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Systemic Therapeutic Options for Carcinoid

Marianne Pavel,a Mark Kidd,b and Irvin Modlinb

“Carcinoids” are mostly slow-growing neuroendocrine neoplasms (NENs) with low proliferativeactivity. A wide range of therapeutic options with variable efficacy exist, including locoregionalablative strategies. Thereafter, some patients may not require medical therapy for years dependingon the rate of progression or recurrence. However, the majority of patients require systemictreatment and therein lies the dilemma, since no antiproliferative agent is currently approved forcarcinoids. Somatostatin analogs (SSAs), and to a lesser extent interferon-alpha, are standardtherapy for carcinoids associated with the carcinoid syndrome. These drugs have some antiprolif-erative efficacy. SSAs rarely lead to tumor remission but may modestly prolong time to tumorprogression. Chemotherapy is of limited value in carcinoids with low proliferation indices but maybe useful in higher grade tumors. Peptide receptor-targeted radionuclide therapy may be of benefitand is mostly used after medical therapies fail. However, it is considered an investigational modality.More recently, targeted drugs such as mammalian target of rapamycin (mTOR) inhibitors andanti-angiogenics have been investigated. Objective remissions are rare. Their value remains to berigorously elucidated. Increased efficacy requires a better understanding of the underlying tumorbiology and identification of molecular pathological criteria to allow appropriate preselection ofcandidates for targeted therapies.Semin Oncol 40:84-99 © 2013 Elsevier Inc. All rights reserved.

The term carcinoid (Karzinoide) was initially in-troduced in 1907 by the German pathologistOberndorfer who described a series of diminu-

tive cancers in the intestinal tract that he identified asbenign tumors.1 Over the succeeding half century, con-fusion regarding the cell of origin of these tumors waselucidated by Feyrter’s delineation of the diffuse neu-roendocrine system and Ciaccio’s description of theenterochromaffin cells.2 The identification of the pa-thology of the tumors and their neuroendocrine phe-notype was provided by Masson.3 The term “carcinoid”was subsequently applied by the pathologists Williamsand Sandler in 1963 in referring to different tumorsdepending on their location (foregut, midgut, and hind-gut) in the embryonic gut. They proposed that theselocations characterized three distinct groups of tu-mors.4 The term “carcinoid” was initially introducedwithin the World Health Organization (WHO) classifi-

cation for gastro-entero-pancreatic (GEP) neuroendo-crine tumors (NETs) in 1980. Thereafter, in 2000, thisclassification was modified and replaced by a patholog-ical categorization recognizing three distinct histologi-cal groups of tumors (well-differentiated NET, well-differentiated neuroendocrine carcinoma [NEC], andpoorly differentiated NEC) and defined by the organ-specific origin of the tumor. In the most recent WHOclassification (2010), the term “neuroendocrine neo-plasm” (NEN) has been used and the pathological grad-ing has become one of the essential components. Basedon immunostaining of Ki-67 or mitotic count, threegroups of NENs are currently defined by the WHO/European Neuroendocrine Tumor Society (ENETS)—NET G1: �2%, NET G2: 3–20; NEC G3 �20% Ki-67(Table 1).5 In this classification, the term “carcinoid” ispreserved for NET G1. Unfortunately, the terms “carci-noid” and “low-grade NET,” or “well- and moderatelydifferentiated NETs” are frequently used synony-mously. It is rare that “carcinoids” arise in the pancreas.For NENs of pulmonary or thymic origin, a differentclassification is used that defines three distinct sub-groups: typical carcinoid, atypical carcinoid, and largecell and small cell NEC (Table 1). In contrast to theclassification for GEP-NETs, mitosis and necrosis areimportant for differentiating these groups.6 The classi-fication systems, as currently defined, are useful forclinical and pathological purposes. However, it is be-coming apparent that they are simplistic in that they

aCharité University Medicine, Berlin, Germany.bYale University, School of Medicine, New Haven, CT.Conflicts of interest: M. Pavel is a consultant for Novartis, Ipsen, and

Pfizer, and received speaker honoraria from Novartis, Pfizer, andIpsen. The other authors have no disclosures.

Address correspondence to Marianne Pavel, MD, Charité UniversityMedicine Berlin, Campus Virchow Klinikum, Augustenburger Platz 1,13353 Berlin, Germany. E-mail: [email protected]

0270-9295/ - see front matter© 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1053/j.seminoncol.2012.11.003

Seminars in Oncology, Vol 40, No 1, February 2013, pp 84-9984


fail to incorporate molecular pathological criteria thatwill be necessary to specifically identify the precisecharacteristics of widely divergent individual tumors. Ittherefore has become evident that the complex andheterogeneous group of lesions are not adequatelyserved by being grouped under the archaic term “car-cinoid.” Here, the term “NENs” is used when discuss-ing the tumors as a group, but NETs/“carcinoids” isused as needed to be consistent with the terminologyin the cited publication.7 Similarly, the embryologicalnomenclature is used when this is included in thereferenced publication. Use of both “carcinoid” and,for example, foregut tumor, should not be interpretedas acceptance of these archaic terms but rather as apragmatic decision to facilitate discussion using thehistomorphologic classifications.

Overall, “carcinoids” (NENs–NET G1; poorly differ-entiated variants of NEN are, per definition, excludedfrom this grouping) exhibit a generally indolent clinicalpattern of behavior. Unfortunately, systemic treatmentshave been explored in heterogeneous groups of pa-tients (including both “carcinoids” of a variety of sites,as well as islet cell tumors/pancreatic NENs), although,more recently, a belated recognition of the differencesin tumor biology between primary tumor sites (differ-ent cells of origin) has led to clinical trials in distinctsubtypes of NEN, such as pancreatic or small intestinalNENs. While gastric, rectal, and lung NENs most fre-quently exhibit benign behavior, small intestinal le-sions are more frequently malignant upon diagnosis(Table 2). As a consequence, data referable to systemictherapies are mostly related to small intestinal NENs.These lesions have been reported as metastatic in ap-proximately 50% of patients at diagnosis.8,9 This con-trasts strikingly with an analysis of 780 cases withbronchopulmonary carcinoids, where 2% of the pa-tients with typical carcinoids and 21% of the patients

with atypical carcinoids present with stage IV disease,respectively.10,11 Thus, data on therapeutic outcome ofdifferent systemic therapies are very limited for NENsof either lung, thymic, gastric, or rectal origin, andmost data are based only on small case series. Given thelack of adequately powered studies and the heteroge-neity of the data, the various therapeutic options arepresented and discussed for the mixed group of “car-cinoids.”

In order to provide a representative overview of thecurrent therapeutic status (despite the limitations), thePubMed database (January 1, 1980–August 6, 2012)was searched using “carcinoid” in combination withterms including ‘systemic therapy’ (n � 246), ‘oc-treotide’ (n � 861), ‘lanreotide’ (n � 90), ‘chemother-apy’ (n � 1624), ‘interferon’ (n � 284), ‘peptide re-ceptor radionuclide therapy’ (n � 81), ‘everolimus’(n � 24), ‘sunitinib’ (n � 17), ‘targeted therapy’ (n �93), ‘angiogenesis inhibitors’ (n � 33), and ‘bevaci-zumab’ (n � 13). We included in our analysis all pro-spective trials, and retrospective studies only if large insize. Case reports were excluded, as were studies onpoorly differentiated NENs or studies that focused oncontrol of pancreatic NEN exclusively, since these arecovered in other articles in this issue of Seminars. Toprovide a contemporary overview, American Society ofClinical Oncology (ASCO) abstracts detailing results ofclinical trials within the last 5 years are included (n �8). A total of 606 manuscripts were identified by thissearch; 58 (9.6%) were included in the final review.

TREATMENT OPTIONS—AN OVERVIEW

Systemic therapeutic options for “carcinoids”/NETG1 (the term carcinoid is also applied for NET G2)comprise a group of agents that have become referredto as targeted agents.12 Inherent in this descriptive

Table 1. The Different Classification Systems (1980–2010) for Gastro-entero-pancreatic NENs and theClassification System (2004) for Bronchopulmonary and Thymic NENs

WHO 1980

Classification of Gastro-entero-pancreatic NENsClassification of

Bronchial/Thymic NENs

WHO 2000 WHO 2010/ENETS AJCC Classification WHO 2004

Carcinoid Well-differentiatedendocrine tumor

Neuroendocrine tumor G1(Ki-67 �2%),(carcinoid)

Well differentiated- Low grade (carcinoid/islet

cell tumors)

Typical carcinoid �2mitosis/10 HPF, nonecrosis

Well differentiatedendocrine carcinoma

Neuroendocrine tumor G2(Ki-67 3%–20%)

Moderately differentiated- Intermediate grade

(carcinoid/Islet celltumors)

Atypical carcinoid 2–10mitosis/10 HPF,necrosis

Poorly differentiatedendocrine carcinoma/small cell carcinoma

Neuroendocrine carcinomaG3 (Ki-67 �20%)

- Large cell- Small cell

Poorly differentiated- High grade

Neuroendocrine carcinoma�10 mitosis/10 HPF,vast necrosis

- Large cell- Small cell

Abbreviations: WHO, World Health Organization; ENETS, European Neuroendocrine Tumor Society; AJCC, American Joint Committee on Cancer.

Systemic therapeutic options for carcinoid 85


eponym, is the assumption that all NENs possess thespecific target of interest and that the tumor of anindividual patient expresses the target in a therapeuti-cally susceptible fashion. Currently, apart from the pre-therapeutic delineation of somatostatin receptors,there are little data to validate the presence of a puta-tive drug “target” (receptor or signaling pathway) in alesion. This limitation is likely reflected in the overalldisappointing objective response rates to targeteddrugs including SSAs in NENs (“carcinoids”).

Most “carcinoid”/NET G1 (G2) therapy is termed as“targeted” and includes somatostatin analogs (SSAs),interferon-alpha, newer molecular targeted (signalpathway) therapies (eg, everolimus, vascular endothe-lial growth factor receptor [VEGFR] inhibitors) andpeptide receptor radionuclide therapy (PRRT). The useof systemic chemotherapy is restricted to the moreadvanced and aggressive lesions (including NECs) (Fig-ure 1). A wide variety of commutations and permuta-tions of therapeutic strategies, especially related to theuse of SSAs in hormone-secreting NENs (eg, small in-testinal “carcinoids”), render it difficult to provide aprecise determination of the antiproliferative effective-ness of a specific agent. In many instances, the exactefficacy of a therapy cannot be assessed since it may beadministered in sequence with other modalities. These

include locoregional approaches (embolization, che-moembolization) and/or cytoreductive surgery.

In the past, the endpoint in clinical trials was objec-tive tumor remission. Currently, progression-free sur-vival (PFS) or time to tumor progression (TTP) areoften used as surrogate endpoints. None of the cur-rently available drugs provides a cure, but stabilizationof the disease associated with prolongation of PFS maybe considered a therapeutic benefit since this maytranslate into an increase in overall survival. It hasbecome accepted that any survival benefit related toone drug exclusively is unlikely given the generallyfavorable outcomes in many patients (�80% survival at5 years is not atypical for, eg, midgut NENs).8,9,13

Parameters that impact therapeutic decision makinginclude the functionality (hormone-secreting status ofthe lesion), tumor histology and grading, the site of theprimary tumor, expression of somatostatin receptorsbased on the results of somatostatin receptor imaging,and the tumor burden, as well as the presence ofextrahepatic disease.14–19 The therapeutic options dis-cussed here focus principally on the issue of inhibitionof cell proliferation (tumor control) as opposed toinhibition of bioactive product secretion (symptomcontrol).

Table 2. Biological and Clinicopathological Features of NENs (“Carcinoids”) by Organ Site

Origin Cell Type

TumorTypes

(WHO)

Incidence(age-

adjusted)*Prevalence(all NENs)† Secretory Products

Association WithHereditarySyndromes

Metastatic(%)*

5-YearSurvival(SEER)‡

Small intestine EC NET G1NET G2

0.67 19 Serotonin (Familial?) 30–50 80

Thymus EC TCAC

0.02 1 ACTHNF

(MEN-1) 31 24

Colon ECL

NET G1NET G2

0.2 12 Serotonin/NF — 30 45

Stomach ECLECG (Antrum)

NET G1NET G2

0.3 7 Histamine/SerotoninGastrin

MEN-I 9–15 30

Duodenum ECD, G, L

NET G1NET G2

0.19 2 SerotoninGastrin/NF

MEN-I 9 54

Lung EC TCAC

1.35 29 SerotoninHistamine5-OH-Tryptophan

MEN-I 5#

21#

19

Rectum ECL

NET G1NET G2

0.86 20 NF — 0–5% 24

Pancreatic§ ECA,B,D,G, PP

NET G1NET G2

0.32 7 SerotoninCalcitonin

MEN-IVHL

64 35

NOTE. The organ sites are tabulated in accordance with metastatic rate except for pancreas, which is included as a comparator.Abbreviations: SEER, Surveillance, Epidemiology and End Results; AC, atypical “carcinoid”; EC, enterochromaffin cell; ECL, enterochromaffin-like cell; G,

gastrin cell; L, enteroglucagon cell; MEN-I, multiple endocrine neoplasia type I; NET, neuroendocrine tumor; NF, nonfunctioning tumor; TC, typical“carcinoid”; VHL, von Hippel Lindau syndrome; ZES, Zollinger Ellison syndrome.

*Age-adjusted incidence � SEER 17 (1988–2004).8†Prevalence of all NENs � SEER 17 (1973–2007).9‡Five-year survival data, Modlin et al (unpublished data). Survival data relates to metastatic disease only and refers to “cause-specific”

rather than “observed” survival.8 The latter overestimates the mortality associated with the disease since it includes any cause of death.Cause-specific survival was obtained from the SEER 17 database and reflects “actual” survival from the diagnosed cancer which is morecommensurate with clinical practice.

§Pancreas includes all tumors not only those currently termed “carcinoids” and is included as a comparison for other NENs. Forpancreas-specific details see Kulke et al in this issue.

86 M. Pavel, M. Kidd, and I. Modlin


THERAPEUTIC AGENTS

Somatostatin Analogs

NENs express a high density of somatostatin recep-tors (especially subtype 2) and, as a consequence, ini-tial therapeutic strategies focused on the developmentof agents that targeted these receptors. SSAs haveproven effective in the three decades since their intro-duction.20 Two synthetic analogs of native somatosta-tin-14, octreotide and lanreotide, are approved stan-dard therapies for control of symptoms of the carcinoidsyndrome, such as flushing and diarrhea.21–23 SSAs bindwith high affinity to somatostatin receptor subtypes 2and 5, which are expressed in high density on mostGEP-NENs.24,25 SSAs inhibit secretion of biogenicamines and other mediators, thus leading to completeor partial relief of flushing and/or diarrhea associatedwith the carcinoid syndrome in 40%–90% of the pa-tients.21,26–28 Octreotide is available as subcutaneous(SC) and long-acting intramuscular (IM) formulations(at 10-, 20-, and 30-mg dosages; Novartis), and lan-reotide as a long-acting IM formulation (60-, 90-, and120-mg Autogel; Ipsen). The dosages are selected andadapted depending on the severity of the syndromeand the extent of disease. Patients on long-acting SSAsmay require additional SC injections of octreotide forbreakthrough symptoms. Dose escalation with eitherSC or IM SSAs may provide further improvement ofsyndrome control.29–31 Lanreotide is currently not ap-proved in the United States for the treatment of carci-noid disease.

Based on the data from prospective and retrospec-tive studies and from a single prospective, placebo-controlled trial (Placebo controlled, double-blind, pro-spective, Randomized study on the effect of OctreotideLAR in the control of tumor growth in patients with

metastatic neuroendocrine MIDgut tumors, PROMID)of 85 patients, octreotide LAR is considered a therapeu-tic option for tumor growth control. The mechanismsunderlying the antiproliferative action of SSAs remainpoorly understood and include direct and indirect ef-fects, such as G1 cell cycle arrest and induction ofapoptosis, as well as the inhibition of the release ofgrowth factors (eg, insulin-like growth factor-1 [IGF-1],epidermal growth factor [EGF], insulin, gastrin) fromtumor cells and the extracellular tumor surroundingmatrix.32,33 The PROMID study demonstrated a prolon-gation of median TTP in metastatic, non-resectablemidgut NENs. The median TTPs were 14.3 and 6.0months in patients treated with octreotide LAR 30 mgand placebo, respectively. Patients with functionallyactive and inactive tumors were noted to have a similarbenefit.34 Consistent with these results are data fromthe placebo arm of a large trial investigating the effi-cacy of octreotide � everolimus in NENs35; the medianPFS for octreotide in the placebo arm of therapy-naïvepatients was 13.6 months (Table 3). Several trials, in-cluding the PROMID study, have indicated low objec-tive response rates (0%–8%), with disease stabilizationoccurring in 50%–67% of patients.26,34,36 However, itshould be noted that the rigorous delineation of diseasestabilization is a difficult and complex situation giventhe current limitations in sensitivity of the assessmenttechniques available.

While octreotide LAR 30 mg was used in thePROMID trial, and the antiproliferative activity of lan-reotide AG 120 mg is currently under clinical investiga-tion (an ongoing trial of lanreotide v placebo [Controlledstudy of Lanreotide Antiproliferative Response in NET orCLARINET] addresses the value of lanreotide in intesti-nal and pancreatic NETs), the optimal antiproliferative

Figure 1. Evolution of therapy for NENs (“carcinoids”). Overview of the development of therapeutic agents, providing ageneral sense of NEN treatment as it pertains to “carcinoid” disease per se. Approved drugs are shown in yellow boxes (colorfigure may be viewed online). Dates in parenthesis indicate publication year.



dose for octreotide and lanreotide still requires rigor-ous delineation. There are also no data to determine theappropriate time point for initiation of SSAs. This re-flects a number of issues, including the inability todefine for a specific tumor the natural tumor biology,the overall indolent tumor growth pattern, and thepossibility of spontaneous tumor growth arrest. Sincethere are no data on improvement of overall survivalassociated with the early use of SSAs, it remains anunanswerable question as to when treatment should beinitiated. While the PROMID study was performed intherapy-naïve patients to prevent tumor progression,observation with imaging and tumor markers may bean alternative approach to SSAs, especially in asymp-tomatic patients with low tumor burden. While themajority of tumors may express the target (demon-strated, eg, by somatostatin receptor scintigraphy), thismay not necessarily correlate with objective responsesor duration of disease control. Biomarkers to preselectpatients that may benefit from therapy are currentlyunavailable. Positive somatostatin receptor imagingwas not required for inclusion in the PROMID study.

Octreotide is only approved by the US Food andDrug Administration (FDA) for symptom control. Theoriginal application was not designed to assess the drugas an antiproliferative agent and to date octreotide hasnot been approved as an antiproliferative agent in NETtherapy by the FDA. Despite this, a number of neuroen-docrine tumor societies have supported the use ofoctreotide as an antiproliferative agent and this recom-mendation is included in a variety of national guidelines(National Comprehensive Cancer Network [NCCN],North American Neuroendocrine Tumor Society [NA-

NETS], and ENETS). The NCCN guidelines specificallyrecommend octreotide in patients with “clinically sig-nificant” tumor burden without prior observation.37

The basis for the inconsistency between the FDA andthe recommendations of the various societies is unclearbut may reflect recognition of the lack of other ap-proved therapies.

Relevant clinical data on the efficacy of SSA arelacking for specific subtypes of NENs, such as lung,thymic or rectal “carcinoids.” The ENETS guidelinesindicate that SSAs may be considered a therapeuticoption not only in midgut but also in NENs of othersites if slowly progressive or categorized as G1 NETs.16

Several studies support efficacy of SSA in gastric type Iand II NENs associated with chronic atrophic gastritis.SSAs may lead to complete remission of these le-sions.33,38–40; these, however, recur after withdrawal oftherapy.41 Since these tumors are very rarely metastatic(�5%), it remains unclear if SSAs improve long-termoutcome, but use may facilitate follow-up investiga-tions and be helpful in complex cases with high num-bers of lesions. Overall, however, the use of an expen-sive agent with some adverse effects that requiresmonthly lifelong injection for a benign, usually asymp-tomatic disease, such as type I gastric “carcinoid”seems to offer little, clinical advantage and cannot berecommended based on the available data.

Peptide Receptor Radionuclide Therapy

This form of therapy (PRRT) embodies the combi-nation of two agents: a target directed SSA linked to anisotope capable of providing cytotoxic radiation emis-

Table 3. Efficacy Details of Targeted Therapies in Prospective NENs (“Carcinoids”) Trials

AgentNo. of

Patients Design Type of NEN PR (%) SD (%) PD (%) Median PFS Reference

Octreotide LAR 30 mg vplacebo

42 PCT Midgut 2 67 23.8 14.3† *Rinke et al, 200934

43 2.3 37 53 6Octreotide LAR 30 mg

(therapy-naïve)43 PCT NENs with CS 2 81 12 13.6 Pavel et al, 201135

90Y-edotreotide 90 MCT NENs with CS 4 70 26 16.3 Bushnell et al, 201043

90Y-DOTATOC 265 Phase II Midgut NENs 26.8** ND ND ND Imhof et al, 201144

IFN v STZ/5-FU# 64 MCT NENs‡ 9 63 9 14.1 Dahan et al, 201059

Phase III 3 56 31 5.5Sunitinib (� SSA in 54%) 41 Phase II NENs 2.4 83 14.6 10 Kulke et al, 200875

Everolimus � octreotide 30 Phase II NENs 17 80 3 15.7 Yao et al, 200862

Everolimus � octreotide 216 PCT NENs with CS§ 2 84 14 16.4 Pavel et al, 201135

Placebo � octreotide 213 2 81 12 11.3

Abbreviations: CS, carcinoid syndrome; MCT, multicenter trial; NEN, neuroendocrine neoplasms; PCT, placebo-controlled trial; PD, progressive disease; PR,partial response; SD, stable disease (all objective responses as assessed by radiological imaging).

*Objective response at 6 months as assessed by WHO criteria.†TTP not PFS.‡Pancreatic NENs included.§Midgut 51%; lung 15%, colon 7%, pancreas 5%, liver 3% and others.#Although 5-FU/STZ is not considered a targeted therapy, for comparative purposes and completeness, this has been included.**Any morphological response. PRRT data cited do not provide adequate information for rigorous analysis or direct comparison but are

presented as a general comparator for the therapy. Only data from the midgut group are presented.



sions. Using this principle, a number of radiolabeledSSAs have been investigated in a limited number ofprospective and retrospective studies. Most studies in-clude heterogeneous patient populations comprisingdifferent primary tumor sites and functionality andhave been undertaken using either 90Y-DOTA-Phe1-Tyr3-Octreotide (90Y-DOTATOC) or 177Lu-DOTA-Tyr3-octreotate (177Lu-DOTATATE). Objective responserates range between 0%–34%.42–44 Some studies reporthigh rates of disease stabilization but did not requiredisease progression prior to PRRT therapy. Some alsoincluded patients with stable disease.42 Different de-signs and criteria of response assessment have thusbeen applied and individual studies are often not com-parable.

In a large phase II study with 90Y-DOTATOC (3.7GBq/m2; median, 2 cycles) including among others,small intestinal NENs (n � 265), bronchial “carcinoids”(n � 84) and unknown primaries (n � 67), a “morpho-logical” response, defined as any measurable decreasein the sum of the longest diameters of all pre-therapeu-tically detected tumor lesions, was reported in 26.8%,28.6%, and 34% of the groups, respectively. The overallresponse rate in this trial (�1,100 patients) was 34%.44

In a prospective, open-label, multicenter trial, in 90patients with NENs associated with the carcinoid syn-drome refractory to octreotide who received treatmentwith three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide,partial tumor remissions were much lower (4%), butdisease stabilization was achieved in 74%. Median PFSwas favorable given the 16.3 month time frame (Table3). This study provides more reliable data on tumorresponse with PRRT due to its inclusion requirements.These included at least one measurable tumor lesionthat demonstrated disease progression prior to enroll-ment and used an assessment of response according tothe criteria proposed by the Southwest OncologyGroup (SWOG). The radiopeptide also exhibited someefficacy in syndrome control, which was the primaryendpoint of the trial. The median duration of improve-ment of diarrhea and hot flushes was rather short (13.8and 9.7 weeks, respectively) but lasted for up to 21weeks in some patients.43

PRRT is, in general, well tolerated. However, somesignificant adverse outcomes have been described.Based on the analysis of more than 1,000 patientstreated with 90Y-DOTATOC, a permanent renal toxicityof grade 4–5 was observed in 9.2%, and 12.8% devel-oped grade 3 to 4 transient hematologic toxicities.44

Two patients had severe bone marrow disease includ-ing myelodysplastic syndrome after two cycles andacute myeloid leukemia after four cycles.44 The latteradverse event also has been described in other studiesin individual patients.45 In contrast, the study with90Y-edotreotide reported a lower rate of kidney toxicity(3%) that was also reversible. Careful consideration of

medical history (arterial hypertension, diabetes melli-tus) is important for selection of patients for PRRT.46

According to ENETS guidelines, PRRT is a recom-mended treatment after failure of medical therapies.However, both NCCN and ENETS consider PRRT asinvestigational, and stress the need for further random-ized trials to evaluate the benefit and potential toxici-ties. An international study comparing treatment with177Lu-DOTA0-Tyr3-octreotate to high-dose octreotidelong-acting release (LAR) (60 mg/mo) in patients withinoperable, progressive, somatostatin receptor-positivemidgut NENs is currently underway (www.clinical.trials.gov).

Interferon-Alpha

Interferon receptors are expressed in NENs andtherefore provide a putative target for therapeutic in-tervention.47 Interferons bind to a common receptor atthe surface of tumor cells and, via induction of theJAK-STAT pathway, initiate transcription of interferon-inducible genes.48 Inhibition of secretion and prolifer-ation is mediated via direct and indirect effects. Inter-feron-alpha (IFN) is standard treatment for syndromecontrol of the carcinoid syndrome albeit frequentlyused as second-line therapy if SSAs are either not toler-ated or patients are refractory to SSAs over time. Symp-tom control is achieved in 40%–70% of the pa-tients.21,49,50 The recommended dose of IFN is 3–5 �106 U SC thrice weekly. The use of IFN is limited by itsside effects such as influenza-like symptoms, fatigue,and weight loss, among others. Alternatively, for bettertolerability, pegylated IFN (80–150 �g/week SC) maybe considered, although data in patients with NENs arelimited51,52 and pegylated IFN is not yet approved forthis indication.

As with SSAs, the use of IFN is associated withdisease stabilization in 50%–60% of patients, while sig-nificant tumor shrinkage only occurs in approximately10%–15%.21,49,53 These results stem from limited studiesrepresenting heterogeneous primary tumor sites andfunctionality, and different endpoints (either biochem-ical and/or radiological). There is no evidence fromtwo prospective, randomized controlled trials that thecombination therapy of a SSA and IFN increases tumorresponse or TTP when used as first-line treatment inprogressive NENs, although both studies were under-powered.54,55 The study by Faiss et al was a three-armstudy that assessed the antiproliferative efficacy of IFN-�2b (5 � 106 U, three times per week SC) in compar-ison to lanreotide (1 mg, three times per day SC) and tothe combination of both lanreotide and IFN-�2b asfirst-line therapy in 80 patients with progressive GEP-NENs. The study included foregut (n � 36), midgut(n � 30), hindgut (n � 3), and unknown (n � 11)tumors. Both drugs were equally effective with respectto objective response (3.7% v 4% partial remission rate



and 26% and 28% stable disease rate at 12 months),while the combination was not superior to mono-therapy, and was associated with more side effects.54

Patients with midgut NENs had significantly longer TTPcompared with foregut lesions. However, this may re-flect the natural tumor biology of midgut NETs ratherthan drug efficacy per se. The trial by Arnold et al wasa two-arm prospective trial in 105 patients with GEP-NENs including 43% midgut tumors. The study wasconstructed to assess the antiproliferative efficacy ofoctreotide (3 � 200 �g/d) � interferon-�2a (4.5 � 106

U thrice weekly) versus octreotide alone. It failed todemonstrate a significantly different outcome (objec-tive response and TTP) between combination andmonotherapy. Treatment failures occurred in 50% ofpatients within 6 months in each treatment arm.55 Incontrast, in a randomized trial in 68 patients withmetastatic midgut NENs, the risk of progression wasreduced by addition of IFN to octreotide compared tooctreotide alone, but this was not associated with asurvival benefit.56 Although the use of early combina-tion therapy of SSA and IFN is not supported by thesetrials, it has been proposed that in selected patients theaddition of IFN to SSA may be useful for more effectivesymptom control (flushing and/or diarrhea), or im-proved tumor growth control.56–58

A French multicenter trial in 64 patients with ad-vanced NENs of different sites addressed the questionof the antiproliferative efficacy of IFN-�2a (3 � 106 Uthree times per week SC) in comparison to streptozo-tocin/5-fluorouracil (5-FU) chemotherapy. Median PFSwas the primary endpoint; PFS was longer with IFN-�2a but not significantly different from STZ/5-FU (14.1months v 5.5 months). In the chemotherapy arm, onepatient (3%) with a small intestinal primary tumor hada partial response, while three patients (9%), two withsmall intestinal and one with an unknown primary,exhibited a partial tumor response with IFN. The ratesof stable disease were not different (chemotherapy 56%and IFN 63%, respectively) (Table 3).59 A limitation ofthis study is that it included a variety of primary tumorsites including pancreatic NENs. Hematologic toxicitieswere more frequent with IFN, whereas nausea andrenal toxicity were more frequent in the chemotherapyarm, but these were mostly mild (grade 1–2 protein-uria).59 Data for IFN from other disease sites are rare. Asmall study in patients with typical bronchial “carci-noids” demonstrates that IFN � octreotide treatmentresulted in stable disease in a low number of patients(15%; 4/27 patients) and this lasted for a median of 15months.60

NCCN and ENETS guidelines advise that IFN can beconsidered as a treatment option in metastatic progres-sive NENs, although the data for this recommendation,as we describe, are less than optimal.

Mammalian Target of Rapamycin Inhibitors

Mammalian target of rapamycin (mTOR) representsa major regulatory component of a number of cellularmetabolic events, including energy usage and prolifer-ation. Theoretically, it therefore provides access to anideal therapeutic node necessary for cell function. Tem-sirolimus and everolimus are two mTOR inhibitors thathave been investigated in advanced NENs. Thirty-sevenpatients with progressive tumors including 21 patientswith midgut NENs were treated with 25 mg/wk intra-venous (IV) temsirolimus. In this group, the partialremission rate was 4.8%, while 57% achieved stabledisease after prior disease progression within 6months. The median TTP was 6 months in these pa-tients.61

In a phase II trial, everolimus was evaluated in com-bination with octreotide in 30 patients. The high dis-ease control rate (partial remissions in 17%, stable dis-ease in 80%) along with a median PFS of 15.7 monthswas promising.62 In a large placebo-controlled phase IIItrial in 429 patients with progressive NENs, patientswere randomized to receive octreotide LAR witheverolimus or placebo. The primary endpoint of thestudy, PFS according to central radiological reading,was 16.4 months in the everolimus arm and 11.3months in the placebo/octreotide-only arm (Table 3).However, the predefined threshold for statistical signif-icance was not reached.35 Multivariate analysis and lo-cal radiological analysis support some efficacy ofeverolimus,63 it remains unclear, however, which pa-tient subgroups (primary tumor site and grading) mighthave a preferential benefit. A subgroup analysis identi-fied some potential primary tumor sites that mightparticularly benefit. Median PFS was with 13.6 monthsin favor of the everolimus arm compared to 5.6 monthsin the placebo/octreotide arm in bronchial/lung NENs(n � 44), while in a subgroup of colonic NENs (n �28), the median PFS was more than double that of theplacebo arm (29.9 v 13 months). Despite these obser-vations, the precise role of everolimus as a therapeuticagent remains to be defined.

Predictive biomarkers are not yet available for pre-selection of patients for mTOR inhibitor treatment.However, expression of mTOR and downstream signal-ing components (including p-4EBP1, p-S6K andp-eIF4E) has been reported in NENs.64,65 Expressionlevels were higher in foregut than in midgut tumors,while mTOR positivity was significantly higher in tu-mors with higher proliferative activity.64 In the tem-sirolimus trial, paired baseline and post-treatment biop-sies were analyzed to address this issue in a smallnumber of samples (n � 13). Interestingly, higher base-line levels of phosphorylated mTOR were predictiveof tumor response, and increases in the expressionof phosphorylated AKT and decreases in phosphor-ylated mTOR after 2 weeks on treatment were asso-



ciated with an increased TTP.61 However, the pre-dictive value of these biomarkers requiresconfirmation in other studies.

While everolimus has been approved for pancreaticNENs, the data for its efficacy in other NENs are re-garded as controversial. Thus, the RADIANT-2 (RAD001in advanced neuroendocrine tumors, second trial)study, which included mostly (51%) small intestinal“carcinoids,” failed to achieve its primary endpoint.More recently a placebo-controlled trial in progressivegastrointestinal and lung “carcinoids” (RADIANT-4) hasbeen initiated to assess the antiproliferative efficacy ofeverolimus as a monotherapy (www.clinical.trials.gov).Nevertheless, the current NCCN guidelines recom-mend the use of everolimus in clinically significantprogressive disease as one of several therapeutic op-tions. The ENETS guidelines recommend everolimus innon-pancreatic NETs after failure of all other medicaltherapies.

Angiogenesis Inhibitors

A feature of NENs is the evidence of angiogenesis andincreased vascularity in comparison to other tumortypes.66 Consideration of this biological variable as a ther-apeutic target has led to the development of agents thatinhibit tumor vessel development.67 Anti-angiogenicdrugs have recently been evaluated in small phase II trialsin NENs, including midgut and pancreatic NENs. Drugstargeting VEGF (the monoclonal antibody bevacizumab),small molecules that inhibit the receptor tyrosine kinasesof VEGFR and/or platelet-derived growth factor receptor(PDGFR; vatalanib, sunitinib) or VEGFR, PDGFR, c-KITand Raf kinases (sorafenib), and other compounds withdifferent anti-angiogenic mechanisms (eg, thalidomide,endostatin) have been investigated. In these studies(which included heterogeneous patient populations), noobjective remissions were achieved with vatalanib, thalid-omide, or endostatin.68–70 Although high rates of diseasestabilization were observed, in the absence of a placeboor observational arm, it remains unclear whether this wasrelated to the natural tumor biology or the study drugs.These drugs are not investigated in current clinical trials.

While there are no studies on monotherapy of bevaci-zumab in NENs, the drug has been evaluated in combina-tion with several other compounds, including octreotide,chemotherapeutic agents (5-FU or capecitabine/oxalipla-tin, temozolomide), 2-methoxyestradiol (a metabolite ofestradiol with antiangiogenic properties including inhibi-tion of hypoxia-inducible factor [HIF]-1�), sorafenib oreverolimus.52,71–74 A phase II trial of octreotide with eitherbevacizumab (15 mg/kg every 3 weeks) or pegylated IFN(0.5 �g/kg/wk) in 44 patients identified a higher responserate in the bevacizumab arm compared to IFN (18% v0%).52 This provides the basis for an ongoing SWOGphase III randomized trial in advanced NENs, comparingbevacizumab � octreotide to IFN � octreotide. In all

other combination therapies with bevacizumab, it re-mains unclear if the addition of the antibody improvesefficacy since the benefit of the investigated single drugsor drug combinations has not been fully elucidated, andheterogeneous patient populations have been studied. Inmost instances, objective remissions have been lackingwith these combinations with a few exceptions.

While sunitinib is an approved therapy in pancreaticNENs, data on sunitinib in midgut or NENs from othersites (carcinoids) are limited to a single phase II trialincluding 40 patients. Fourteen patients had lung or stom-ach (foregut) primary tumors. In this trial, every secondpatient received SSAs along with sunitinib. The objectiveresponse rate was low (2.4%) (Table 3),75 and the medianPFS (10 months) was not longer than might have beenexpected with SSA alone. Neither the size of the study northe outcome supports the use of sunitinib in these tu-mors. Preliminary results of a phase II study withsorafenib identified partial responses in 10% of the pa-tients. The inclusion of those patients with minor re-sponses provided a 17% response rate. However, the drugwas associated with toxicity (skin and gastrointestinalsymptoms, fatigue) in 43% of patients.76 The initial resultsof a Spanish multicenter trial with a combination ofsorafenib and bevacizumab demonstrated a similar re-sponse rate (10%) to that obtained with sorafenib alone.77

The potential benefit of a higher disease control rate withcombination therapies including anti-angiogenic drugsmay, overall, be limited by the potential adverse eventsassociated with these agents. Given the lower toxicity,bevacizumab is currently the preferred drug in clinicaltrials with anti-angiogenics.

CHEMOTHERAPY-BASED PROTOCOLS

Systemic Chemotherapy

While most commonly used in non-neuroendocrinetumors, there has been a recent re-evaluation of chemo-therapy in NENs. Objective response rates range between0%–33% for chemotherapeutic drugs including 5-FU,streptozotocin, and dacarbazine, when used as mono-therapy or in combination.78–82 While cisplatin-based che-motherapy is standard therapy in poorly differentiatedNENs, this treatment is associated with low response ratesin “carcinoids” and is associated with high toxicity.83,84 Atpresent, it is therefore not recommended in well-differen-tiated NENs or “carcinoids.” However, oxaliplatin-basedchemotherapy has been investigated in NENs after thefailure of other medical therapies. The largest trials eval-uated the combination therapy of streptozotocin or doxo-rubicin and 5-FU. The results are included in Table 4.

Streptozotocin-Based Regimens

The efficacy of systemic chemotherapy in well-differ-entiated advanced (G1) NENs is limited. Although widelyused,71,82,85 its precise role is not well-defined. There are



inconsistencies between the various clinical studies withrespect to response rate and response criteria (ie, end-point analysis of biochemical response versus tumor re-sponse). Phase III comparative trials are lacking or verylimited in both gut and lung NENs. The largest studyreported is a comparative trial of 5-FU/doxorubicin versusstreptozotocin/5-FU.81 There were no differences in theobjective response rates (15.9% v 16%) and PFS (4.5 v 5.3months) between the treatment arms. The study reporteda benefit in median survival for the streptozotocin armwith 24.3 months compared to 15.7 months for doxoru-bicin, and may thus be considered in selected patientswhere chemotherapy is considered a therapeutic op-tion.81 A variety of primary tumor sites (25% small intes-tine, followed by other, unknown, lung and rectum) wereincluded. In contrast, in a prospective French multicentertrial with 32 patients with progressive NENs including ahigher percentage of small intestinal primary tumors(63%), the objective response rate was only 3% (onepatient with a small intestinal NEN), while stable diseasewas achieved in 59%. Median PFS was 5.5 months andthus similar to the other trial.59,81 Subgroups were too smallto assess any preferential response in either study. A series ofsmall case studies indicate that objective response in bron-chial “carcinoids” is lacking. In seven patients, the use ofstreptozotocin and 5-FU was associated with progressivedisease in all patients; stable disease was, however, initiallyobserved in two patients treated with streptozotocin anddoxorubicin for 8 and 10 months, respectively.60

In a retrospective analysis including 33 NENs, the ob-jective response rate was 25% with a three-drug regimenof streptozotocin/5-FU and cisplatin.82 Although thisstudy is small and based on heterogeneous primary tumorsites (lung [n � 8], gastrointestinal [n � 9], ovarian [n �1], unknown primary [n � 15]), there was a suggestionthat chemo-sensitivity increased with increasing mitoticcount; response rates of 15% were noted with 0–1 mito-sis/10 high-power fields (HPF), and 29% with 2–4 mito-sis/10 HPF, respectively.82 Other small series support thatresponse to chemotherapy is dependent on the prolifer-ative activity.86 In a prospective trial of 86 patients withGEP-NENs (including 20% foregut, 33% unknown, and48% pancreatic NENs) comparing a three-drug (capecit-abine, streptozotocin, and cisplatin) and two-drug regi-men (capecitabine, streptozotocin), the disease controlrates and PFS did not differ between the regimens.87

There are therefore no data supporting the idea thatthree-drug regimens are superior to two drugs (withoutplatinum). Metronomic chemotherapy may provide anattractive alternative approach. This strategy facilitatesdose reduction, which has the advantage of limiting ad-verse effects but in addition, allowing combinations ofother drugs. The metronomic use of 5-FU in combinationwith octreotide was associated with partial responses in24% and a high rate of disease stabilization (69%). Thisregimen was well tolerated and may warrant further in-vestigation.88

Tab

le4

.Sy

stem

icC

hem

oth

erap

yin

NEN

s(“

Car

cin

oid

s”)

Ag

ent(

s)N

o.

of

Pati

ents

Typ

eo

fN

ENEn

rollm

ent

Cri

teri

aO

bje

ctiv

eR

esp

on

se(%

)D

urat

ion

of

Res

po

nse

(mo

)PF

S/TT

PO

vera

llSu

rviv

al(m

o)

Ref

eren

ce

STZ

�5-

FUv

DO

XO

172

NEN

sPr

ogre

ssio

n22

v21

7.75

v6.

5N

D16 12

Engs

trom

etal

,19

8484

STZ

�5-

FUv

DO

XO

�5-

FU78 85

Mix

edN

ENs

(car

cino

ids)

Mix

ed:

Sym

pto

ms,

bioc

hem

./ra

diol

.16

v(1

5.4%

SD)

15.9

(15.

3%SD

)5.

3v

4.5

ND

24.3

15.7

Sun

etal

,20

0580

STZ

�5-

FU32

Mix

ed,

mos

tm

idgu

tN

ENs

PDra

diol

ogic

alan

d/or

bioc

hem

ical

3(5

6%SD

)N

D5.

5/8.

530

.4D

ahan

etal

,20

0959

STZ

�5-

FU�

cisp

latin

(72%

first

line)

79Pa

ncre

asG

IO

ther

NEN

sPD

radi

ol.

orbi

oche

m.

38/2

5†N

D9.

131

.5Tu

rner

etal

,20

1081

Tem

ozol

omid

e*24

(lung

n�

12)

Lung

NEN

sTh

ymic

NEN

sA

dvan

ced

dise

ase

31(3

1%SD

)0

(71%

SD)

ND

ND

ND

Ekeb

lad

etal

,20

0793

Tem

ozol

omid

e*17

(sm

alli

ntes

tinal

n�

10)

Smal

lint

estin

alO

ther

Prog

ress

ion

0(S

D70

%)

0(S

D10

0%)

ND

ND

ND

Mai

reet

al,

2009

94

Tem

ozol

omid

e�

beva

cizu

mab

19N

ENN

D0

ND

7.3

18.8

Cha

net

al,

2012

71

Tem

ozol

omid

eth

alid

omid

e29

(“ca

rcin

oid”

n�

14)

NEN

ND

7N

DN

DN

DKu

lke

etal

,20

0995

Abb

revi

atio

ns:

DO

XO

,do

xoru

bici

n;ST

Z,

stre

pto

zoto

cin;

5-FU

,5-

fluor

oura

cil;

ND

,no

data

;PD

,p

rogr

essi

vedi

seas

e;SD

,st

able

dise

ase.

* Ret

rosp

ectiv

est

udie

s.†P

ancr

eatic

/GI

and

othe

rN

EN.



Alkylating Agents(Dacarbazine, Temozolomide)

Early reports suggested a high tumor control rate withdacarbazine in metastatic midgut NENs.89 Combinationchemotherapy did not appear to increase the objectiveresponse rates. Only one of nine patients developed apartial response on combination therapy with dacarba-zine and 5-FU.90 In two prospective trials with multidrugtreatment (dacarbazine, 5-FU, and epirubicin), a partialtumor remission was achieved in two of 20 and one ofnine NENs, respectively.91,92 In a separate study, the re-sponse rate with dacarbazine was 8.2% after failure ofstreptozotocin-based chemotherapy.81 Thus, objective re-missions remain a rare event with dacarbazine and rangebetween 8%–11%.

More recently, temozolomide, an oral alkylating agentsharing the same metabolite with dacarbazine, has beenexplored either as mono- or combination therapy. Retro-spective analysis of temozolomide as monotherapy sug-gests efficacy in treating bronchial and pancreaticNENs.93,94 Ekeblad et al noted an objective remission rateof 30% in bronchial “carcinoids” (n � 13) with advanceddisease stages, suggesting this agent may warrant addi-tional study in larger trials. Although objective responsesare lacking in NENs with temozolomide (� bevaci-zumab), a high rate of disease stabilization was noted insmall intestinal, thymic, and NENs of other origin in avariety of small trials and a case series (Table 4).71,94,95

Absence of methyl guanine methyl transferase (MGMT)expression, a DNA repair enzyme involved in induction ofcancer cell resistance to some alkylating agents, eg, temo-zolomide, appears to be an important biological require-ment to achieve tumor remission. MGMT staining hasbeen examined in NENs.96 Expression correlated withtumor responses; only one of 44 patients (2%) experi-enced an objective response; this patient was MGMT-negative.96

Platinum-Based Chemotherapy

While cisplatin and etoposide is standard treatment forpoorly differentiated NEC, it has no efficacy in well dif-ferentiated NENs83 and is associated with significant toxicitysuch as bone marrow suppression and polyneuropathy.More recently, oxaliplatin-based systemic chemotherapy hasbeen explored in NENs either in combination with 5-FU(FOLFOX [folinic acid � 5-fluorouracil � oxaliplatin]) orcapecitabine (XELOX [capecitabine � oxaliplatin]) � bev-acizumab (Table 5). Based on small patient numbers, objec-tive responses have been observed mainly in foregut NENs,including pancreatic (18%–33%), bronchial (up to 60%), andthymic tumors, while only stable disease was noted in smallintestinal NENs.73,97–101 When used as second-line ther-apy after failure of SSA, stabilization of the disease maybe achieved in 60%–100% of NENs, including smallintestinal tumors (Table 5).

Overall, systemic chemotherapies have a very limited

role in the management of NENs. Chemotherapy shouldbe considered in individual patients once there is evi-dence of failure with other therapies, such as locoregionaltherapies, SSAs and IFN or PRRT in the absence of alter-native antiproliferative drugs. Additional, well-con-structed studies evaluating the benefit of these toxic che-motherapeutic regimens therefore should be consideredto clarify which additional subgroups of patients maybenefit. Currently, based on the observed toxicity (poly-neuropathy, ototoxicity, nephrotoxicity, bone marrowsuppression), oxaliplatin-based chemotherapy should bereserved for patients with NENs that display a high pro-liferative activity (Ki-67 �10%–15%) or rapid tumorgrowth over a 3- to 6-month period.

THERAPY OF THE UNKNOWN PRIMARY

In patients with “carcinoids” of unknown primary(CUP), imaging and pathology should be used to seek toidentify the location and origin of the primary tumor sincetreatment strategies differ substantially between foregutand midgut NENs. This reflects the generally accepteddogma that the former are generally more biologicallyaggressive and therefore require more effectual therapy.The immunohistochemical identification of CDX-2 orTTF-1 may indicate the presence of a small intestinal orbronchial/thymic primary tumor, respectively.102 Stainingof Islet-1 may indicate a primary tumor in the pancreas.103

Molecular high resolution imaging, such as 68Ga-DOT-ATOC positron emission tomography (PET)/computedtomography (CT) with tri-phasic CT or the use of othermolecular tracers (eg, 18F-DOPA, 11C-HTP) may be ofadded value in the identification of the primary tumor. Inaddition, these modalities are more effective in addressingthe extent of disease and thus may better inform thera-peutic decision-making.104,105 Alternatively, somatostatinreceptor scintigraphy can be used, preferably as single-photon emission CT (SPECT)/CT, although this provides alower sensitivity study as compared to PET/CT. If noprimary tumor is identified by imaging modalities, orendoscopy/colonoscopy then treatment decisions are pri-marily guided by histological grading. Therapy may sub-sequently be complemented by information on growthvelocity assessed by conventional imaging. Other param-eters that guide therapeutic decision-making include func-tionality of the tumor and somatostatin receptor status.Thus patients with functioning NEN, such as the carci-noid syndrome will typically be treated with SSA and/orIFN. In nonfunctioning NENs, classified as G1 NETs, a“watch and wait” strategy may be adopted. In some cen-ters SSAs may be used if somatostatin receptors have beenidentified by imaging studies. If progression is noted,PPRT may be an option although not historically availablein the United States. In patients with a higher grading(NET G2 or moderately differentiated NENs) a “watch andwait” strategy may be risky, especially if the tumor burdenis high. In such patients, one must have a low threshold



Tab

le5

.Pl

atin

um-B

ased

Ch

emo

ther

apy

inW

ell-

and

Mo

der

atel

yD

iffe

ren

tiat

edN

ENs

(“C

arci

no

ids”

)

Reg

imen

No

.o

fPa

tien

tsPr

og

ress

ive

atSt

udy

Entr

yH

isto

log

y/Pr

imar

yTu

mo

rSi

tes

Ob

ject

ive

Res

po

nse

PR(%

)

Ob

ject

ive

Res

po

nse

SD(%

)PF

S/TT

P(m

o)

Med

ian

Ove

rall

Surv

ival

(mo

)R

efer

ence

Cis

pla

tin15

NI

NI

1/15

(7%

)N

I1.

8N

IM

oert

elet

al,

1986

78

Etop

osid

e�

cisp

latin

13N

IO

vera

ll5

smal

lbow

el2

lung

3ce

cum

/col

on1

rect

um2

CU

P

0/13

(0%

)11

/13

(85%

)3

10.5

Moe

rtel

etal

,19

9182

Irin

otec

an�

cisp

latin

15*

NI

Ove

rall

4Sm

allb

owel

6p

ancr

eas

3co

lon

2re

ctum

1lu

ng2

CU

P

011

/15

(73)

4.5

11.4

Kulk

eet

al,

2006

83

Cap

ecita

bine

�ox

alip

latin

27PD

afte

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rall

5Br

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ial

11EP

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stin

al4

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rs

8/27

(30)

3/5

(60%

)3/

11(2

7%)

0/7

(0%

)N

D

13/2

7(4

8)1/

5(2

0%)

5/11

(45%

)7/

7(1

00%

)N

D

2040

Baje

tta

etal

,20

0796

Gem

cita

bine

�ox

alip

latin

18PD

Ove

rall

5Sm

allB

owel

5Pa

ncre

as4

Lung

2Th

ymus

4O

ther

17 NI

2/5

(40%

)N

I1/

2(5

0%)

NI

12/1

8(6

7)7.

023

.4C

assi

eret

al,

2009

98

FOLF

OX

-4‡

16PD

Ove

rall

2br

onch

ial,

5p

ancr

eas,

2st

omac

h2

cecu

m1

each

ileum

,co

lon,

rect

um2

CU

P

010

/16

(62.

5)4.

5N

DPa

pe

etal

,20

0699

FOLF

OX

-6�

beva

cizu

mab

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treo

tide‡

11PD

Ove

rall

6EP

T5

CT

3/11

(27)

2/6

(33)

1/5

(20)

8/11

(72)

4/6

(67)

4/5

(80)

ND

ND

Veno

oket

al,

2008

100

Cap

ecita

bine

�ox

alip

latin

�be

vaci

zum

ab‡

40†

�PD

Ove

rall

20EP

T15

CU

P5

CT

7/31

(23)

6/19

(32)

1/11

(9)

NI

22/3

1(7

1)13

.7N

DKu

nzet

al,

2010

73

Abb

revi

atio

ns:C

T,ca

rcin

oid

tum

or;C

UP,

carc

inoi

dof

unkn

own

prim

ary;

ND

,no

data

rep

orte

d;N

I,no

tin

dica

ted;

NR,

not

reac

hed;

PD,p

rogr

essi

vedi

seas

e;PR

,par

tialr

emis

sion

;SD

,sta

ble

dise

ase;

SSA

s,so

mat

osta

tinan

alog

s.*1

8p

atie

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into

tal,

only

15ev

alua

ble.

†40

pat

ient

sin

tota

l,on

ly31

eval

uabl

e.‡A

bstr

act

pre

sent

atio

ns(A

SCO

).



for considering locoregional therapies followed by sys-temic treatment (eg, IFN or SSAs � everolimus or PRRT).In patients with significant tumor growth within 3–6months, the use of systemic chemotherapy should beconsidered.

INTEGRATION OF THERAPIES

For all targeted therapies investigated in NENs thus far,tumor remissions are a notably rare event (�10%). Al-though it has been widely reported that there is a highrate of disease stabilization ranging between 67%–84%,the methodologies for assessing this parameter are insen-sitive and limited. PFS has, overall, been reported to rangebetween 13.6 months and 16.4 months for different ther-apies with the caveat that direct comparisons are notapplicable. In the case of sunitinib and streptozotocin-based chemotherapy, the PFS was lower (10 months and5 months, respectively) (Tables 3 and 4). These modestresponses may reflect the tumor biology, which is asso-ciated with slow tumor growth and long survival timesexceeding 60% and reaching up to 90% at 5 years.9,106

Systemic chemotherapy may be an option in se-lected patients who have tumors with a relatively highproliferative rate at diagnosis or in the course of thedisease if the tumor converts to a more malignantphenotype. It is not recommended for early use in themanagement of NENs.

As long as evidence of superiority of a specific treat-ment compared to another is lacking, therapeutic strat-

egy is frequently based on individualized decision-mak-ing. While this may occur in an interdisciplinary settingthat assesses the different components of an individualpatients’ disease, strategy is often determined by treat-ment availability and the philosophy of the clinicians. Amajor consideration is the avoidance of toxicity and theneed to maintain the relatively good quality of lifeevident in patients. Based on the available informationthat has been evaluated in this review, a treatmentalgorithm is proposed for the optimization of the ther-apeutic management of these tumors (Figure 2).

CONCLUSION

There are very limited data suggesting “targeted” ther-apy is effective in NENs. The most relevant predictableagents, however, are the SSAs, although data from onlyone small placebo controlled trial are available to supportan antiproliferative effect.34 When SSAs fail, IFN is consid-ered in some countries despite the substantial adverseevents associated with such therapy. The former (espe-cially octreotide) are recommended as first line therapeu-tic option in midgut NENs based on the PROMID studyand the marginal evidence that SSAs may have efficacy inlow proliferating (�2% Ki-67) tumors.34 It has been sug-gested by inference that a similar strategy should be con-sidered in other NENs, such as rectal or bronchial, al-though no rigorous data exist to support this. While thereis some evidence that SSAs are effective in type I gastric“carcinoids,” it is dubious as to whether treatment with a

Well differentiated NEN (NETG1/G2)

Functioning NEN Carcinoid Syndrome

SSAs IFN

Non-Functioning NEN

Debulking surgery Hepatic artery (chemo)

embolization Local ablative Therapy

SD, but bulky disease; ongoing symptoms and/or progression

Tumor Follow-up q 3-6 mon.

Echocardiography q 12 mon. if abnormal (CHD) q 3-6 mon.

SD

Poorly differentiated NEC

SD Ki67 <2%

SSAs or Watch & Wait

Clinical trial

PD SD, if high tumor load

SSAs or IFN and loco-regional

therapy

PRRT (if octreoscan positive)

or: Everolimus*or: Clinical trial

Cisplatin + Etoposide

chemotherapy

Rapidly progressive and/or Ki67>20%

PD

Consider Chemotherapy

(e.g. metronomic 5-fluorouracil;

capecitabine/oxaliplatin) STZ +/- 5-FU

PD

Clinical Trial with targeted

therapies

PD and/or extrahepatic disease

PD or extrahepatic > hepatic tumor load or not amenable to local therapies

SSAs or IFN; locoregional

therapy if confined to

the liver

Slowly progressive and /or Ki67>2-10%

Clinical Trial: Pasireotide

LX 1606

Ongoing Symptoms, SD or slowly progressive

*if available/approved

SSAs (if SRS+) and

chemotherapy

Ki67>10-20%

PD

PD

Everolimus*(if not used before) or:

Figure 2. Potential therapeutic algorithm in metastatic non-resectable midgut NENs/“carcinoids.”



disease regarded as approximately 98% benign warrantstherapeutic intercession. IFN is mostly used after failure ofSSA monotherapy or in the rare event that SSAs are nottolerated as a first-line intervention. With respect to tumorgrowth control after SSA failure, IFN may represent anoption especially in the case when locoregional therapieshave already been used or are not useful, eg, in dissemi-nated extrahepatic disease.

Despite these observations, it should be specificallynoted that none of the currently available agents providesa cure for neuroendocrine tumor disease. In addition, anyassessment of therapeutic outcome for individual sub-types of NENs with respect to specific therapies is limitednot only by the paucity of patient numbers but also by themarked differences in tumor biology. This is reflected bydifferent survival times for different tumor primary sitesirrespective of the disease stage at diagnosis.8,9 These twoissues as well as the fact that none of the drugs is ap-proved for antiproliferative therapy, notwithstanding thedifficulty in developing and identifying targeted therapies,has led to a focus on the development of trials that acceptthe failure of curative therapy. Current studies thus focuson combination therapies with the aims of improvingresponse rates or prolonging response duration. The maincombination partners include, but are not restricted toSSA, mTOR inhibitors, and angiogenesis inhibitors, a strat-egy that appears to be more market-oriented rather thanscientifically or biologically focused. This observation re-flects the fact that there exists a paucity of rigorouspreclinical data that provide any scientific rationale forthese combination therapies. Although mTOR and VEGF-targeted agents are being explored in clinical trials,35,75

their explicit role in the antiproliferative management ofcarcinoids still requires considerable elucidation. Futureselection of targeted therapies for carcinoids requirescareful consideration especially in respect of recently re-ported significant toxicity and potentially increased mor-tality associated with the use of novel targeted drugs incancer therapy.107 Other studies examining SSAs with abroader receptor agonist profile (pasireotide) and an oralserotonin synthesis inhibitor, LX1606, are under clinicalinvestigation in the expectation of optimizing carcinoidsymptom control.

The key limitation in the utility of currently availableagents remains the inability to preemptively identifytargets in a particular tumor. Current technology isrelatively insensitive and unable to identify subtle re-sponses to therapy. Hence, a vital mandate in improv-ing outcome is the identification of appropriate bio-markers that can be used as parameters of therapeuticefficacy and thereby guide therapy. The need to definecross-talk between the pathways involved in growthpromoting signals and the integration of tumor mi-croenvironment signaling is a critical requirement todeveloping more effective therapeutic agents.

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Author's personal copy - wrenlaboratories.com · Author's personal copy fail to incorporate molecular pathological criteria that will be necessary to speci cally identify the precise

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