The Evolving Landscape of Neuroendocrine Tumors

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The Evolving Landscapeof Neuroendocrine Tumors

Emily K. Bergsland

Neuroendocrine tumors (NET) encompass a heterogeneous group of tumors demonstrating variedclinical behavior. The field has recently witnessed several important developments stemming fromimprovements in histopathological classification schemes, advanced imaging techniques, and adeeper understanding of the molecular mechanisms underlying tumor progression (in both spo-radic and hereditary cancers). Platinum-based chemotherapy remains the mainstay of therapy forhigh grade carcinomas. In contrast, the treatment of advanced well-differentiated NET depends onsite of origin, underlying tumor biology, and whether or not the patient is symptomatic. Soma-tostatin analogs continue to play a key role in controlling hormone-mediated symptoms. Inaddition, octreotide has demonstrated anti-tumor activity in midgut carcinoids. Novel somatostatinanalogs (for use alone or in the context of peptide receptor radiotherapy or imaging) are on thehorizon. Agents targeting VEGF- and mTOR-pathway signaling have been approved for pancreaticneuroendocrine tumors. In addition, two RET inhibitors have been approved for medullary thyroidcancer, evidence for a fundamentally new treatment paradigm (based on the use of targetedagents). Despite the advances, there remains a serious unmet need for additional treatment optionsfor refractory high-grade neuroendocrine carcinomas, paragangliomas/pheochromocytomas, adre-nocortical carcinomas, and progressive carcinoid tumors. Furthermore, the role of liver-directedtherapy in the context of available systemic approaches needs clarification. Steady progress isanticipated, however, given the unprecedented number of ongoing clinical trials related to NET(including studies focused on symptom control, genetics, imaging, and novel therapies).Semin Oncol 40:4-22 © 2013 Elsevier Inc. All rights reserved.

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The last decade has witnessed major changes inour understanding of the genetics, classification,and treatment of neuroendocrine tumors (NET).

hese advances are especially important given that thencidence of NET is increasing, and the prevalence ofhe disease is even greater due to its relatively indo-ent nature. The classification schemes for NET havevolved considerably over the last decade, withhanges in tumor nomenclature, an emphasis on theistinction between well-differentiated and poorlyifferentiated tumors, and routine incorporation ofi67 as a proliferative marker. The basic premise thatigh-grade tumors should be treated according to smallell lung cancer algorithms remains unchanged. With

UCSF Helen Diller Family Comprehensive Cancer Center, San Fran-cisco, CA.

Conflicts of interest: E. Bergsland has served as a consultant to Novartisand Lexicon Pharmaceuticals.

Address correspondence to Emily K. Bergsland, MD, UCSF Helen DillerFamily Comprehensive Cancer Center, 1600 Divisadero St, San Fran-cisco, CA 94115. E-mail: [email protected]

0270-9295/ - see front matter© 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.seminoncol.2012.11.013
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espect to well-differentiated tumors, however, weow have a greater appreciation for the differencesetween pancreatic NETs and carcinoid tumorswhich, in turn, may vary based on site of origin). Thisistinction has led to drastic changes in trial design,

ncluding stratification of patients according to site (ifot exclusion of specific disease types altogether) andisease-specific drug approvals (eg, everolimus andunitinib for pancreatic NETs). In short, our treatmentaradigm for NET is changing, highlighting the fact that“one size fits all” approach no longer applies in thisisease.

HISTOPATHOLOGICAL CLASSIFICATION

The classification, grading, and staging systems forNET have evolved steadily over the several years. Up-dated guidelines have been proposed by numerousorganizations, including the World Health Organization(WHO), the European Neuroendocrine Tumor Society(ENETS), the American Joint Committee on Cancer(AJCC), and the North American Neuroendocrine Tu-mor Society (NANETS).1�4 While no standard scheme
exists, modifications have largely aimed to establish
minars in Oncology, Vol 40, No 1, February 2013, pp 4-22

mailto:[email protected]

http://dx.doi.org/10.1053/j.seminoncol.2012.11.013

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The evolving landscape of neuroendocrine tumors 5

standard terminology (especially for gastrointestinalNET) and incorporate proliferative index as fundamen-tal component of grading, making a clear distinctionbetween poorly differentiated and well-differentiatedNET. Most recently, considerable energy has been ded-icated to identifying minimum elements for pathologyreports, such that any NET classification scheme can beapplied.

In terms of nomenclature, except for tumors origi-nating above the diaphragm, there has been a shiftaway from the term “carcinoid” in favor of the term“well-differentiated NET.” In addition, organ-specificterms such as “islet cell tumor” and “insulinoma” are nolonger commonly used. The 2010 WHO classificationof tumors of the gastrointestinal tract, pancreas, andliver specifies that well-differentiated neuroendocrineneoplasms be classified as “neuroendocrine tu-mors.”4�6 Application of the descriptor “neuroendo-rine carcinoma” is limited to high-grade (G3), poorlyifferentiated neoplasms (HGNEC). The family ofGNEC includes a number of subtypes, including ex-

rapulmonary small cell carcinoma, a large cell variant,nd an entity characterized by both small and large cellomponents.5,7 This classification system separates

NETs into two clinically meaningful groups (G1/G2,well-differentiated NET v G3, poorly differentiatedNET), which are characterized by vastly different be-haviors and responses to therapy.

The proliferative rate figures heavily in all moderngrading schemes and is generally assessed by countingmitotic figures or by calculating the percentage of cellslabeled by immunohistochemistry for Ki67.8�10 Contro-versy remains regarding the specific cutpoints used todelineate low-, intermediate-, and high-grade tumors.Furthermore, emerging data suggest that within thehigh-grade (G3) category (Ki67 �20%), there is a spec-trum of clinical behavior suggesting that tumors with aKi67 �55% may be less sensitive to chemotherapy andexhibit more indolent behavior.11 The impact of thesefindings on future NET classification schemes and treat-ment algorithms remains to be determined. Further-more, it is important to keep in mind that the value ofthe Ki67 is limited by the fact that the proliferativeindex can vary regionally throughout the tumor, lead-ing to the potential for underestimating tumor gradebased on a single biopsy.12,13 In addition, it can be ahallenge to accurately assess the proliferative indexhen the sample is small (eg, fine-needle aspirate).14

In terms of staging, a tumor-node-metastasis (TNM)staging system for NET was not included in the AJCCstaging manual until 2010.2 Additional classification sys-tems exist.15,16 As such, future updates to the AJCCsystem are likely.

GENETICS OF NETS

While the majority of NETs are sporadic, several
familial (inherited) syndromes account for the small v
subgroup of tumors that are inherited. Over the pasttwo decades, numerous syndromes have been identi-fied, with familial small intestinal NET and familial para-ganglioma syndrome being the most recent additions.Advances in our ability to analyze the molecular genet-ics of cancer have led to additional insights into themechanisms underlying the development of sporadicNETs.

The majority of inherited tumors arise in the contextof multiple endocrine neoplasia type 1 (MEN-1 syn-drome), multiple endocrine neoplasia type 2 (MEN-2),von Hippel Lindau (VHL) syndrome, neurofibromato-sis, and tuberosclerosis.17�19 These syndromes are allrelatively well characterized. MEN-1 syndrome occursin the context of alterations in the MEN-1 gene, whichencodes for the menin protein (which in turn bindsdozens of protein partners).19

MEN-2 can be divided into three clinical syndromes:MEN-2A, MEN-2B, and familial medullary thyroid can-cer (FMTC).18 Regardless of the clinical subtype, nearly100% of affected families harbor a RET (rearranged

uring transfection) mutation. RET is a proto-oncogenehat encodes for the RET transmembrane receptor ty-osine kinase (which binds members of the glial celline derived neurotrophic factor20 and activates PI3K/AKT and RAS-dependent signaling).21 Interestingly, spe-ific RET mutations appear to dictate disease pheno-ype and tumor aggressiveness.22 Germline mutationsn RET account for 25% of patients with MTC and amall subgroup of patients presenting with pheochro-ocytoma.23 In addition, somatic mutations of the RET

proto-oncogene are occasionally found in sporadicpheochromocytomas and nearly half of sporadic MTCs(nearly all of these are the M918T mutation).24,25

Germline mutations in the VHL gene are distributedthroughout the coding sequence and evident in nearlyall families with VHL syndrome.26 Renal cell carcinomas the classic tumor type associated with VHL disease,ut pancreatic NETs are also relatively common (iden-ified in up to 15% of patients), and paragangliomas/heochromocytomas can occur.25,27 Of note, the exactolecular mechanism underlying the development ofET in VHL is unknown, but lack of degradation ofypoxia-inducible factor (HIF) in the absence of theHL protein leads to upregulation of angiogenic factors

like vascular endothelial growth factor [VEGF]) pre-umably contributing to tumor growth.28

A small subgroup of patients (�5%) with neurofibro-matosis type 1 (NF1) develop catecholamine-producingtumors and/or NETs of the periampullary duodenum.29

The NF1 gene encodes for the protein neurofibromin,which is known to inhibit the PI3K/AKT/mTOR path-way via suppression of RAS.30 Tuberosclerosis genesSC1 and TSC2 also are regulated by neurofibrominhrough mammalian target of rapamycin (mTOR) acti-
ation.30 Interestingly, pheochromocytomas/paragan-

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gliomas are typically associated with NF1, whereas tu-berosclerosis is linked to pancreatic NET.17

While pancreatic NETs can occur in the setting oftuberosclerosis, neurofibromatosis, VHL syndrome,and MEN-1, most tumors are sporadic. The VHL gene isnot mutated in sporadic pancreatic NETs, but wholeexome sequencing suggests that MEN-1, DAXX/ATRX,and mTOR pathway gene alterations (including PTENand TSC-2) are common.31 Furthermore, gene expres-sion profiling supports a role for PI3K/AKT/mTOR insporadic pancreatic NETs, an observation that is ofparticular interest given the evidence that the mTORinhibitor everolimus delays progression in thesetumors.32

Familial paraganglioma/pheochromocytoma is asso-ciated with NF1, MEN-2A, MEN-2B, and VHL syndromebut is most commonly seen in the setting of mutationof succinate dehydrogenase (SDHx) subunit genes(SDHB, SDHC, SDHD, SDHA, and SDHAF2), whichncode portions of the mitochondrial complex II (anssential component of the electron transport chainnd tricarboxylic acid cycle).33,34 SDHx genes arehought to function as tumor-suppressors, with loss ofunction leading to pseudo-hypoxia and angiogene-is.34,35 While speculative at present, these findingsuggest that inhibitors of VEGF and/or HIF activity mayave efficacy in tumors harboring SDH complex alter-tions. Other authors have suggested that loss of SDHunction alters epigenetic processes (eg, methylation),eads to dysregulation of G-protein–coupled receptors,nd/or genomic instability.36,37 Mutations in any of the

genes abolish SDHx enzyme activity and leads to al-tered protein expression.38 The loss of protein expres-ion (especially with SDHB mutation) is the basis formerging interest in using immunohistochemistry tocreen for SDHx-related familial syndromes.35,38 Ofote, the precise location of the SDHx subunit muta-ion can impact tumor distribution and whether or nothe tumor is catecholamine-producing. Mutations inDH assembly factor 2 (SDHAF2), which stabilizesDHA, also have been recently identified, causing yetnother form of familial paraganglioma (patients typi-ally present with head and neck tumors).39

The drivers underlying most truly sporadic pheo-paragangliomas/paragangliomas remain unknown.29 Al-erations in SDH pathway function have been demon-trated to occur in sporadic tumors. Somatic deletions ofDH genes have been observed.40 Occult germline muta-ions in SDH genes are also identified in over 20% ofases.35,41 Taken together, nearly 30% of cases of paragan-lioma/pheochromocytoma occur in the setting of a he-editary cancer syndromes caused by a germline muta-ion.38 As such, genetic testing should strongly be

considered in patients younger than 45 years of ageand/or with malignant, bilateral, or multifocal tumors.

Until recently, the genetic events leading to the
development of ileal carcinoid were largely unknown.
Familial small intestinal NET is a rare syndrome that isinherited in an autosomal-dominant fashion and shouldbe considered in patients with a compelling familyhistory. While chromosome 18 alterations are relativelycommon in affected families, global gene expressionprofiles are not significantly different between sporadicand familial tumors, suggesting the possibility of a com-mon pathogenic mechanism.42 Loss of chromosome 18s common in sporadic ileal carcioids, but other geneticvents also have been described.42�44

The pathogenesis of adrenal cortical carcinoma(ACC) remains somewhat of a mystery, as most tumorsappear to be sporadic. Recent reports suggest thatSonic Hedgehog (Shh) and Wnt are mediators of adre-nocortical lineage and organ homeostasis.45 Constitu-ive activation of Wnt signaling due to loss-of-functionutations in the tumor-suppressor gene APC or gain-

f-function mutation in �-catenin frequently occurs inoth adenomas and carcinomas, suggesting that Wntathway alterations are an early event in the oncogenicrocess. Loss of p53 might cooperate with additionalenetic insults such as IGF2.45

In summary, the last decade has witnessed ad-vances in our understanding of the genetic altera-tions driving the development of NET. Understand-ing of the mutations underlying sporadic tumorshave lagged behind that of familial tumors. Neverthe-less, sequencing whole cancer cell genomes andother emerging laboratory techniques should pro-vide should provide important clues regarding po-tentially novel therapeutic drug targets and the com-mon genetic alterations in both familial and sporadicNET (Table 1).

SOMATOSTATIN ANALOGS

Somatostatin receptor expression is typical for NETsand is the basis for the development and use of soma-tostatin analogs (SSTa) for the control of hormone-mediated symptoms.46 Octreotide was approved in the

nited States for this purpose in 1988, with a long-cting version available shortly thereafter (lanreotide ispproved in Europe for the control of hormone-medi-ted symptoms). While the availability of SSTa revolu-ionized the treatment of patients with carcinoid syn-rome (controlling symptoms in approximately 70% ofatients), some patients are intolerant of the drug andventual resistance to therapy is common.47�50 Recentata suggest that a robust biochemical response is onlyeen in approximately 40% of patients.51 As such, much

effort has been focused on identifying more efficacioussomatostatin analogs, exploiting the fact that up to fivedifferent G-protein–coupled somatostatin receptors(SSTR1–5) are expressed in tumors, but octreotide andlanreotide primarily bind to SSTR-2 and �5.52,53

Although an antiproliferative effect of SSTa was sus-
pected for years, it was not until the results of the

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PROMID study (Placebo-controlled, double-blind Ran-domized study on the effect of Octreotide LAR in thecontrol of tumor growth in patients with metastaticneuroendocrine MIDgut tumors) that a cytostatic effectwas documented in a prospective trial.54 The data fromthis study suggest that octreotide delays progression inpatients with advanced small bowel NETs. Importantly,the PROMID study did not address the optimal timingof therapy (up-front or at the time of disease progres-sion). Furthermore, questions remain regarding theideal dose of octreotide for antiproliferative effect, thecytostatic benefits of octreotide in NET arising outsideof the small bowel, and its relative value in the settingof high tumor burden and/or G2 tumors. The potentialactivity of other SSTa is also unknown, although theresults of the CLARINET study (Controlled study ofLanreotide Antiproliferative Response in Neuroendo-crine Tumors; a phase III trial in patients with nonfunc-

Table 1. Ongoing Trials: Genetics of NET

Study Bas

Hereditary Paraganglioma:Evaluation of Screening Methodsto Detect Tumors in SDH-PositiveCarriers

Identificat(SDHD,germlin

Study Investigating MEN1 andSDHD in Familial Carcinoid Tumors

More thanfamily wbiopsy ctumor

Ascertainment of Peripheral Blood orSaliva Samples for GeneticEpidemiology Studies of FamilialCancers

History ofbreast, oprostateHodgkinleukemisarcomaneoplasmalignafirst degsuccessipart of afamily s

Natural History of Familial CarcinoidTumor

Memberswhich twimmedihave hacarcinoi

Adrenal Tumors—Pathogenesis andTherapy

Adrenal tu

Studying genes in samples fromyounger patients withadrenocortical tumor

Adrenal cup to ag

Source: http://www.cancer.gov/clinicaltrials/search (10/2012).

tional mid-gut carcinoid tumors and pancreatic neu- r

roendocrine tumors) should be available in the nearfuture (Table 2).

Recent efforts have focused on the development ofpan-receptor SSTa as a means of improving the controlof tumor growth and/or hormone-mediated symptomsin neuroendocrine tumors. Pasireotide is an example ofa pan-receptor SSTa with several fold higher affinity forSSTR-5, �3, and �1 compared to octreotide (but loweraffinity for SSTR-2).55 It is not yet known if the ex-

anded binding affinity will translate into improvedfficacy (either in the first-line or salvage setting afterctreotide). The results of a randomized study in pa-ients with refractory carcinoid syndrome are pending;everal other trials assessing anti-tumor activity and/orymptom control are ongoing (Tables 2 and 3).

Peptide receptor radiotargeted therapy (PRRT) is alsonder study. Used widely in Europe, PRRT exploits thexpression of SSTR on NET as a means of delivering

ibility Lead Site/Sponsor

an SDHSDHC)tion

Centre Hospitalier Regional etUniversitaire d’Angers, France

ember of aistory ofed carcinoid

Rutgers

rs of theolon,s, non-oma,

tissuecrineotherresenting inatives or inerations ascted cancere.

Memorial Sloan-Kettering CancerCenter

ilies inore

od relativesointestinalrs

National Institute of Diabetesand Digestive and KidneyDiseases

y imaging University of Wuerzburg

carcinoma, Children’s Oncology Group

ic Elig

ion ofSDHD,e muta

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ms, orncies pree relve gen

suspeyndromof famo or m

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orticale 21

adiolabeled SSTa (using indium 111, yttrium 90, and/or

http://www.cancer.gov/clinicaltrials/search

8 E.K. Bergsland

Table 2. Selected Clinical Trials: Somatostatin Analogs in Well-Differentiated NETs

Study Phase Basic Eligibility Lead Site/Sponsor

Somatostatin AnalogsStudy of Pasireotide Long Acting

Release (LAR) in Patients WithMetastatic NeuroendocrineTumors (NETs)

II Advanced carcinoid orpancreatic neuroendocrinetumors

H. Lee Moffitt Cancer Centerand Research Institute atUniversity of South Florida/Novartis PharmaceuticalsCorp, USA

Safety and Tolerability ofPasireotide LAR in CombinationWith Everolimus in AdvancedMetastatic NETs

I Grade 1/2 advancedpulmonary orgastroenteropancreaticneuroendocrine tumor

Novartis Pharmaceuticals Corp,Germany

Dose Escalation Study ofPasireotide (SOM230) in PatientsWith Advanced NeuroendocrineTumors (NETs)

I Well- or moderatelydifferentiatedneuroendocrine tumor/carcinoma

Novartis Pharmaceuticals Corp,USA

Study of Pasireotide in PatientsWith Rare Tumors ofNeuroendocrine Origin

II Rare tumors ofneuroendocrine origin(including pancreatic NET)

Novartis Pharmaceuticals Corp

Study of lanreotide autogel innon-functioning entero-pancreatic endocrine tumors(CLARINET)*

III Nonfunctional, well- ormoderately differentiatedNET in the intestine orpancreas with locallyadvanced or metastaticdisease

Ipsen

Everolimus vs Placebo in theTreatment of Patients WithAdvanced NeuroendocrineTumors (GI or Lung Origin)(RADIANT-4)

III Well-differentiated NET of GIor lung origin


Peptide ReceptorRadiotherapy (PRRT)

Safety and Efficacy Study of In-111Pentetreotide to TreatNeuroendocrine Tumors

II/III Neuroendocrine tumors withprior chemotherapy and/orradiation

Radio Isotope Therapy ofAmerica

A Study Comparing TreatmentWith 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR inPatients With Inoperable,Progressive, SomatostatinReceptor Positive MidgutCarcinoid Tumours†

III Progressive mid-gutcarcinoid (PFS)

Advanced AcceleratorApplications

DOTA-TOC in MetastasizedNeuroendocrine Cancer

II Advanced neuroendocrinecancer; (�) somatostatinreceptor subtype 2scintigraphy

Universitaetsspital-Basel,Switzerland

177Lutetium-DOTA-OctreotateTherapy in SomatostatinReceptor-ExpressingNeuroendocrine Neoplasms

II Somatostatin receptor-expressing neuroendocrineneoplasms

Excel Diagnostic ImagingClinics—Westchase District,USA

*Enrollment completed.†Approved, not yet active.



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lutettium 177 radionuclides).56 This strategy is not readilyavailable in the United States, largely due to the lack ofprospective randomized trials demonstrating the value ofPRRT relative to other available treatments (and the cur-rent paucity of centers with the expertise to administerthis therapy). The primary toxicities associated withPRRT appear to be renal damage and bone marrow sup-pression, the severity of which may depend on the choiceof SSTa, chelator, and/or radionuclide, number of cycles,radiation dose, and use of renal protective amino acidsolutions.57,58 Randomized trials are planned; the resultsshould lend important insight into the relative utility ofthis treatment strategy (Table 2).

SYSTEMIC THERAPY FOR CARCINOID

Aside from somatostatin analogs, there are no systemicagents routinely used in the United States to treat carci-noid tumors. While commonly employed as an anti-tumoragent, octreotide is approved in the United Statesbased onits ability to treat hormone-mediated symptoms, not basedon the results of the PROMID study.54 Not surprisingly,the identification of agents with documented anti-tumoractivity remains an area of intense interest. Octreotideaffords symptom control and/or apparent anti-tumor ac-tivity in many patients, but additional strategies are des-perately needed. As noted above, novel SSTa and PRRTare under study.55,56 Interferon is occasionally used (and is

Table 3. Selective Clinical Trials: Supportive Care

Study B

An Efficacy and Safety Study ofSomatuline Depot (Lanreotide)Injection to Treat CarcinoidSyndrome

Carcinoid (primary)(flushingnave or re

A Study to Assess NeuroendocrineTumour (NET) PatientsCurrently Treated by SomatulineAutogel for History of CarcinoidSyndrome Associated WithEpisodes of Diarrhea

DiagnosedtreatmentAutogel

TELESTAR (Telotristat Etiprate forSomatostatin AnalogueRefractory CarcinoidSyndrome)*

Well-differecarcinoidstable SSA

Phenoxybenzamine VersusDoxazosin inPheochromocytoma Patients

Planned fortumor

Evaluation of side effects ofmitotane in ACC

Planned tre

*Approved, not yet active.Source: http://www.cancer.gov/clinicaltrials/search (10/2012

approved for this indication in Europe), owing more to its m

potential for inducing a biochemical response than aradiographic response.59,60 However, its toxicity limits itsutility in common practice. Chemotherapy is of limitedvalue, with response rates generally �20%.61,62

Recent data support the potential value of VEGFand/or mTOR as therapeutic targets in carcinoid. Theresults of phase II studies with oral inhibitors of VEGFreceptor signaling suggest the potential for a cytostaticeffect in carcinoid.63,64 Phase III studies are planned but

ave not yet been performed with this class of agent.ompelling results from a phase II study assessing oc-

reotide long-acting release (LAR) plus bevacizumab oregylated interferon were the basis for an ongoing phase

II study in high-risk carcinoid (Southwest Oncologyroup [SWOG]-0518).65 Accrual to this study has beenompleted and the results are eagerly awaited. Numerousther anti-VEGF agents are under study in carcinoidTable 4).

The mTOR pathway also appears to be a potentiallyalid target in carcinoid. The results of the RADIANT-2RAD001 in Advanced Neuroendocrine Tumors) phase IIItudy of everolimus plus octreotide LAR versus octreotideAR plus placebo were confounded by informative cen-oring stemming from discordance between the local andentral review.66 There was a trend towards improvedrogression-free survival (PFS), but the results did noteet the predefined statistical boundary. As such, everoli-

atients With NETs

ligibility Lead Site/Sponsor

ng unknownnoid syndromerrhea); treatment

ive to octreotide

Beaufour IpsenInternational SNC

ET and receivingomatuline

Beaufour IpsenInternational SNC

NETs w/history ofme refractory topy

Lexicon Pharmaceuticals,Inc

al removal of the University Medical CenterGroningen

t with mitotane University of Wuerzburg

for P

asic E

includiw carci�/- diasponswith Nwith S

ntiatedsyndrothera

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atmen

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us is not approved for this indication. The RADIANT-4


Table 4. Selected Clinical Trials: Systemic Agents for Well-Differentiated NETs (carcinoid, pancreatic neuroendocrine tumors)Study Phase Basic Eligibility Lead Site/Sponsor

ChemotherapyCapecitabine and Temozolomide for Neuroendocrine

CancersII Progressive, well- or moderately-differentiated NET (RR) Herbert Irving Comprehensive Cancer Center at Columbia University

Medical Center, USAPhase II Randomized Study of Capecitabine and

Streptozocin With Versus Without Cisplatin inPatients With Unresectable or MetastaticNeuroendocrine Tumors

II Chemotherapy-nave; gastroentero-neuroendocrine tumorsof the foregut, pancreatic neuroendocrine tumors, NETof unknown primary (RR)

Addenbrooke’s Hospital, UK

VEGF InhibitorTemozolomide and Pazopanib Hydrochloride in

Treating Patients With Advanced PancreaticNeuroendocrine Tumors That Cannot Be RemovedBy Surgery

I/II Pancreatic neuroendocrine tumors Robert H. Lurie Comprehensive Cancer Center at NorthwesternUniversity

Study of Pazopanib Monotherapy in Patients WithUnresectable, Metastatic Neuroendocrine Tumor

II Unresectable low- to intermediate-grade NET (RR) Samsung Medical Center, Korea

A Study of Axitinib in Advanced Carcinoid Tumors II Well- and moderately differentiated neuroendocrinetumors of the aerodigestive tract, as well as rareprimary sites (renal, ovarian, thymic, hepatic)

H. Lee Moffitt Cancer Center; National Comprehensive CancerNetwork

Capecitabine, Temozolomide and Bevacizumab forMetastatic or Unresectable PancreaticNeuroendocrine Tumors*

II Well- to moderately differentiated PNET Stanford Cancer Center; National Cancer Institute

Bevacizumab Plus Somatostatin Analogue andMetronomic Capecitabine in Patients WithAdvanced Neuroendocrine Tumors

II Well-differentiated neuroendocrine carcinoma (RR) Azienda Ospedale S. Luigi at University of Torino, Italy

Octreotide and Interferon alfa-2b or bevacizumab intreating patients with metastatic or locallyadvanced, high-risk neuroendocrine tumor(SWOG-0518)

III High-risk, advanced low- or intermediate-gradeneuroendocrine carcinoma (carcinoid, atypicalcarcinoid)

SWOG/NCI

mTOR InhibitorEverolimus and octreotide with or without

bevacizumab in treating patients with locallyadvanced or metastatic pancreatic neuroendocrinetumors that cannot be removed by surgery(CALGB 80701)†

II Progressive pancreatic NET CALGB/NCI

Safety and Tolerability of Pasireotide LAR inCombination With Everolimus in AdvancedMetastatic NETs

I Grade 1/2 advanced pulmonary or gastroenteropancreaticneuroendocrine tumor

Novartis Pharmaceuticals Corporation, Germany

Phase II Study of Temsirolimus and Bevacizumab inPatients With Locally Advanced, Recurrent,Metastatic, or Progressive Endometrial Cancer,Ovarian Epithelial Cancer, HepatocellularCarcinoma, Islet Cell Cancer, or Carcinoid Tumor(All permanently closed to enrollment except IsletCell)

II Advanced islet cell tumor Mayo Clinic Cancer Center

Phase I Study of Cixutumumab, Everolimus, andDepot Octreotide Acetate in Patients WithAdvanced Low- to Intermediate-GradeNeuroendocrine Carcinoma

I Low or intermediate grade neuroendocrine carcinoma M. D. Anderson Cancer Center at University of Texas

10E.K.

Bergsland

Table 4. ContinuedStudy Phase Basic Eligibility Lead Site/Sponsor

Everolimus Combined With Octeotride LAR to TreatAdvanced GI NET

II Progressive non-functioning, well differentiated advancedGI NET

Grupo Espanol de Tumores Neuroendocrinos

Study of Everolimus Treatment in Newly-diagnosedPatients With Advanced GastrointestinalNeuroendocrine Tumors

II Well or moderately differentiated advanced (metastatic orunresectable) GI or pancreatic NET

Hellenic Cooperative Oncology Group

Safety and Efficacy of RAD001 in Chinese PatientsWith Advanced Pulmonary Neuroendocrine Tumor

I Newly diagnosed advanced carcinoid tumors orprogressed after first-line treatment is eligible

Novartis Pharmaceuticals Corporation

3-arm Trial to Evaluate Pasireotide LAR/EverolimusAlone/in Combination in Patients WithLung/Thymus NET*

II Well differentiated neuroendocrine carcinoma of the lungand thymus


RAMSETE: RAD001 in Advanced and MetastaticSilent Neuro-endocrine Tumors in Europe

II Progressive, Low- or intermediate-grade, nonfunctional,nonpancreatic NET

Novartis

Efficacy of Everolimus Alone or in Combination WithPasireotide LAR in Advanced PNET (COOPERATE-2)

II Progressive PNET Novartis Pharmaceuticals Corp

Efficacy and Safety of BEZ235 Compared toEverolimus in Patients With Advanced PancreaticNeuroendocrine Tumors*

II Progressive PNET Novartis Pharmaceuticals Corp

BEZ235 Phase II Trial in Patients With AdvancedPancreatic Neuroendocrine Tumors (pNET) AfterFailure of mTOR Inhibitor Therapy*

II PNET refractory to mTOR inhibitor Novartis Pharmaceuticals Corp

OtherCabozantinib in Advanced Pancreatic

Neuroendocrine and Carcinoid Tumors*II Carcinoid or PNET; PNET pt must have had prior VEGF

inhibitorMassachusetts General Hospital

Biological Study of Resveratrol’s Effects on Notch-1Signaling in Subjects With Low GradeGastrointestinal Tumors

Low grade NET University of Wisconsin Paul P. Carbone Comprehensive CancerCenter

Phase I Study of Seneca Valley Virus-001 (NTX-010)With or Without Cyclophosphamide in PediatricPatients With Relapsed or RefractoryNeuroblastoma, Rhabdomyosarcoma, or RareTumors With Neuroendocrine Features

I Histologically confirmed diagnosis of 1 of the following:Neuroblastoma, rhabdomyosarcoma, Wilms tumor,Retinoblastoma, Adrenocortical carcinoma, Carcinoidtumor (age 3�21)

Children’s Oncology Group

YF476 in Patients With Type II Gastric CarcinoidsAssociated With Zollinger-Ellison Syndrome

II Patients with Zollinger-Ellison syndrome and type II gastriccarcinoids or their precancerous cells. (size and numberof type II gastric carcinoids)

National Institute of Diabetes and Digestive and Kidney Diseases

*Approved, but not yet active.†Enrollment completed.


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12 E.K. Bergsland

study recently opened and is designed to address the roleof everolimus in nonfunctional progressive lung and gas-trointestinal carcinoid tumors. Additional studies withmTOR inhibitors are ongoing (Table 4).

Future clinical trials in carcinoid should be performedwith careful consideration of the interpatient heterogene-ity that characterizes the disease.67 Given the difficultieselated to imaging in carcinoid the primary endpointhould be chosen wisely, and the criteria for declaringadiographic response should be clear. Concurrentnd/or previous exposure to octreotide should be takennto account, as should the extent of tumor progression attudy entry. In addition, a subset analysis from the RADI-NT-2 study suggests that other factors may impact out-ome, including site of primary tumor, baselinehomogranin level, and distribution of metastatic diseaseeg, bone metastases).68

The relatively indolent nature of carcinoid is offset bythe fact it has proven resistant to nearly every systemicagent tested. While widely used as an anti-tumor agent,the data in support of octreotide’s cytostatic effect arefairly limited, and restricted to tumors originating in thesmall bowel or of unknown primary site.54 The develop-ment of additional therapies has been confounded byinherent challenges related to studying carcinoid (eg, im-aging, interpatient heterogeneity). Advances in our under-standing of carcinoid tumor biology, coupled with a ra-tional approach to clinical trial design, will hopefullyfacilitate the identification of novel therapeutic strategiesand predictive markers to guide patient selection.

SYSTEMIC THERAPY FOR PANCREATIC NETS

In contrast to carcinoid, significant progress has beenmade in the development of novel treatments for pancre-atic NETs over the past several years. Everolimus andsunitinib were both approved as single agents for thetreatment of progressive pancreatic NET in 2011.Sunitinib is an oral tyrosine kinase inhibitor that inhibits avariety of kinases, including VEGF receptor-1 and-2, plate-let derived growth factor receptor (PDGFR-alpha and-beta), colony-stimulating factor receptor �1, and Flt-3,nd RET.69 Accrual to the phase III trial was stopped

before a pre-planned efficacy analysis, based on an analy-sis of enrolled patients suggesting that treatment withsunitinib was associated with improved PFS in patientswith progressive pancreatic NET (11.4 months withsunitinib v 5.5 months with placebo; hazard ratio, 0.42;95% confidence interval, 0.26�0.66; P �.001).70 Consis-tent with a largely cytostatic effect, the objective responserate was only 9.3% (v 0% with placebo). The drug wasgenerally well tolerated, the most frequent side effectsbeing diarrhea, nausea, vomiting, asthenia, and fatigue.Treatment did not appear to adversely affect quality oflife. Mature survival data are not yet available; however,
the most recent analysis showed no significant difference
between the two study arms (placebo patients had theoption to receive sunitinib post-progression).71

The mTOR inhibitor everolimus was compared to pla-cebo in a phase III trial in patients with progressivepancreatic NET (the RADIANT-3 study).72 Treatment withverolimus was associated with a significant improve-ent in PFS (11.6 v 4.6 months; hazard ratio, 0.35; log-

ank P �.0001) without improving overall survival (rec-gnizing that the survival analysis was confounded by theross-over design). Like sunitinib, the radiographic re-ponse rate was low, but the agent was relatively wellolerated. Since their approval in 2011, both agents haveound a place in the treatment of patients with progres-ive pancreatic NET. However, the optimal sequence hasot been defined, nor has the precise benefit of eithergent in the setting of refractory disease. In addition,iomarkers predictive of response have yet to be identi-ed but could prove important in the sequencing ofherapies and/or selection of one agent over another.mportantly, work by Jiao et al suggest that only a minor-ty of patients with pancreatic NET have tumors thatarbor mutations in the mTOR pathway.31 It is not yetnown if such tumors are more likely to respond toverolimus. Given the recent validation of both mTORnd VEGF as targets for therapy in pancreatic NETs, theesults of Cancer and Leukemia Group B (CALGB) 80701a phase II study exploring everolimus with or withoutevacizumab in pancreatic NET) are keenly awaitedTable 4).

In terms of other treatment options, numerous studiesre ongoing (Tables 2 and 4). The results of the CLARI-ET study are highly anticipated and should provide in-

ight into the anti-tumor efficacy of SSTa (lanreotide) inancreatic NET. The role of PRRT and/or liver-directedherapy is similarly unclear, as prospective randomizedtudies have not been performed. Finally, much contro-ersy surrounds the optimal chemotherapy regimen forancreatic NETs. Typically reserved for patients withulky disease or other situations when tumor regressionould be ideal, several agents have been studied. While

pproved for use in pancreatic NETs, the value of strep-ozocin-based treatment is the subject of much debate,ith response rates as low as 6% in some trials.73,74 That

aid, Kouvaraki et al reported the results of a retrospectivetudy evaluating a three-drug regimen (streptozocin, 5-flu-rouracil, doxorubicin) and demonstrating a 39% re-ponse rate in 84 patients.75 More recently, temozolo-

mide-based regimens have gained traction based onseveral small prospective and retrospective studies involv-ing a variety of drug combinations, doses, and schedules.Most of the prospective studies suggest response rates inthe 30%–45% range in pancreatic NETs.76�78 In contrast,Strosberg et al reported a 70% response rate with cape-citabine plus temozolomide in the first-line setting (basedon retrospective data).79 Data from randomized studiesare lacking, but several studies are planned and/or ongo-
ing (Table 4). In addition, studies validating the potential

tt[eS�npchgu


predictive value of O6-methylguanine DNA methyltrans-ferase (MGMT) in patients treated with temozolomide areplanned.78,80

REGIONAL THERAPY FOR NETS

While resection is often curative in patients with local-ized well-differentiated NETs, its role in the treatment ofpatients with advanced disease remains controversial. Re-section of the primary tumor in the setting of metastasesmay be associated with improved overall survival, partic-ularly in patients with small bowel tumors.81,82 However,randomized trials are lacking. As such, in the asymptom-atic patient, much depends on the morbidity of theplanned procedure and the overall pace of the disease.

Resection or palliative debulking of liver metastases isalso frequently considered in the patient with relativelystable disease.83 Randomized controlled trials have notbeen performed, but the available data suggest the poten-tial for improved hormone-mediated symptoms and im-proved overall survival in carefully selected patients.84

Importantly, however, emerging data suggest that evenR0 resections are not curative, with a recurrence rate ofup to 99% at 10 years.84 Despite the high risk of recur-rence, there is no significant evidence to support the useof adjuvant therapy of any type post-resection.

Other liver-directed therapies are also widely used (eg,hepatic arterial embolization [HAE] or hepatic arterialchemoembolization [HAC]), with much attention re-cently focused on selective internal radiation therapy(SIRT) with 90Y-labeled microspheres.85,86 Treatment ap-

Table 5. Selective Clinical Trials: Liver-Directed T

Study Ba

Best Therapy for Patients WithNeuroendocrine Tumors (local ablativetherapy such as TACE or SIRT, surgeryand RFA with peptide receptorradiotherapy).

Advanc

Neo-adjuvant Peptide Receptor MediatedRadiotherapy With 177 Lutetium inFront of Curative Intended LiverTransplantation in Patients WithHepatic Metastasis of NeuroendocrineTumors (NEO-LEBE)

Low-intNET;metascanditransp

Doxorubicin Beads in Treating PatientsWith Unresectable Liver MetastasesFrom Neuroendocrine Tumors

Diagnoneurometasfor ra(eg, rtransp


pears to be relatively well tolerated, with radiographic

response rates �50%.87 Randomized trials are lacking,thus the benefit of SIRT relative to ablation, HAE, or HACis unknown (Table 5). Use of targeted agents as an adjunctto liver-directed therapy is another area of study. Ulti-mately, the risks and benefits of surgical intervention andother liver-directed therapies must be weighed carefully,with the goal of individualizing each patient’s therapeuticplan, depending on extent and pace of disease, symp-toms, and systemic treatment options. Trials aimed atdefinitively delineating the role of liver-directed treat-ments versus systemic treatments are needed.

ADVANCES IN UNUSUAL NETS

Historically, advanced MTC has proven extremely dif-ficult to treat given its inherent resistance to chemother-apy.88 Recently, however, expanding on the known linkbetween RET mutation and MTC, the RET tyrosine kinasereceptor has been validated as a target for therapy.89 Morehan 300 patients with metastatic MTC were randomizedo receive vandetanib (an oral tyrosine kinase inhibitorTKI] targeting RET, VEGF receptor [VEGFR], and thepidermal growth factor receptor [EGFR]) or placebo.ignificant improvements in PFS (hazard ratio, 0.46; P.001) and response rate (45% v 13%, P �.001) were

oted, leading to US Food and Drug Administration ap-roval for this indication in April 2011. While definitiveonclusions could not be drawn, vandetanib appeared toave greater activity in patients harboring sporadic orermline RET mutations. Numerous other TKIs are alsonder investigation in MTC.88,90,91 In fact, cabozantanib

y for NETs

ibility Lead Site/Sponsor

de I/II NET Zentralklinik Bad Berka, Germany

ate gradectable liverndr liveron

Universitaets – Kinderklinik, Germany

epaticineot suitableerapiesn or liveron)

Sidney Kimmel ComprehensiveCancer Center at Johns HopkinsNational Cancer Institute

herap

sic Elig

ed, gra

ermediUnresetases adate folantati

sis of hendocrtases ndical thesectiolantati

also recently received US Food and Drug Administration


hPPTtrtt

aagp([e

h

todemsssie

an

gafcrm

cR

14 E.K. Bergsland

approval based on improved progression-free survival inpatients with progressive MTC.90 The value of these otheragents compared to vandetanib and/or in the setting ofvandetanib failure is unknown. Furthermore, the utilityvandetanib in pheochromocytomas and/or paraganglio-mas harboring RET mutations is uncertain. Dedicatedinhibitors of the mTOR pathway and/or VEGF signalingare also of potential interest in pheochromocytoma, para-ganglioma, and MTC (Table 6).

Adrenocortical carcinomas (ACCs) originate in the ste-roid-hormone producing adrenal cortex. Recent advancesin diagnosis include immunohistochemical stains thatmay distinguish ACC from renal cell carcinoma, pheo-chromocytoma/paragangliomas, and other tumors.92,93

Emerging evidence suggests that malignant adrenocorti-cal tumors are globally hypomethylated as compared withnormal adrenal cortex and benign tumors. Methylationprofile differences may also help to distinguish betweenprimary benign and malignant adrenocortical tumors.94

Treatment for this disease has remained fairly staticover the past several years, with mitotane serving as themainstay of therapy for advanced disease. Long awaiteddata from the FIRM-ACT study (First International Ran-domized trial in locally advanced and Metastatic Adreno-cortical Carcinoma Treatment) were recently reported.62

The FIRM-ACT trial was a randomized phase III trial ofetoposide-doxorubicin-cisplatin (EDP)-mitotane versusstreptozocin-mitotane in patients with advanced adreno-cortical carcinoma. Patients with disease progressionwere offered the alternative regimen as second-line ther-apy. In the first line setting, patients receiving EDP-mito-tane experienced a longer PFS (5.0 months v. 2.1 months;

azard ratio, 0.55; 95% confidence interval, 0.43 to 0.69;�.001) and higher response rate (23.2% v 9.2%,

�.001) than those assigned to streptozocin-mitotane.here was no difference in overall survival, which was

he primary endpoint of the study. Importantly, theates of serious adverse events were no different be-ween groups suggesting that EDP-mitotane is an op-ion to consider in selected patients.

Not surprisingly, targeted therapy has emerged as anrea of interest in ACC as additional treatment strategiesre desperately needed (Table 7). Several studies are on-oing exploring the utility of agents targeting the IGF-1Rathway signaling. Agents targeting other tyrosine kinasesincluding VEGFR and fibroblast growth factor receptorFGFR]) and inhibitors of mTOR signaling are also undervaluation.95,96

HIGH-GRADE NEUROENDOCRINE CARCINOMAS

Despite the advances achieved in the treatment ofwell-differentiated NETs over the past several years, ther-apy for extrapulmonary HGNECs remains suboptimal. Pa-tients almost always present with metastatic disease, andthe median survival remains poor.97,98 Progress has been

ampered by several factors, most notably the rarity of

he disease, the potential for organ-specific differences inutcome, and the fact that the relatively rapid pace ofisease limits accrual to clinical trials (eg, patients notligible due to impaired end organ function, poor perfor-ance status, and/or need to initiate therapy urgently). As

uch, platinum-based chemotherapy remains the main-tay of therapy in patients with both localized and meta-tatic disease. Resection and/or radiation also play a rolen selected patients, but even in apparently localized dis-ase, eventual dissemination is likely.98

Interestingly, while HGNECs are typically thought torepresent an aggressive type of tumor within the NETspectrum, recent data suggest that these tumors maymore closely resemble poorly differentiated carcinomasthan well-differentiated NETs, suggesting a non-neuroen-docrine cell lineage.99 Support for a stem cell precursor inHGNEC comes from recent work suggesting that expres-sion of nestin, a class VI intermediate filament proteinexpressed in stem/progenitor cells during central nervoussystem development, may be prognostic in patients withlarge cell neuroendocrine carcinoma of the lung.100 Thepplicability of these finds to tumors that are extrapulmo-ary in origin is unknown.

Additional work is needed to characterize the patho-enesis and molecular features of HGNECs and to identifydditional therapeutic targets. No standard therapy existsor treatment in the second line setting or beyond.98 Smallell lung cancer regimens are commonly employed, andecent data suggest that temozolomide-based regimensay also be active in this setting.101 The role of targeted

agents in the treatment of HGNECs is unknown.

ADVANCES IN IMAGING

Neuroendocrine tumors can be difficult to reliablymeasure with conventional cross-sectional imaging.67 Theomplications resulting from informative censoring in theADIANT-2 trial in carcinoid exemplify this point.66 Cases

in which the local reviewer called progression prema-turely (relative to the central reader) were censored, lead-ing to a smaller number of events, and loss of power. This,coupled with the known limitations of other imagingmodalities (eg, 111In-DPTA-octreotdie scintigraphy), hasfueled efforts to develop additional imaging tools withimproved sensitivity and specificity.102

Computerized tomography (CT) scans are routinelyused to image NET. A noncontrast CT scan is of limitedvalue when assessing primary tumors or hepatic lesions,which are best visualized as enhancing or hypervascularlesions on the early and late arterial phase images.103

Recent advances in imaging include use of multi-detectorCT, which allows appropriate arterial phase imaging. Amultiphase scan (early, late arterial and portal venous)improves the sensitivity when imaging the liver and pan-creas and is now considered standard procedure.104,105

Magnetic resonance imaging (MRI) is another valuable
imaging modality for the detection and staging of NET.


Table 6. Selected Clinical Trials in Pheochromocytoma, Paraganglioma, and Medullary Thyroid Cancer

Study Phase Basic Eligibility Lead Site/Sponsor

RAD001 in Pheochromocytoma orNonfunctioning Carcinoid

II Progressivepheochromocytoma orextra-adrenalparaganglioma or carcinoid

Seoul National UniversityHospital

Phase II Study of PazopanibHydrochloride in Patients WithAdvanced or ProgressiveMalignant Pheochromocytomaor Paraganglioma

II Malignant secretory ornon-secretorypheochromocytoma orparaganglioma that isunresectable

Mayo Clinic Cancer Center

First International RandomizedStudy in Malignant ProgressivePheochromocytoma andParaganglioma: FIRSTMAPPPstudy (sunitnib)

II Progressive malignantpheochromocytoma andparaganglioma

Institut Gustave Roussy; InstitutNational du Cancer; ENSAT-CANCER European Networkfor the Study of AdrenalTumours

Iodine 131Metaiodobenzylguanidine inTreating Patients WithRecurrent, Progressive, orRefractory Neuroblastoma orMalignant Pheochromocytomaor Paraganglioma

II Recurrent, progressive, orrefractory neuroblastomaor malignantpheochromocytoma orparaganglioma

Memorial Sloan-KetteringCancer Center

Study of Sunitinib in Patients WithRecurrentParaganglioma/Pheochromocytoma

II Advanced malignantparaganglioma orpheochromocytoma cancer

Toronto Western Hospital;Pfizer Inc

To compare the effects of twodoses of vandetanib in patientswith advanced medullarythyroid cancer

IV Advanced medullary thyroidcancer (MTC)

Astra Zeneca

Vandetanib to treat children andadolescents with medullarythyroid cancer

I/II Unresectable or metastaticmedullary thyroid cancer

National Cancer Institute

Safety and tolerability ofvandetanib in Japanese patientswith medullary thyroid cancer

II Advanced or metastatic MTC Astra Zeneca

Lithium in medullary thyroidcancer

II Advanced or metastatic MTC University of Wisconsin

Pazopanib in medullary thyroidcancer

II Advanced or metastatic MTC National Cancer Institute

LBH589 in metastatic thyroidcancer

II Metastatic medullary ordifferentiated thyroidcancer

University ofWisconsin/Novartis

Everolimus in progressive,recurrent, unresectable ormetastatic thyroid cancer

II Differentiated thyroid cancer(including MTC)

Leiden University MedicalCenter

Pasireotide and everolimus inradio-iodine refractorydifferentiated and medullarythyroid cancer

II Progressive, radioiodine-refractory disease

Winship Cancer Institute ofEmory University/Novartis

SOM230 with or withouteverolimus in patients withmedullary thyroid cancer

II Progressive MTC Federico II University MedicalCenter



osp

iitbua

16 E.K. Bergsland

Imaging should be performed post-contrast in a dynamicand delayed fashion.102,105 Done properly, MRI may evenffer better detection of liver metastases than CT. Diffu-ion-weighted imaging is a newer technique that has theotential to identify and characterize tumors.106 One re-

cent study suggested that differences in apparent diffu-sion characteristic (ADC) may be used to discriminatebetween well-differentiated and poorly differentiatedNET.107

Functional imaging may well hold the most promise interms of yielding advances in the near future. For years,111In-DTPA octreotide scintigraphy has been the mainstayof functional imaging for NET.56,108 Combining conven-tional imaging with single-photon emission computerized

Table 7. Selective Clinical Trials: ACC

Study Phase

Clinical TrialClinical trial of dovitinib in first-line

metastatic or locally advanced non-resectable ACC*

II A

A study of OSI-906 in patients withlocally advanced or metastatic ACC(GALACCTIC)*

III P

Mitotane with or without IMC-A12 intreating patients with recurrent,metatastic, or primary ACC thatcannot be removed by surgery*

II U

Phase II study of axitinib with evaluationof the VEGF pathway in metastatic,recurrent or primary unresectableadrenocortical cancer

II A

Efficacy of adjuvant mitotane treatment(ADIUVO)

L

Cisplatin-based chemotherapy and/orsurgery in treating young patientswith ACC

III N

Diagnosis/MonitoringStudy of Adrenal Gland Tumors T

German ACC registry A

Studying genes in samples fromyounger patients with adrenocorticaltumor†

A

*Active, not yet recruiting.†Study ongoing; not recruiting patients.

Source: http://www.cancer.gov/clinicaltrials/search (10/2012

tomography (SPECT) allows for better anatomical local-

ization, particularly when performed in the context ofhybrid SPECT-CT imaging.109 However, the value of oc-treotide scintigraphy is limited by the dependence onSSTR-2 expression, uptake by non-neuroendocrine tu-mors and background binding in normal tissues.110 Futuremprovements in somatostatin analog-based functionalmaging are likely to stem from the use of newer analogshat have a higher affinity for SSTR-2 or wider spectrum ofinding affinity.56,111 New chelators (eg, DOTA) are alsonder investigation, in part because they are more stablend may be used with other radionuclides (eg, 90Y and

177Lu) for PET imaging and PRRT (Table 8).Traditional PET scanning using 18F-fluorodeoxyglucose

has limited value in the assessment of well-differentiated

Eligibility Lead Site/Sponsor

ed ACC PhaseSpanish OncologyGenito-Urinary Group

sly treated ACC Astellas Pharma Inc

table recurrent,y advanced, ortatic ACC

University of Chicago; NCI

at has not respondedndard treatments

NCI

ermediate risk ofe

University of Turin, Italy

diagnosed ACC, upe 21

Children’s OncologyGroup/NCI

of the adrenals, as indicated byusly obtained

ng studies and/oremical investigationrmonal secretion

NIH—Warren GrantMagnuson ClinicalCenter

agnosis or treated inany

University of Wuerzburg

p to age 21 Children’s OncologyGroup

dvanc

reviou

nreseclocallmetas

CC thto sta

ow-intrelapsewlyto ag

umorglandprevioimagibiochof hoCC diGermCC, u

).

NET but may be reasonable to consider in the setting of


pswb

o

adtaahrt

smm


negative 111In-octreotide scintigraphy and/or tumors witha high Ki67 proliferative index.112 PET imaging using18F-fluoro-L-thymidine (18F-flt) is also of interest, given its

otential to assess tumor cell proliferation (DNA synthe-is). However, its utility is limited by the fact that manyell-differentiated NETs have a proliferation index that iselow the level of detection.113

While not widely available in the United States, there issignificant interest in the use of gallium 68–labeled soma-tostatin analogs for the detection of NETs (Table 8). Inaddition to potential improvements in image quality, PETscanning with 68Ga-labeled somatostatin analogs affordsthe advantages of relatively short scanning time and lowradiation exposure compared to traditional 111In-DTPA-ctreotide scintigraphy.110,114 Future advances in the func-

tional imaging of NETs are likely to stem from the contin-ued development of other novel PET imaging agents,including those based on serotonin or catecholamine pre-cursors.115,116

SUPPORTIVE CARE

Our ability to ameliorate the symptoms associated withNETs has improved over the years, owing in large part to

Table 8. Selected Trials: Imaging and NET

Title Basic

The Reproducibility of DiffusionWeighted MagneticResonance Imaging forNeuroendocrine Tumor LiverMetastases

Well-differentgastroentero

Natural History andManagement of PancreaticLesions in Von Hippel-LindauDisease

Patients �12have been dVHL

68Ga-Labeled OctreotideAnalogues PET in Duodenal-Pancreatic NeuroendocrineTumours*

Duodenal-pan

123I-MIBG Scintigraphy inPatients Being Evaluated forNeuroendocrine Tumors*

Clinical indicaimaging topresence, exneuroendoc

11C-Acetate PET/CT Non-FDG-Avid Tumors

Newly diagno(including Noften non-Fonly low int

68Ga-DOTA-NOC-PET Imagingof Neuroendocrine Tumors

NETs

*Approved, not yet active.Source: http://www.cancer.gov/clinicaltrials/search (10/2012

the use of somatostatin analogs, improved techniques for s

decreasing tumor bulk, and advances in our understand-ing of NET biology.117,118 An assessment of tumor-associ-ted and hormone-mediated symptoms should be a stan-ard component of the care of these patients. In addition,he potential for treatment-related side effects (eg, nauseand myelosuppression from chemotherapy, hypertensionnd fatigue from sunitinib, steatorrhea from SSTa, andyperlipidemia and mouth sores from everolimus) war-ants consideration, particularly in the setting of chronicherapy with agents that are largely cytostatic.70,72,119

In patients with functional tumors, acute hormone-mediated symptoms and signs (eg, diarrhea, peptic symp-toms, hypoglycemia, hypercalcemia) should be ad-dressed, with somatostatin analogs often playing a majorrole.47,117,118 The potential for long-term consequences ofhormone excess or its treatment should also be consid-ered (eg, carcinoid heart disease from serotonin excess,vitamin B12 deficiency from chronic pharmacologic main-tenance of the achlorhydric state, pancreatic insufficiencyfrom octreotide).119�121 In addition, careful attentionhould be paid to identifying the triggers of hormone-ediated symptoms (eg, exercise and lack of frequenteals in the setting of insulin excess, or certain foods and

lity Lead Site/Sponsor

ET ofatic origin

Memorial Sloan-Kettering CancerCenter

f age whoed with

National Cancer Institute

NETs Arcispedale S. Maria Nuova

r 123I-MIBGe for ther status of

mors

Vancouver Coastal Health

morshich ared or showuptake

Tel-Aviv Sourasky MedicalCenter, Israel

Hadassah University Hospital,Isreal

Eligibi

iated Npancre

years oiagnos

creatic

tion foevaluattent, orine tused tuET), w

DG aviensity

).

tress in the setting of serotonin excess).122 In the case of


gledigpc

itNrfi

18 E.K. Bergsland

carcinoid syndrome specifically, use of a multidisciplinaryteam (eg, anesthesiologist, medical oncologist, surgeon,and/or cardiologist) to map out a plan for perioperativesupportive care (eg, supplemental octreotide, colloid)can be instrumental in minimizing the risk of carcinoidcrisis during an elective surgical procedure.123�125

Future advances in supportive care for NETs arelikely to stem from the identification of novel therapiesand/or our ability to successfully debulk tumors. Forexample, in addition to general anti-tumor efficacy inpancreatic NETs, everolimus has been associated withimprovement in symptoms related to insulin excess.126

The precise value of targeted agents, PRRT, and spe-cific chemotherapy regimens with respect to symptomcontrol remains somewhat ill-defined, but is an area ofintense interest. Selected symptomatic patients benefitfrom surgical debulking procedures for hepatic tumors,resulting in reduced pain and/or hormone-relatedsymptoms.127 As such, it is possible that advances in thearea of liver directed therapies (eg, selective internalradiation therapy) will translate into improved pallia-tion of symptoms, but randomized trials are needed.Surgical intervention for chronic obstruction and/ormesenteric ischemia associated with primary smallbowel neuroendocrine tumors can also lead to amarked improvement in quality of life, thus should bea consideration in patients with otherwise indolentdisease.128

In terms of agents specifically designed for symptompalliation, a novel SSTa and a tryptophan hydroxylaseinhibitor are under study. Pasireotide is one example of aSSTa with a broader spectrum of binding activity thanoctreotide that is currently being investigating in the set-ting of octreotide-refractory disease.55,129 Studies are on-oing to assess if the changes in binding specificity trans-ate into improved symptom control and a favorable sideffect profile. Telotristat etiprate (LX-166) is a novel agentesigned to inhibit tryptophan hydroxylase, a key enzyme

nvolved in serotonin biosynthesis. Preliminary data sug-est that the orally bioavailable drug may have activity inatients with octreotide-refractory diarrhea related to car-inoid syndrome.130 A phase III trial is planned (Table 3).

As additional agents with antitumor efficacy aredentified, one important issue will be to minimizereatment related toxicity. For most well-differentiatedETs, treatment has proven to be cytostatic at best,

equiring chronic therapy for relatively modest bene-ts.54,66,70,131 Thus, in a disease with survival measured

in years, choice of agent, timing of initiation of therapy,and supportive measures to minimize treatment-relatedtoxicity are important considerations.

SUMMARY

The last several years have witnessed remarkableadvances in the area of NET. Novel imaging modalities
have been developed, new drug targets have been
identified for cancer treatment as well as symptomcontrol, and there has been a major effort to under-stand the genetic changes underlying the developmentof both sporadic and familial tumors. Importantly, dif-ferent subtypes of NET are now widely recognized,prompting major modifications to existing classifica-tion schemes and revolutionizing our approach to clin-ical trial design. A number of novel treatment strategiesare under study (largely in carcinoid and pancreaticNETs), with two new agents approved for use in pro-gressive pancreatic NETs (everolimus and sunitinib), aswell as MTC (cabozantanib and vandetanib) in the last2 years.

Despite remarkable progress in understanding thegenetic alterations underlying paraganglioma and pheo-chromocytoma, little progress has been made in termsof systemic therapy. Similarly, progress in the treat-ment of high-grade NETs and ACCs is sorely lacking.Ongoing research aimed at understanding the molecu-lar events underlying disease progression will hopefullylead to improved outcomes in these patients.

AcknowledgementThe author gratefully acknowledges editorial supportfrom Pamela Gonzales.

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The Evolving Landscape of Neuroendocrine Tumors