17

      Grade 3/4, 4
      All grade, 45

      Grade 3/4, 1
      All grade, 34

      Grade 3/4, 0
      All grade, 59

      Grade 3/4, 5
      All grade, 22

      Grade 3/4, 4
      Placebo18All grade, 4

      Grade 3/4, 0
      All grade, 5

      Grade 3/4, 0
      All grade, 29

      Grade 3/4, 1
      All grade, 30

      Grade 3/4, 2
      All grade, 39

      Grade 3/4, 2
      All grade, 2

      Grade 3/4, 0
      Yao 2011
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      Extended follow up (20.1months) [everolimus vs. placebo]: Diarrhoea, all grade: 34.3 vs. 10.3%; stomatitis, all grade: 52.9 vs. 12.3%; stomatitis, grade 3/4, 4.9% vs. 0%.
      Everolimus217NRAll grade, 13

      Grade 3/4, 4
      All grade, 20

      Grade 3/4, 2
      All grade, 15

      Grade 3/4, 0
      All grade, 34

      Grade 3/4, 3
      All grade, 64

      Grade 3/4, 7
      Placebo13NRAll grade,<1

      Grade 3/4, 0
      All grade, 18

      Grade 3/4, 0
      All grade, 6

      Grade 3/4, 0
      All grade, 10

      Grade 3/4, 0
      All grade, 17

      Grade 3/4, 0
      Chemotherapy (n=2)
      Moertel 1992
      • Moertel C.G.
      • Lefkopoulo M.
      • Lipsitz S.
      • Hahn R.G.
      • Klaassen D.
      Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
      Chlorozotocin0NRAny
      Leukopenia: any,<4×109 cells/litre.
      , 43

      Severe
      Leukopenia: severe:<2×109 cells/litre.
      , 2
      Any, 22
      Thrombocytopenia: any,<100×109 cells/litre.


      Severe
      Thrombocytopenia: severe:<50×109 cells/litre.
      , 6
      NRAny, 43

      Severe, 2
      Any, 6

      Severe, 0
      Any, 0

      Severe, 0
      Streptozocin + Fluorouracil3Any
      Leukopenia: any,<4×109 cells/litre.
      , 81

      Severe
      Leukopenia: severe:<2×109 cells/litre.
      , 41
      Any
      Thrombocytopenia: any,<100×109 cells/litre.
      , 8

      Severe
      Thrombocytopenia: severe:<50×109 cells/litre.
      , 6
      Any, 81

      Severe, 41
      Any, 33

      Severe, 2
      Any, 19

      Severe,
      Streptozocin + Doxorubicin0Any
      Leukopenia: any,<4×109 cells/litre.
      , 80

      Severe
      Leukopenia: severe:<2×109 cells/litre.
      , 20
      Any
      Thrombocytopenia: any,<100×109 cells/litre.
      , 0

      Severe
      Thrombocytopenia: severe:<50×109 cells/litre.
      , 0
      Any, 80

      Severe, 20
      Any, 5

      Severe, 0
      Any, 5

      Severe, 0
      Moertel 1980
      • Moertel C.G.
      • Hanley J.A.
      • Johnson L.A.
      Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
      Streptozocin54
      Treatment group not reported.
      Mild
      <4000 to ⩾2000/mm3.
      , 5%; moderate
      <2000 to ⩾1000/mm3.
      , 0%; severe
      <1000/mm3.
      , 0%
      Mild
      <150,000 to ⩾100,000/mm3.
      , 5%; moderate
      <100,000 to ⩾50,000/mm3.
      , 0%; severe
      <50,000/mm3.
      , 0%
      Mild, 24%; moderate, 24%; severe, 36%NR0
      Streptozocin + Fluorouracil0Mild
      <4000 to ⩾2000/mm3.
      , 52%; moderate§§, 10%; severe
      <1000/mm3.
      , 10%
      Mild
      <150,000 to ⩾100,000/mm3.
      , 4%; moderate
      <100,000 to ⩾50,000/mm3.
      , 12%; severe
      <50,000/mm3.
      , 12%
      Mild, 32%; moderate, 32%; severe, 22%5
      Mixed treatments (n=1)
      Pavel 2008

      Pavel M, Heuck F, Plockinger U, Pape UF, Tiling N, Rinke A, et al. Prospective randomized trial: Biotherapy versus chemotherapy in malignant nonfunctional neuroendocrine tumors of the pancreas and brochial tract (ENET-1). ASCO GI conference. 2008.

      Streptozotocin/FluorouracilNRNRMain AEs nausea, emesis, mucositis, electrolyte disturbance and thromboembolism
      OctreotideMain AEs: abdominal pain and meteroism
      Thrombocytopenia: any,<100 × 109 cells/litre.
      Thrombocytopenia: severe:<50 × 109 cells/litre.
      § Leukopenia: any,<4 × 109 cells/litre.
      Leukopenia: severe:<2 × 109 cells/litre.
      †† Treatment group not reported.
      ‡‡ <4000 to ⩾2000/mm3.
      §§ <2000 to ⩾1000/mm3.
      ¶¶ <1000/mm3.
      ††† <150,000 to ⩾100,000/mm3.
      ‡‡‡ <100,000 to ⩾50,000/mm3.
      §§§ <50,000/mm3.
      ¶¶¶ Extended follow up (20.1 months) [everolimus vs. placebo]: Diarrhoea, all grade: 34.3 vs. 10.3%; stomatitis, all grade: 52.9 vs. 12.3%; stomatitis, grade 3/4, 4.9% vs. 0%.
      Table 6Summary of safety data reported in non-RCT studies.
      Study referenceTargeted therapy (n = 6)Chemotherapy (n = 15)Mixed treatments (n = 4)SSA/radionuclide therapy (n = 9)Liver directed therapies (n = 6)Interferon (n = 1)Endostatin (n = 1)
      Incidence of withdrawals: no. of studies (enrolled patients)NR1 (29)NR1 (15)NRNRNR
      Incidence of withdrawals: range, %10013
      Incidence of treatment-related deaths: no. of studies (enrolled patients)1 (15)NRNRNR1
      All patients were alive at time of publication of the abstract.
      NRNR
      Incidence of treatment-related deaths: range, %7
      Incidence of AEs: no. of studies (enrolled patients)NRNR1 (35)NRNRNRNR
      AE data not reported for the subset of patients (20/42) with pNET.
      Incidence of AEs: range, %
      Incidence of SAEs: no. of studies (enrolled patients)NR1NR1 (27)NRNRNR
      Incidence of SAEs: range, %80
      Incidence of neutropenia: no. of studies (enrolled patients)1 (160)4 (148)NRNRNR1 (22)NR
      Grade 1-2 neutropenia: range, %651-1666
      Leukocyte count <4.0×109/l: grade not explicitly reported.
      Grade 3–4 neutropenia: range, %323–64
      Incidence of thrombocytopenia: no. of studies (enrolled patients)3 (182)1 (51)1 (30)NRNR1 (22)NR
      Grade 1–2 thrombocytopenia: range, %5–501438
      Platelet count fall to <150×109/l: grade not explicitly reported.
      Grade 3–4 thrombocytopenia: range, %3–17225%
      Incidence of nausea: no. of studies (enrolled patients)2 (175)4 (86)2 (46)NRNRNRNR
      Grade 1–2 nausea: range, %30–368–2113
      Grade 3–4 nausea: range, %0–13–132
      Incidence of diarrhoea: no. of studies (enrolled patients)2 (54)6 (221)2 (46)NRNRNRNR
      Grade 1–2 diarrhoea: range, %305–1218
      Grade 3–4 diarrhoea: range, %5–90–1311
      Incidence of vomiting: no. of studies (enrolled patients)1 (150)4 (126)NRNRNRNRNR
      Grade 1–2 vomiting: range, %1638–71
      Grade 3–4 vomiting: range, %03–14
      Incidence of fatigue: no. of studies (enrolled patients)3 (95)1 (29)2 (65)NRNRNRNR
      Grade 1–2 fatigue: range, %7876
      Grade 3–4 fatigue: range, %0–979––11
      Incidence of hypertriglyceridaemia: no. of studies (enrolled patients)2 (32)NR1 (30)NRNR1 (22)NR
      Grade 1–2 hypertriglyceridaemia: range, %424433
      Rise in serum triglycerides: grade not explicitly reported.
      Grade 3–4 hypertriglyceridaemia: range, %3–63
      Incidence of rash: no. of studies (enrolled patients)4 (231)1 (29)1 (30)NRNRNRNR
      Grade 1–2 rash: range, %41–6135
      Grade 3–4 rash: range, %1–635
      Incidence of pneumonitis: no. of studies (enrolled patients)2 (175)NRNRNRNRNRNR
      Grade 1–2 pneumonitis: range, %8–19NR
      Grade 3–4 pneumonitis: range, %0NR
      Incidence of hypertension: no. of studies (enrolled patients)NRNR2 (65)NRNRNRNR
      Grade 1–2 hypertension: range, %
      Grade 3–4 hypertension: range, %2–12
      AE data not reported for the subset of patients (20/42) with pNET.
      Leukocyte count <4.0 × 109/l: grade not explicitly reported.
      § Rise in serum triglycerides: grade not explicitly reported.
      Platelet count fall to <150 × 109/l: grade not explicitly reported.
      †† All patients were alive at time of publication of the abstract.

      Discussion

      This systematic review was undertaken to assess non-surgical treatments for pNET. Robust methods were used to identify all relevant studies and assess the methodological quality of the included studies.
      RCTs represent the gold standard study design for assessment of treatment efficacy. However, there are few RCTs performed to date to assess the efficacy and tolerability of treatment options in the management of pNET. This is partly due to the complexity and clinical heterogeneity of pNETs and a perception that these tumours were “too rare” to undertake adequately-powered RCTs. As a result, most of the published evidence base comes from single-arm non-randomised studies. While recently conducted non-randomised studies have employed validated criteria to measure patient response [
      • Kulke M.H.
      • Lenz H.-J.
      • Meropol N.J.
      • Posey J.
      • Ryan D.P.
      • Picus J.
      • et al.
      Activity of sunitinib in patients with advanced neuroendocrine tumors.
      ,

      Hobday T, Holen K, Donehower R, Camoriano J, Kim G, Picus J, et al. A phase II trial of gefitinib in patients with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. ASCO GI conference. 2006.

      ,

      Hobday T, Rubin J, Holen K, Picus J, Donehower R, Marschke RF, et al. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): A phase II Consortium (P2C) study. ASCO GI conference. 2007.

      ], many older ‘historical’ studies lacked standardised inclusion criteria (e.g. including heterogenous tumour subtypes, and patients with varied severity of disease, extent of prior therapy, evidence of disease progression at study entry and other prognostic factors) and standardised outcomes [
      • Kulke M.H.
      • Siu L.L.
      • Tepper J.E.
      • Fisher G.
      • Jaffe D.
      • Haller D.G.
      • et al.
      Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting.
      ] are were not adequately powered to provide robust information on treatment responses and survival [

      Walter T, Krzyzanowska MK. Quality of Clinical Trials in Gastro-Entero-Pancreatic Neuroendocrine Tumours. Neuroendocrinology. 2012.

      ,

      Phan AT. Metastatic pancreatic neuroendocrine tumors (pNET): Placing current findings into perspective. Cancer Treatment Reviews. 2012.

      ]. Fig. 2 indicates that over the last three decades, while studies examining chemotherapy regimens have continued to enrol a consistently small number of patients (<50 patients), the last five years has seen the publication of adequately powered studies (both observational and RCTs) examining targeted therapies enrolling a larger number of patients. Such studies are both sufficiently powered and report clinically meaningful endpoints such as PFS and OS and have indicated the feasibility of conducting robust RCTs.
      Figure thumbnail gr2
      Fig. 2Relationship between date of publication and number of patients enrolled in clinical studies.
      There are currently no head-to-head RCTs comparing the efficacy of licensed treatments in this indication in the first-line setting or studies evaluating the optimal sequencing of available therapies.
      Results from the present review indicate that over the last three decades, the criteria used to address response in pNET have progressed from clinical / biological responses to the use of validated WHO and RECIST criteria. However, these criteria have been validated for cytotoxic chemotherapy. As the use of targeted agents increases, patients may benefit from novel criteria (e.g. Choi) which assess both tumour density/necrosis in addition to change in tumour size. Targeted therapies can induce extensive regions of necrosis within a tumour. Although the induction of tumour necrosis may be associated with clinical benefit, RECIST criteria are restricted to measuring tumour size and so unlike the Choi criteria, they are insensitive to changes in tumour density and may therefore underestimate the anti-tumour effect of targeted agents in pNET, which are generally insidious in nature. While the utility of the Choi criteria have been established in the management of gastrointestinal stromal tumours (GIST) [
      • Benjamin R.S.
      • Choi H.
      • Macapinlac H.A.
      • Burgess M.A.
      • Patel S.R.
      • Chen L.L.
      • et al.
      We should desist using RECIST, at least in GIST.
      ], ongoing studies will report on their sensitivity and precision in assessing the response of pNET to targeted therapies [

      Grande E, Jose Diez J, Pachon V, Angeles Vaz M, Longo F, Guillen C, et al. Response by Choi criteria to sunitinib plus octreotide LAR in a functional heavily pretreated advanced pancreatic neuroendocrine tumor. Anticancer Drugs. 2011;22(5):477–479.

      ,

      ClinicalTrials.gov. NCT01525550. A study of the efficacy and safety of sunitinib in patients with advanced well-differentiated pancreatic neuroendocrine tumors.

      ,

      Hentic O, Dreyer C, Zappa M, Hammel P, Mateescu C, Bouattour M, et al. Response evaluation usinf RECIST and CHOI criteria in patients with well-differentiated pancreatic neuroendocrine tumors (pNET) treated with sunitinib or everolimus. J Clin Oncol. 2012;30:Suppl; abstr e14660.

      ].
      Despite the limitations in the robustness of its data, systemic cytotoxic chemotherapy has a role in the management of pNET; indeed it is recommended as a first-line treatment option by the European Neuroendocrine Tumour Society [
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • Kloppel G.
      • Lopes J.M.
      • O’Connor J.M.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      ]. However, there is scope for improved, robust evidence of its efficacy from future RCTs.
      Several new targeted agents have been developed and investigated in recent studies although again the majority of these have been assessed in non-randomised studies (Table 2). This review identified two RCTs assessing targeted therapies: one examining sunitinib [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ] and one everolimus [
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ]. Based on these results, these agents are valid and applicable treatment options for patients with advanced pNET in daily practice. However, there remain as yet a number of unexplored issues such as the optimal positioning of these drugs with respect to each other and, indeed, chemotherapy; the feasibility, safety and efficacy of combining these treatments with other modalities (e.g. liver-directed therapy, or radionuclide therapy); as well as their role in other stages of the disease pathway (e.g. neoadjuvant or as an adjuvant therapy to surgery) [
      • Jensen R.T.
      Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors.
      ].
      Furthermore, the concept of personalised patient-specific treatment depending on tumour histology, comorbid conditions and objectives of treatment as part of an optimised treatment algorithm is becoming increasingly important [

      Phan AT. Metastatic pancreatic neuroendocrine tumors (pNET): Placing current findings into perspective. Cancer Treatment Reviews. 2012.

      ]. For example, patients with a high tumour burden or mitotically active tumour (as measured by Ki67 index) may benefit from an antiproliferative treatment such as chemotherapy. However, for those patients with low-grade tumours or lower tumour burden, consideration of the patient’s quality of life is of utmost importance. In such cases, results from the phase III sunitinib RCT indicate that clinical benefits were gained without adversely affecting quality of life [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ].
      Whilst the majority of published evidence comes from non-randomised studies, the two recently published studies [
      • Raymond E.
      • Dahan L.
      • Raoul J.L.
      • Bang Y.J.
      • Borbath I.
      • Lombard-Bohas C.
      • et al.
      Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
      ,
      • Yao J.C.
      • Shah M.H.
      • Ito T.
      • Bohas C.L.
      • Wolin E.M.
      • Van Cutsem E.
      • et al.
      Everolimus for advanced pancreatic neuroendocrine tumors.
      ] assessing the targeted therapies have indicated the feasibility of conducting robust trials which report clinically meaningful endpoints such as PFS and OS. Following publication of the sunitinib trial, the United States Food and Drug Administration (FDA) has issued a recommendation that interim efficacy analyses should be carefully planned in order to reduce the risk of overestimating treatment effects [
      • Blumenthal G.M.
      • Cortazar P.
      • Zhang J.J.
      • Tang S.
      • Sridhara R.
      • Murgo A.
      • et al.
      FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.
      ]. Further research will be required to confirm the efficacy of these novel therapies and to define the ideal treatment algorithm for the management of pNET. These trials will require international collaboration and should ideally be designed following multidisciplinary clinical input and include patients classified according to histological guidelines specifically developed for pNETs to ensure homogenous enrolment of patients. In addition, future trials should assess alternative treatment strategies incorporating effective agents, used concurrently or sequentially dependent on tumour characteristics, which may replace the concept of a single therapy per patient.

      Conflict of interest statement

      Stephen Mitchell is an employee of Abacus International and was a paid consultant to Pfizer in connection with the development of this manuscript. Juan Valle and Martin Eatock received an honorarium in conjunction with development of the manuscript. Zahava Gabriel, Roxanne Ferdinand and Ben Clueit are paid employees of Pfizer.

      References

        • Ramage J.K.
        • Davies A.H.G.
        • Ardill J.
        • Bax N.
        • Caplin M.
        • Grossman A.
        • et al.
        Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
        Gut. 2005; 54: iv1-iv16
        • Goldin S.B.
        • Aston J.
        • Wahi M.M.
        Sporadically occurring functional pancreatic endocrine tumors: review of recent literature.
        Curr Opin Oncol. 2008; 20: 25-33
        • Yao J.C.
        • Hassan M.
        • Phan A.
        • Dagohoy C.
        • Leary C.
        • Mares J.E.
        • 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. 2008 Jun 20; 26: 3063-3072
        • Pape U.F.
        • Bohmig M.
        • Berndt U.
        • Tiling N.
        • Wiedenmann B.
        • Plockinger U.
        Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a German referral center.
        Ann N Y Acad Sci. 2004; 1014: 222-233
        • Kouvaraki M.A.
        • Ajani J.A.
        • Hoff P.
        • Wolff R.
        • Evans D.B.
        • Lozano R.
        • et al.
        Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. [Erratum appears in J Clin Oncol 2005 Jan 1;23(1):248].
        J Clin Oncol. 2004; 22: 4762-4771
        • Ramage J.K.
        • Davies A.H.G.
        • Ardill J.
        • Bax N.
        • Caplin M.
        • Grossman A.
        • et al.
        Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours.
        Gut. 2005; 54: 0017-5749
        • Delaunoit T.
        • Neczyporenko F.
        • Rubin J.
        • Erlichman C.
        • Hobday T.J.
        Medical management of pancreatic neuroendocrine tumors.
        Am J Gastroenterol. 2008; 103: 475-483
        • Strosberg J.R.
        • Nasir A.
        Biology and treatment of metastatic gastrointestinal neuroendocrine tumors.
        Gastrointest Cancer Res. 2008; 2: 113-125
        • Falconi M.
        • Bartsch D.K.
        • Eriksson B.
        • Kloppel G.
        • Lopes J.M.
        • O’Connor J.M.
        • et al.
        ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
        Neuroendocrinology. 2012; 95: 120-134
        • Reidy D.L.
        • Tang L.H.
        • Saltz L.B.
        Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors.
        Nat Clin Pract Oncol. 2009; 6: 143-152
        • Bajetta E.
        • Procopio G.
        • Pusceddu S.
        • Pietrantonio F.
        • Milione M.
        • MacCauro M.
        • et al.
        From biology to clinical experience: Evolution in the knowledge of neuroendocrine tumours.
        Oncol Rev. 2009; 3: 79-87
        • Kaltsas G.
        • Mukherjee J.J.
        • Plowman P.N.
        Grossman Ashley B. The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours.
        Clin Endocrinol (Oxf). 2001; 55: 575-587
        • Kaltsas G.A.
        • Papadogias D.
        • Makras P.
        • Grossman A.B.
        Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues.
        Endocr Relat Cancer. 2005; 12: 683-699
        • Reidy-Lagunes D.
        • Thornton R.
        Pancreatic neuroendocrine and carcinoid tumors: what’s new, what’s old, and what’s different?.
        Curr Oncol Rep. 2012; 14: 249-256
        • Metz D.C.
        • Jensen-Robert T.
        Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors.
        Gastroenterology. 2008; 135: 1469-1492
        • Modlin I.M.
        • Oberg K.
        • Chung D.C.
        • Jensen R.T.
        • de Herder W.W.
        • Thakker R.V.
        • et al.
        Gastroenteropancreatic neuroendocrine tumours.
        Lancet Oncol. 2008; 9: 61-72
        • Fjallskog M.L.
        • Janson E.T.
        Treatment of endocrine pancreatic tumors.
        Acta Oncol. 2005; 44: 329-338
        • Toumpanakis C.
        • Meyer T.
        • Caplin M.E.
        Cytotoxic treatment including embolization/chemoembolization for neuroendocrine tumours.
        Best Pract Res Clin Endocrinol Metabolism. 2007; 21: 131-144
        • Modlin I.M.
        • Pavel M.
        • Kidd M.
        • Gustafsson B.I.
        Review article: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours.
        Alimentary Pharmacology and Therapeutics. 2010; 31: 169-188
        • Plockinger U.
        • Wiedenmann B.
        Biotherapy.
        Best Pract Res Clin Endocrinol Metabolism. 2007; 21: 145-162
      1. NCCN. NCCN Practice Guidelines in Oncology. 2009.

        • Kulke M.H.
        • Siu L.L.
        • Tepper J.E.
        • Fisher G.
        • Jaffe D.
        • Haller D.G.
        • 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. 2011; 29: 934-943
        • Ramage J.K.
        • Ahmed A.
        • Ardill J.
        • Bax N.
        • Breen D.J.
        • Caplin M.E.
        • et al.
        Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).
        Gut. 2012; 61: 6-32
        • Jensen R.T.
        • Cadiot G.
        • Brandi M.L.
        • de Herder W.W.
        • Kaltsas G.
        • Komminoth P.
        • et al.
        ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes.
        Neuroendocrinology. 2012; 95: 98-119
      2. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. http://www.cochrane-handbook.org.

        • Chambers R.
        • Rodgers M.
        • Woolacott N.
        Not only randomized controlled trials, but also case series should be considered in systematic reviews of rapidly developing technologies.
        J Clin Epidemiol. 2009; 62: 1253-1260
        • Moertel C.G.
        • Hanley J.A.
        • Johnson L.A.
        Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma.
        N Engl J Med. 1980; 303: 1189-1194
        • Moertel C.G.
        • Lefkopoulo M.
        • Lipsitz S.
        • Hahn R.G.
        • Klaassen D.
        Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
        N Engl J Med. 1992 Feb 20; 326: 519-523
        • Miller A.B.
        • Hoogstraten B.
        • Staquet M.
        • Winkler A.
        Reporting results of cancer treatment.
        Cancer. 1981; 47: 207-214
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubinstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
        J Natl Cancer Inst. 2000 Feb 2; 92: 205-216
        • Juni P.
        • Altman D.G.
        • Egger M.
        Systematic reviews in health care: assessing the quality of controlled clinical trials.
        BMJ. 2001; 323: 42-46
      3. Pavel M, Heuck F, Plockinger U, Pape UF, Tiling N, Rinke A, et al. Prospective randomized trial: Biotherapy versus chemotherapy in malignant nonfunctional neuroendocrine tumors of the pancreas and brochial tract (ENET-1). ASCO GI conference. 2008.

        • Raymond E.
        • Dahan L.
        • Raoul J.L.
        • Bang Y.J.
        • Borbath I.
        • Lombard-Bohas C.
        • et al.
        Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
        N Engl J Med. 2011; 364: 501-513
        • Yao J.C.
        • Shah M.H.
        • Ito T.
        • Bohas C.L.
        • Wolin E.M.
        • Van Cutsem E.
        • et al.
        Everolimus for advanced pancreatic neuroendocrine tumors.
        N Engl J Med. 2011; 364: 514-523
        • Blumenthal G.M.
        • Cortazar P.
        • Zhang J.J.
        • Tang S.
        • Sridhara R.
        • Murgo A.
        • et al.
        FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.
        Oncologist. 2012; 17: 1108-1113
        • Kulke M.H.
        • Lenz H.-J.
        • Meropol N.J.
        • Posey J.
        • Ryan D.P.
        • Picus J.
        • et al.
        Activity of sunitinib in patients with advanced neuroendocrine tumors.
        J Clin Oncol. 2008; 26: 3403-3410
      4. Hobday T, Holen K, Donehower R, Camoriano J, Kim G, Picus J, et al. A phase II trial of gefitinib in patients with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. ASCO GI conference. 2006.

      5. Hobday T, Rubin J, Holen K, Picus J, Donehower R, Marschke RF, et al. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): A phase II Consortium (P2C) study. ASCO GI conference. 2007.

        • Hammel P.
        • Castellano D.
        • Van Cutsem E.
        • Niccoli P.
        • Faivre S.
        • Patyna S.
        • et al.
        Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.
        Pancreas. 2011; 40: 327
      6. Walter T, Krzyzanowska MK. Quality of Clinical Trials in Gastro-Entero-Pancreatic Neuroendocrine Tumours. Neuroendocrinology. 2012.

      7. Phan AT. Metastatic pancreatic neuroendocrine tumors (pNET): Placing current findings into perspective. Cancer Treatment Reviews. 2012.

      8. Signorovitch J, Swallow E, Kantor E, Wang X, Metrakos P. Overall survival with everolimus, sunitinib, and placebo for advnaced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials. J Clin Oncol. 2012;30(Suppl 4):Abstract 237.

        • Benjamin R.S.
        • Choi H.
        • Macapinlac H.A.
        • Burgess M.A.
        • Patel S.R.
        • Chen L.L.
        • et al.
        We should desist using RECIST, at least in GIST.
        J Clin Oncol. 2007; 25: 1760-1764
      9. Grande E, Jose Diez J, Pachon V, Angeles Vaz M, Longo F, Guillen C, et al. Response by Choi criteria to sunitinib plus octreotide LAR in a functional heavily pretreated advanced pancreatic neuroendocrine tumor. Anticancer Drugs. 2011;22(5):477–479.

      10. ClinicalTrials.gov. NCT01525550. A study of the efficacy and safety of sunitinib in patients with advanced well-differentiated pancreatic neuroendocrine tumors.

      11. Hentic O, Dreyer C, Zappa M, Hammel P, Mateescu C, Bouattour M, et al. Response evaluation usinf RECIST and CHOI criteria in patients with well-differentiated pancreatic neuroendocrine tumors (pNET) treated with sunitinib or everolimus. J Clin Oncol. 2012;30:Suppl; abstr e14660.

        • Jensen R.T.
        Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors.
        N Engl J Med. 2011; 364: 564-565
      12. Faivre S, Niccoli P, Raoul JL, Bang Y-J, Borbath I, Valle JW, et al., editors. Updated Overall Survival (OS) Analysis From A Phase Iii Study Of Sunitinib Vs Placebo In Patients (Pts) With Advanced, Unresectable Pancreatic Neuroendocrine Tumor (Net). ESMO; 2012 28th September-2nd October; Vienna, Austria.

        • Vinik A.
        • Cutsem E.V.
        • Niccoli P.
        • Raoul J.L.
        • Bang Y.J.
        • Borbath I.
        • et al.
        Progression-free survival (PFS) by blinded independent central review (BICR) and updated overall survival (OS) of sunitinib versus placebo for patients with progressive, unresectable, well differentiated pancreatic neuroendocrine tumor (NET).
        Pancreas. 2012; 41: 350
        • Yao J.C.
        • Lombard-Bohas C.
        • Baudin E.
        • Kvols L.K.
        • Rougier P.
        • Ruszniewski P.
        • et al.
        Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial.
        J Clin Oncol. 2010; 28: 69-76
        • Duran I.
        • Kortmansky J.
        • Singh D.
        • Hirte H.
        • Kocha W.
        • Goss G.
        • et al.
        A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.
        Br J Cancer. 2006; 95: 1148-1154
      13. Kulke M, Blaszkowsky A, Zhu AX, Florio S, Regan E, Ryan DP, et al. Phase I/II study of everolimus (RAD001) in combination with temozolomide (TMZ) in patients with advanced pancreatic neuroendocrine tumors (NET). ASCO GI conference. 2010.

        • Bukowski R.M.
        • Tangen C.
        • Lee R.
        • Macdonald J.S.
        • Einstein Jr, A.B.
        • Peterson R.
        • et al.
        Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: A Southwest Oncology Group study.
        J Clin Oncol. 1992; 10: 1914-1918
        • Eriksson B.
        • Skogseid B.
        • Lundqvist G.
        • Wide L.
        • Wilander E.
        • Oberg K.
        Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors.
        Cancer. 1990; 65: 1883-1890
        • Fjallskog M.L.
        • Janson E.T.
        • Falkmer U.G.
        • Vatn M.H.
        • Oberg K.E.
        • Eriksson B.K.
        Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors.
        Neuroendocrinology. 2008; 88: 53-58
      14. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol. 2001;12(8):1139–1143.

        • Bajetta E.
        • Ferrari L.
        • Procopio G.
        • Catena L.
        • Ferrario E.
        • Martinetti A.
        • et al.
        Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours.
        Ann Oncol. 2002; 13: 614-621
        • Moertel C.G.
        • Lavin P.T.
        • Hahn R.G.
        Phase II trial of doxorubicin therapy for advanced islet cell carcinoma.
        Cancer Treat Rep. 1982; 66: 1567-1569
        • Bajetta E.
        • Catena L.
        • Procopio G.
        • De Dosso S.
        • Bichisao E.
        • Ferrari L.
        • et al.
        Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?.
        Cancer Chemotherapy and Pharmacology. 2007; 59: 637-642
        • Fjallskog M.L.
        • Granberg D.P.
        • Welin S.L.
        • Eriksson C.
        • Oberg K.E.
        • Janson E.T.
        • et al.
        Treatment with cisplatin and etoposide in patients with neuroendocrine tumors.
        Cancer. 2001; 92: 1101-1107
        • Bajetta E.
        • Rimassa L.
        • Carnaghi C.
        • Seregni E.
        • Ferrari L.
        • Di Bartolomeo M.
        • et al.
        5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors.
        Cancer. 1998; 83: 372-378
        • Kulke M.H.
        • Stuart K.
        • Enzinger P.C.
        • Ryan D.P.
        • Clark J.W.
        • Muzikansky A.
        • et al.
        Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.
        J Clin Oncol. 2006; 24: 401-406
        • Moertel C.G.
        • Kvols L.K.
        O CMJ, Rubin J. Treatment of Neuroendocrine Carcinomas with Combined Etoposide and Cisplatin Evidence of Major Therapeutic Activity in the Anaplastic Variants of These Neoplasms.
        Cancer. 1991; 68: 227-232
        • Rivera E.
        • Ajani J.A.
        Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma.
        Am J Clin Oncol. 1998; 21: 36-38
      15. Sprenger A, Wied M, Mueller HH, Klose K, Arnold R. Effect of dacarbacine (DTIC) on tumor growth in patients with metastatic neuroendocrine gastroenteropancreatic (GEP) tumors. Gastroenterology. 2000;118(4 Suppl. 2 Part 1):AGA A647.

      16. Strosberg J, Choi J, Gardner N, Kvols L. First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide. ASCO GI conference. 2008.

        • Brixi-Benmansour H.
        • Jouve J.L.
        • Mitry E.
        • Bonnetain F.
        • Landi B.
        • Hentic O.
        • et al.
        Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma.
        Dig Liver Dis. 2011; 43: 912-916
        • Kwekkeboom D.J.
        • Teunissen J.J.
        • Bakker W.H.
        • Kooij P.P.
        • de Herder W.W.
        • Feelders R.A.
        • et al.
        Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors.
        J Clin Oncol. 2005; 23: 2754-2762
        • Butturini G.
        • Bettini R.
        • Missiaglia E.
        • Mantovani W.
        • Dalai I.
        • Capelli P.
        • et al.
        Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma.
        Endocr Relat Cancer. 2006; 13: 1213-1221
        • Kvols L.K. B.M.
        • Moertel C.G.
        • Schutt A.J.
        • Rubin J.
        • O’Connell M.J.
        • et al.
        Treatement of Metastatic Islet Cell carcinoam witha Somatostatin Analogue (SMS 201–995).
        Ann Intern Med. 1987; 107: 162-168
        • Forrer F.
        • Waldherr C.
        • Maecke H.R.
        Mueller Brand J. Targeted radionuclide therapy with Y-90-DOTATOC in patients with neuroendocrine tumors.
        Anticancer Res. 2006; 26: 703-707
        • Frilling A.
        • Weber F.
        • Saner F.
        • Bockisch A.
        • Hofmann M.
        • Mueller-Brand J.
        • et al.
        Treatment with (90)Y- and (177)Lu-DOTATOC in patients with metastatic neuroendocrine tumors.
        Surgery. 2006; 140 (discussion 76–77): 968-976
        • Panzuto F.
        • Di Fonzo M.
        • Iannicelli E.
        • Sciuto R.
        • Maini C.L.
        • Capurso G.
        • et al.
        Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma.
        Ann Oncol. 2006; 17: 461-466
        • Saltz L.
        • Trochanowski B.
        • Buckley M.
        • Hefferman B.
        • Niedzwiecki D.
        • Tao Y.
        • et al.
        Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors.
        Cancer (Philadelphia). 1993; 72: 244-248
        • Shojamanesh H.
        • Gibril F.
        • Louie A.
        • Ojeaburu J.V.
        • Bashir S.
        • Abou-Saif A.
        • et al.
        Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma.
        Cancer. 2002; 94: 331-343
        • Waldherr C.
        • Pless M.
        • Maecke H.R.
        • Schumacher T.
        • Crazzolara A.
        • Nitzsche E.U.
        • et al.
        Tumor response and clinical benefit in neuroendocrine tumors after 7.4 Gbq 90Y-DOTATOC.
        J Nucl Med. 2002; 43: 610-616
        • Eriksson B.
        • Oberg K.
        An update of the medical treatment of malignant endocrine pancreatic tumors.
        Acta Oncol. 1993; 32: 203-208
        • Yao J.C.
        • Phan A.T.
        • Chang D.Z.
        • Wolff R.A.
        • Hess K.
        • Gupta S.
        • et al.
        Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study.
        J Clin Oncol. 2008 10; 26: 4311-4318
        • Fjallskog M.L.
        • Sundin A.
        • Westlin J.E.
        • Oberg K.
        • Janson E.T.
        • Eriksson B.
        Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs.
        Med Oncol. 2002; 19: 35-42
        • Hobday T.
        • Pommier R.
        • Cutsem E.V.
        • Panneerselvam A.
        • Saletan S.
        • Winkler R.E.
        • et al.
        Analysis of progression-free survival (PFS) by prior chemotherapy use and updated safety in radiant-3: A randomized, double-blind, placebo-controlled, multicenter, phase III trial of everolimus in patients with advanced low-or intermediate-grade pancreatic neuroendocrine tumors (PNET).
        Pancreas. 2012; 41: 345
        • Moertel C.G.
        • Johnson C.M.
        • McKusick M.A.
        • Martin Jr, J.K.
        • Nagorney D.M.
        • Kvols L.K.
        • et al.
        The management of patients with advanced carcinoid tumors and islet cell carcinomas.
        Ann Intern Med. 1994; 120: 302-309
        • Rhee T.K.
        • Lewandowski R.J.
        • Liu D.M.
        • Mulcahy M.F.
        • Takahashi G.
        • Hansen P.D.
        • et al.
        90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience.
        Ann Surg. 2008; 247: 1029-1035
        • Eriksson B.K.
        • Larsson E.G.
        • Skogseid B.M.
        • Lofberg A.M.
        • Lorelius L.E.
        • Oberg K.E.
        Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors.
        Cancer. 1998; 83: 2293-2301
        • Ajani J.A.
        • Carrasco C.H.
        • Charnsangavej C.
        • Samaan N.A.
        • Levin B.
        • Wallace S.
        Islet cell tumors metastatic to the liver: effective palliation by sequential hepatic artery embolization.
        Ann Intern Med. 1988; 108: 340-344
      17. Kim YH, Ajani JA, Humberto Carrasco C, Dumas P, Richli W, Lawrence D, et al. Selective hepatic arterial chemoembolization for liver metastases in patients with carcinoid tumor or islet cell carcinoma. Cancer Invest. 1999;17(7):474–8.

      18. Capitanio V, Papa M, Zerbi A, Vitali G, De Cobelli F, Venturino M, et al. Transarterial chemoembolization (TACE) of liver metastasis from pancreatic well-differentiated endocrine carcinoma. Neuroendocrinology. 2010:4.

        • Eriksson B.
        • Oberg K.
        • Alm G.
        • Karlsson A.
        • Lundqvist G.
        • Andersson T.
        • et al.
        Treatment of malignant endocrine pancreatic tumours with human leucocyte interferon.
        Lancet. 1986; 2: 1307-1309
        • Kulke M.H.
        • Bergsland E.K.
        • Ryan D.P.
        • Enzinger P.C.
        • Lynch T.J.
        • Zhu A.X.
        • et al.
        Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors.
        J Clin Oncol. 2006; 24: 3555-3561

      Linked Article