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ABSTRACT. Neuroendocrine tumors (NET) are a rare and het-erogeneous group of neoplasms of a relatively indolent na-ture whose incidence and prevalence are increasing. Despitethe advances made in the field of NET over the past years,these tumors eventually progress to metastatic disease inmost of the patients, with a fatal outcome in the majority.Traditional cytotoxic agents remain of limited efficacy; how-ever, recently, a better understanding of molecular pathwayshas provided clues to potential molecular targets for new ther-apeutic strategies. Somatostatin analogs are well known tobe useful for the control of symptoms in functioning tumors,and it was recently demonstrated that they can inhibit tumor

progression in certain disease settings. Moreover, the recentlypublished randomized trials with the multi-TKI sunitinib andwith the mTOR-inhibitor everolimus have demonstrated, forthe first time, their ability to positively impact the natural his-tory of pancreatic NET (PNET). In this short review, we willdiscuss available data on newer molecular targeted agentsfor the treatment of advanced well-differentiated gastro-en-tero-pancreatic NET (GEP-NET). A possible algorithm for theuse of these treatments in the context of the extreme het-erogeneity of GEP-NET presentation will be proposed.(J. Endocrinol. Invest. 35: 930-936, 2012)©2012, Editrice Kurtis

INTRODUCTION

Neuroendocrine tumors (NET) have a highly variable bi-ological behavior: while certain NET remain localized andrespond well to therapy, others present with inoperablemetastatic disease and severe hormonal symptoms. Themechanism(s) underlying this variability is unclear and stilla matter of debate (1). Of the various therapeutic optionsavailable for treating patients with NET [e.g., surgery, so-matostatin analogue therapy, interferon-α (INF-α), pep-tide receptor radiotherapy (PRRT), chemotherapy,chemo-embolisation, etc.], with the exception of surgerywith curative intent, all the currently available treatmentoptions are palliative. The overall prognosis of NET pa-tients differs widely according to extent of disease, his-tological grade and site of the primary tumor. The 5-yrsurvival rates range from 60-90% in patients with local-ized NET following surgery, 50-75% in patients with re-gional lymph node involvement, whereas only 25-40% ofpatients with distant metastases will still be alive 5 yr fromdiagnosis (2).Treatment decisions are based on the clinical status ofthe patient, the local availability of different therapeuticoptions, and most importantly, on the histopathologicalcharacteristics of the tumor (tumor size, proliferation in-dex, depth of invasion, etc.). Therefore, a histologic grad-ing system based on mitotic rate and Ki-67 labeling indexof cell proliferation was proposed by the European Neu-roendocrine Tumour Society (ENETS), dividing NET into

grade 1 (mitotic count <2/10HPF and KI-67<2%), grade2 (mitotic count 2-20/10HPF and KI-67 3-20%), and grade3 (mitotic count >20/10HPF and KI67>20%) (3). Althoughthe cut-off for grade 1 and grade 2 NET has been sug-gested by some studies to be better at 5% rather than2%, the ENET grading system with respect to prognosishas recently been validated and is now incorporated in-to the latest World Health Organization (WHO) 2010 clas-sification which plays a major role in treatment decision:it stratifies NET into NET grade 1 (well differentiated, mildto moderate nuclear atypia, corresponds to ENETS G1),NET grade 2 (well differentiated, mild to moderate nu-clear atypia, corresponds to ENETS G2), NET grade 3(poorly differentiated, marked nuclear pleomorphism,necrosis, corresponds to ENETS G3), mixed adenoneu-roendocrine carcinoma (MANEC) (malignant tumors withmixed glandular and neuroendocrine characteristics, withat least 30% of one component) and hyperplastic andpreneoplastic lesions (4).Effective treatment of these complex neoplasms requiresa multidisciplinary team and an individualized approach,including evaluation of each patient’s unique disease pro-file and consideration of new and emerging treatmentoptions.The recent characterization of specific molecular path-ways of NET has prompted a new era of molecular ther-apies and the development of more selective targetedagents. NET have a number of distinctive features, name-ly increased expression of somatostatin receptors (SSTR),mostly SSTR2 (5), increased tumor vascularization withhigh expression of several proangiogenic molecules (6-8),overexpression of oncogenic receptors such as epider-mal growth factor receptor (EGFR) (9, 10), IGF receptor(11) and their downstream signalling pathway compo-nents PI3K-AKT-mTOR (12). Within this recently charac-terized setting, there is a great, yet unexploited, thera-peutic potential in the field of NET. In this short review,we will discuss new data on somatostatin analogues and

Key-words: NET, neuroendocrine tumors, new drugs, mTOR inhibitors, somatostatinanalogues, tyrosine kinases inhibitors.

Correspondence: S. Grozinsky-Glasberg, MD, Neuroendocrine Tumor Unit, En-docrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew Uni-versity Medical Center, Jerusalem, P.O.B.12000 Israel 91120.

E-mail: simonag@hadassah.org.il

Accepted September 12, 2012.

First published online October 9, 2012.

New drugs in the therapy of neuroendocrine tumors

J. Endocrinol. Invest. 35: 930-936, 2012DOI: 10.3275/8651

S. Grozinsky-Glasberg and D.J. GrossNeuroendocrine Tumor Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Hospital, Jerusalem, Israel

SHORT REVIEW

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on newer molecular targeted agents for the treatment ofadvanced gastro-entero-pancreatic NET (GEP-NET) –based on WHO tumor classification. A possible algorithmfor the use of the different treatment options in the con-text of the extreme heterogeneity of GEP-NET will beproposed.

WELL-DIFFERENTIATED NET GRADE 1 & GRADE 2(WDNET G1 & G2)New data on old drugs: Somatostatin analoguesSomatostatin [somatotropin release-inhibiting hormone(SST)], a small polypeptide hormone present in the hu-man body in two natural forms (14 and 28 amino-acids),is widely distributed throughout the body and binds withhigh affinity to five different subtypes of specific so-matostatin receptors expressed on the cell surface andbelonging to the G protein-coupled receptor family(SSTR1-5) (13). Well known for their marked inhibitory ef-fect on secretion, data regarding their role in the treat-ment of NET as anti-proliferative agents is variable; thisis the result of heterogeneity with respect to tumor origin,histology, sites of metastases, use of different SSA at dif-ferent dosages, lack of significant tumor progression be-fore starting the treatment with SSA, and, until recently,the lack of randomized prospective studies.The recent placebo-controlled prospective randomizedstudy on the anti-proliferative efficacy of octreotide long-acting release (LAR) in patients with metastatic neuroen-docrine midgut tumors (PROMID study) (14) providedcompelling evidence that SSA have direct and indirecteffects on gastrointestinal (GI) NET that go well beyondsymptom control. This phase-3 trial conducted at 18 Ger-man centers enrolled patients with well-differentiated,histologically confirmed, locally inoperable or metastat-ic midgut tumors with or without the carcinoid syndrome.Patients were randomly assigned to receive either oc-treotide LAR 30 mg im (no.=42) or placebo (no.=43) ev-ery 28 days until computed tomography/magnetic reso-

nance imaging-documented tumor progression was con-firmed. Median time to progression was 15.6 months inthe octreotide LAR treatment group vs 5.9 months in theplacebo groups [hazard ratio (HR)=0.33; 95% confidenceinterval (CI) 0.19-0.55; p=0.000017]. At 6 months postpost-treatment, 66% of patients in the octreotide LARgroup exhibited stable disease vs 37.2% of placebo-treat-ed patients, with disease progression rates of 23.8% inthe octreotide LAR group and 53.5% in the placebogroup. Clinical benefit was greatest for patients with lowhepatic tumor load (0-10%) and for those with resectedprimary tumors (14). Fatigue and fever were the most fre-quently reported severe adverse events reported amongoctreotide LAR-treated patients, followed by gastroin-testinal symptoms and hematopoietic adverse events(14). The results of PROMID study are practice changingand have been widely incorporated into clinical guide-lines.Ongoing is a phase-3 study in patients with non-func-tioning GEP-NET comparing the anti-proliferative effectof lanreotide autogel with placebo (Clarinet study); theresults of this study will be available in 2013 (15).

New data on targeted therapies(mTOR inhibitors & tyrosine-kinase inhibitors)Although numerous targeted therapies are under inves-tigation for the treatment of NET, including agents tar-geting the mammalian target of rapamycin (mTOR), vas-cular endothelial growth factor (VEGF) and platelet-de-rived growth factor (PDGF), limited phase-3 trial data areavailable on the effects of these agents for treatment ofGEP-NET.

The PI3K/Akt/mTOR/p70S6K pathwayand mTOR inhibitionOne of the major pathways involved in NET-cell prolifer-ation is the PI3K/Akt/mTOR/p70S6K pathway (Fig. 1). Inmany cancers, over-expression and activation of phos-phatidylinositol 3-kinase (PI3K), which leads in turn to ac-

AMPK AMPATP

Tuberin

Rheb 1/2

mTOR

p70S6K

AKT/PKB Apoptosis

cPKC

RSK 1/2

PI3K

MEK 1/2

ERK 1/2

Raf

Ras

Tyrosine KinaseReceptorCell membrane SS

SS

Cell proliferation & growthCell survival

Tumorigenesis

SS

Fig. 1 - The Ras-Raf-MEK-ERK (mitogen acti-vated protein kinase, MAPK) and PI3K-AKT-mTOR signaling pathways represent signifi-cant and promising molecular targets for ef-fective treatment of neuroendocrine tumors.Tyrosine kinase receptor has at least 2 sur-vival signals that are able to induce cell pro-liferation, namely PI3K/AKT and MAPK/ERKsignalling pathways. Signaling by these pro-tein kinases alters the activity of several pro-teins that regulate cell adhesion and motility,differentiation and proliferation, and cell sur-vival. While tuberin (TSC2) seems to be a crit-ical point of convergence for these two path-ways, important details regarding its regula-tion remain to be solved, such as the effectsof different drugs on ERK or AMPK activity.PI3K: phosphoinositide 3-kinase; AKT/PKB:protein kinase B; Rheb: Ras homolog en-riched in brain; mTOR: mammalian Target OfRapamycin; 70S6K: 70-kDa S6 protein kinase;MEK: MAPK/ERK kinase; MAPK: mitogen-ac-tivated protein kinase; ERK: extracellular sig-nal-regulated kinases; PKC: protein kinase C;RSK: p90 ribosomal S6 kinase; AMPK: AMP-activated protein kinase.

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tivation of Akt, has been demonstrated: both kinases pro-mote cell growth and proliferation, survival and increasedmotility, and promote increased cell size in response tonutrient availability, tissue invasion, and angiogenesis(16). The activation of Akt stimulates downstream pro-teins including mTOR (the ‘mammalian Target of Ra-pamycin’) and p70S6K (the serine/threonine kinase ofp70S6), which both play a significant role in cell growthand proliferation. The serine-threonine kinase mTOR hasemerged as a major effector of cell growth and prolifer-ation via the regulation of protein synthesis and inhibi-tion of apoptosis (17, 18). Rapamycin potently inhibitsdownstream signaling from mTOR. However, in order toimprove the pharmacokinetics of the parent molecule,rapamycin analogues, known as rapalogues, have beendeveloped (temsirolimus, ridaforolimus, and everolimus).The oral mTOR inhibitor everolimus, known also asRAD001 (Novartis Pharma), has been studied most ex-tensively among all targeted drugs in NET patients. Morethan 1000 patients have been treated with everolimus inclinical trials programs. Two phase-2 trials have demon-strated activity of everolimus as monotherapy or in com-bination with octreotide LAR in advanced NET (19, 20).Efficacy of everolimus in advanced, low- or intermediate-grade pancreatic NET was recently confirmed in a largeplacebo controlled trial (RADIANT-3 trial) recruiting 410patients (21). The median progression-free survival (PFS)reached was 11 months in the everolimus arm comparedwith 4.6 months in the placebo arm (HR 0.35; p<0.001).The benefit of everolimus was durable, 34% being sta-ble with everolimus at 18 months in contrast to 9% in theplacebo arm. The adverse events in the RADIANT-3 trialare summarized in Table 1. Based on these results,everolimus has been recently approved by the UnitedStates and European authorities for progressive pancre-atic NET.The RADIANT-2 trial was a large prospective phase-3clinical trial in patients with low- or intermediate-gradelocally advanced or distant metastatic NET with the car-cinoid syndrome, excluding pancreatic NET; everolimus-octreotide were compared with placebo-octreotide in429 patients (22). According to central review, the medi-an PFS was 16.4 months in the everolimus-octreotide LARarm, vs 11.3 months in the placebo-octreotide arm, how-ever, without attaining the predefined p-value, mostprobably due to baseline imbalances including WHO per-formance status and primary site favoring placebo-oc-treotide that confounded the primary analysis. However,after correction of these imbalances by multivariate anal-ysis and adjustment for covariates, a significant 38% re-duction in risk of progression was observed for everoli-mus+octreotide (HR, 0.62; 95% CI, 0.51-0.87; p=0.003).To confirm the utility of everolimus in this patient group,a new phase-3, randomized, double-blind study ofeverolimus (RAD001) vs placebo in the treatment of pa-tients with advanced NET of GI or lung origin without ahistory of carcinoid syndrome is planned, the so-calledRADIANT-4 trial.Everolimus has been shown to be highly effective formanagement of intractable hypoglycemia patients withmetastatic insulinoma. In a small number of patients re-ported so far, normalization of blood glucose was

achieved [after failure of somatostatin analogs, diazox-ide or streptozotocin and 5-fluorouracil (5-FU)] (23-25).The long-term efficacy of everolimus in malignant insuli-noma has still to be evaluated in a larger number of pa-tients.Temsirolimus, another rapamycin analog and mTOR in-hibitor, was evaluated in a phase-2 study including 37patients with advanced GEP NET (26). Whereas the re-sponse rate was modest (5.6%), the median TTP reached6 months, with a 1-yr OS rate of 72%. However, these ef-fects were considered not relevant enough to indicatefurther development of this agent in NET.

Angiogenesis inhibitorsThe overexpression of VEGF and VEGF receptors (VEG-FRs) in many types of NET form the rational for the eval-uation of anti-angiogenic drugs in the treatment of thesepatients. Such agents include anti-VEGF antibodies (be-vacizumab), small molecule tyrosine kinase inhibitors tar-geting the VEGFR and PDGF receptors (PDGFR) namely,vatalanib, sunitinib, sorafenib, and the endogenous an-giogenesis inhibitor endostatin or thalidomide (27).Imatinib mesylate (Novartis Pharma) is a small moleculeselective inhibitor of the c-ABL, PDGFR, and stem cellligand receptor (c-kit) tyrosine kinases. Gross et al. (28)demonstrated that imatinib is not useful for treatment ofpatients with endocrine tumors unresponsive to conven-tional therapies that expressed c-kit and/or PDGF-R, al-so causing significant toxicity in this patient population.Bevacizumab (Genentech, Roche) is a humanized mon-oclonal antibody approved by the Food and Drug Ad-ministration (FDA) in combination with cytotoxic chemo-therapy for metastatic colorectal cancer and non-smallcell lung cancer. In a randomized phase-2 trial beva-cizumab has been administered in combination with oc-treotide-LAR and compared to pegylated INFα-2b in pa-tients with advanced carcinoid tumors (poorly differenti-ated, small-cell, and high-grade NET were excluded) (29).The combination of octreotide and bevacizumab demon-strated a PFS of 95% at 18 weeks vs 68% in the INF arm.These results led to the initiation of a phase-3 trial(SWOG S0518) in advanced NET that is currently re-cruiting patients and investigating the efficacy of oc-treotide LAR plus either INFα-2b or bevacizumab.Sorafenib (Bayer Pharma), the first oral multiple tyrosinekinase inhibitor, is a small molecule targeting VEGFR-1,VEGFR-2, VEGFR-3, PDGFR-β, Flt-1, c-KIT, and Raf ki-nases, being approved by FDA for the treatment of ad-vanced kidney and hepatocellular carcinoma. A phase-2trial in GEP-NET indicated a partial remission rate of 10%(30). Recently, the combination therapy of sorafenib (200mg bid day 1-5 per week) and bevacizumab (5 mg/kgonce every 2 weeks) demonstrated an objective responserate of 10%, comparable to the response rate achievedwith sorafenib alone. However, sorafenib therapy was as-sociated with grade 3-4 toxicity in 43% of patients (31).Sunitinib maleate (Pfizer), a small molecule inhibiting sev-eral receptor tyrosine kinases namely VEGFR-1-3, PDGFR,FLT-3, c-KIT, and RET, has been approved for renal cellcarcinoma and GI stromal tumor. Initially, a phase-2 trialenrolling 107 patients demonstrated a partial remissionrate of 16.7% in pancreatic NET (PNET) compared with

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only 2.4% for NET of other origin (32). Based on theseresults an international randomized placebo-controlledphase-3 trial in advanced PNET was launched compar-ing sunitinib (37.5 mg/day continuous dose) to placeboin patients with well-differentiated PNET (G1/G2) pro-gressing within 12 months prior to the study entry. ThePFS as primary endpoint of the trial was 11.4 months inpatients treated with Sunitinib compared with 5.5 monthsin patients receiving placebo [HR 0.42 p<0.001]. Thestudy demonstrated that Sunitinib has substantial anti-tumor activity in patients with PNET with good overalltolerability. Neutropenia (12%) and arterial hypertension(10%) were among the most frequent G3/4 adverseevents and therefore patients should be carefully fol-lowed for these adverse reactions (33) (Table 1). sunitinibhas been recently approved for the treatment of ad-vanced PNET by United States and European health au-thorities. The precise role in the treatment algorithm forthis compound, as well as its long-term safety, has to bedefined by future prospective randomized clinical trials.Pazopanib is an oral pan-VEGFR inhibitor, which inhibitsPDGFR and c-kit tyrosine kinases. The first study in GEP-NET was done with a combination of pazopanib, 800mg/day and octreotide LAR in advanced low- or inter-mediate-grade GEP-NET (G1/G2) (34) and demonstratedan objective response rate of approximately 12%, similarto that reported for sunitinib. Stable disease was the mostfrequent finding (69%).Another pan-VEGFR inhibitor also targeting PDGFR andc-kit, motesanib (AMG706) is currently under evaluationin combination with octreotide in low-grade NET.

Other growth factor receptor inhibitorsOverexpression of epidermal growth-factor receptor(EGFR) has been associated with poor prognosis and re-sistance to therapy in several tumor types, and it was de-scribed also in GEP-NET (9, 35). The only data reportedso far is related to gefitinib, a small molecule tyrosine ki-nase inhibitor directed to EGFR, which demonstrated adisappointing objective response rates of <7% in aphase-2 study including 96 GEP-NET patients (36).Activation of the IGF-IR appears to represent another im-portant factor for tumor cell proliferation. In a recent

phase-2 study including 25 patients with metastatic well-differentiated GEP-NET, the administration of a mono-clonal antibody (MK-0646) that blocks the IGF receptor,showed disappointing results (37).

New data on chemotherapyThe usual chemotherapeutic combination used in NETG1 or G2, since many years ago, is that of streptozocin,doxorubicin and 5-FU, with clinical benefit in some NET(38). Other more recent studies have yielded similar andeven higher response rates (RR) using other combinationtherapies [streptozocin, 5-FU, and doxorubicin: RR= 39%(39); streptozocin, cisplatin and 5-FU: RR=38% (40); strep-tozocin and doxorubicin: RR=36% (41)]. In a recent non-randomized and retrospective trial of only 30 patientswith advanced G1 and G2 PNET, the combination oftemozolomide and capecitabine induced a RR of up to70%, with a progression-free survival of 18 months and 2yr overall survival of 92% (42). A phase-2 trial using temo-zolomide in combination with thalidomide demonstrat-ed a radiological RR of 25% (45% in PNET and only 7% inGI NET) (27).

POORLY-DIFFERENTIATED NEUROENDOCRINECARCINOMA GRADE 3 (PDNEC G3)

Patients with metastatic poorly differentiated neuroen-docrine carcinoma (PDNEC) usually have a short survival.The chemotherapy combination of cis-platinum andetoposide is frequently used as first-line palliativechemotherapy, with response rates of 42-67%, and witha median duration of response of 8 to 9 months (43).When progression occurs following first-line chemother-apy failure, the disease is usually very aggressive, andpatients have a short survival. Different second-linechemotherapy combinations have been tried, but withpoor results.Temozolomide (TMZ) is an alkylating agent, with activityin glioblastomas, melanomas, and NET (44), being asso-ciated with low MGMT (O6-methylguanine DNA methyltransferase) activity. A recent study evaluated the effectof TMZ in PDNEC patients who had progressed on first-line treatment (45). Twenty-five patients with PDNEC

RADIANT-3 Sunitinib Phase III Trial in PNETYao 2011 (Ref. 21) Raymond 2011 (Ref. 32)

Patients (no.) 204 everolimus + BSC 83 sunitinib + BSC203 placebo + BSC 82 placebo + BSC

Most frequent (≥30%) Everolimus: stomatitis 64%, rash 49%, Sunitinib: diarrhea 59%, nausea 45%,all-grade AE diarrhea 34%, fatigue 31% asthenia 34%, vomiting 34%, fatigue 33%

Placebo: none reported in ≥30% of patients Placebo: diarrhea 39%, vomiting 30%, abdominal pain 32%

Most frequent (≥5%) Everolimus: stomatitis 7%, Sunitinib: neutropenia 12%,grade 3/4 AE anemia 6%, hyperglycemia 5% hypertension 10%, hand-foot syndrome 6%

Placebo: none reported in ≥5% of patients Placebo: abdominal pain 10%, fatigue 8%, back pain 5%

Median exposure to treatment Everolimus: 8.8 Sunitinib: 4.6(months) Placebo: 3.7 Placebo: 3.7

Median follow-up for PFS, OS Everolimus: 17 Sunitinib: 10.2(months) Placebo: 17 Placebo: 11.1

AE: adverse events; BSC: best supportive care; PFS: progression-free survival; OS: overall survival.

Table 1 - Summary of toxicity of molecularly targeted therapies used in the recent phase-3 clinical trials in patients with pancreatic neu-roendocrine tumors (PNET).

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mainly of GI origin were treated with TMZ alone or in com-bination with capecitabine and bevacizumab, and MGMTmethylation was analyzed in tissue specimens. Treatmentwith TMZ alone or in combination with capecitabine andbevacizumab resulted in objective response or stabiliza-tion in 71% of PDNEC patients who failed on first-linechemotherapy, with a median duration of 19 months. Me-dian PFS for all patients was 6 months, and median over-all survival was 22 months. Only one patient had a MGMTpositive methylation, making questionable the need forMGMT evaluation before deciding about therapy withTMZ. These results strongly indicate that TMZ may be use-ful as second-line treatment in PDNEC.

SUMMARY

To date, much of our understanding in pertaining NETmanagement is based on non-randomized phase-2 clin-ical studies. These studies are of limited value as theyhave not compared a treatment under investigationagainst gold standard therapy. Treatment options as well

as treatment priorities vary from center to center, despitenational and international guidelines that have been pub-lished. In this context, results of the recently publishedphase-3 randomized trials with sunitinib and everolimusare particularly relevant, as they have demonstrated forthe first time a positive impact on the outcome of thesetumors. The efficacy of both agents seems similar, with adifferent adverse effects profile, and no formal head-to-head comparisons are expected to be performed in thenear future. An algorithm for treatment approach for gas-troenteropancreatic (GEP) NET, based on our personalexperience, is shown in Figure 2.The anti-tumor effects of the existent drugs are equally ob-scure, but almost certainly include direct effects on prolif-erative signaling pathways, especially those involving PI3Kand Akt, MAPK, activation of apoptosis, growth factors andtheir receptors, effects on angiogenesis, and others. A moredetailed understanding of the role of these mechanisms inNET tumorigenesis will almost certainly aid in the designof more effective drugs and combination treatments. Theanalysis of the individual tumor biological behavior will help

GEPNET

LocalizedGEP NET

GEP NETG1&G2

GEP NETG3

Platinum-basedchemotherapy± adjuvant SSA

Progressivedisease

Termozelomide-basedcombinations,

FOLFIRI, PRRT (?) etc.

Stable andasymptomatic

Follow-up(3-6 m, with clinical,

biochemical andradiological evaluation)

Positive uptake onSRS/Ga68-

DOTATOC/DOTATE-PET-CT

Progressivedisease

Negative uptake onSRS/Ga68-

DOTATOC/DOTATE-PET-CT

SSA +Follow-up every 3 m

Progressivedisease

SSA(dose escalation;

consider also in SRSnegative patients)

+PRRT

SSA(dose escalation;

consider also in SRSnegative patients)

+Chemotherapy

Liver predominantSSA

(dose escalation; consider alsoin SRS negative patients)

+Chemoembolization, RFA

liver debulking surgery

SSA(dose escalation; consider also

in SRS negative patients)+

Biological therapies(everolimus, sunitinib, bevacizumab,

interferon, etc.), clinical trials

Curativesurgery

Follow-up ±adjuvant SSA

AdvancedGEP NET

Fig. 2 - Possible algorithm for treatment approach in patients with localized and advanced gastro-enteropancreatic neuroendocrinetumors (GEP NET). SSA: somatostatin analogues; G: grading; PRRT: peptide receptor radioligand therapy; FOLFIRI: irinotecan withfluorouracil (5FU) and folinic acid; SRS: somatostatin receptor scintigraphy; RFA: radiofrequency ablation.

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to optimize treatment for the specific patient and lead to animproved therapeutic effect/safety profile.

ACKNOWLEDGMENTSDisclosure statementThe author of this manuscript has nothing to declare.

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